Editorials
米国の予算問題解決の遅れは、科学研究に深刻な悪影響を及ぼしている。
Uncertain times p.409
Budgetary delays exacerbate dire outlook for US research.
doi: 10.1038/497409b
科学界は、クローニングによるヒト幹細胞の作成成功に浮かれることなく、倫理的問題を率先して議論していく必要がある。
Double vision p.409
Scientists must ensure that they take the lead in the ethical debate surrounding the therapeutic use of stem cells derived from human clones.
doi: 10.1038/497409a
健康問題に関して、人々にわかりやすく訴えるために科学的知見を単純化し過ぎるのは危険だ。
Shades of grey p.410
It is risky to oversimplify science for the sake of a clear public-health message.
doi: 10.1038/497410a
News
NASAの太陽系外惑星探査機ケプラーが、方向制御装置の不調で、このままでは運用を断念することに。
The wheels come off Kepler p.417
Space telescope’s mission to find planets outside the Solar System is probably over.
doi: 10.1038/497417a
米環境保護局（EPA）長官の議会での承認が難航し、2か月以上もトップ不在の状態に。
Log-jam in agency confirmations p.418
Political squabbles leave US science agencies without heads.
doi: 10.1038/497418a
米国の歳出強制削減の影響で、洪水対策に必要な雪塊や河川の監視に支障が出る恐れが。
US budget cuts hit Earth monitoring p.419
Sequestration threatens records of snow and stream levels in western United States.
doi: 10.1038/497419a
ロシア科学アカデミー総裁が、22年ぶりに交代へ。
Russian academy awaits new head p.420
Reform is in the air at the nation’s oldest research body.
doi: 10.1038/497420a
カリブ海地域のGPS観測網は、政治的対立を越えた科学外交の試金石に。
A network to track Caribbean hazards p.421
Multi-nation effort is a test of scientific diplomacy.
doi: 10.1038/497421a
超高速エレクトロニクスのために、さまざまな物質を使ったハニカム格子の開発が。
Graphene knock-offs probe ultrafast electronics p.422
Honeycomb lattices in different materials enable experiments impossible in the real thing.
doi: 10.1038/497422a
News Features
天体物理学：外を目指して
Voyager: Outward bound p.424
双子のボイジャー探査機が太陽系外へと到達するのを、心待ちにしている研究者がいる。
doi: 10.1038/497424a
公衆衛生：高脂肪食品の真実
The big fat truth p.428
体重超過は必ずしも寿命短縮につながらないことを示す研究成果が増えているが、一部の専門家はこれを無視しようとしている。
doi: 10.1038/497428a
News & Views
老化：役に立つ連絡ミス
Ageing: Beneficial miscommunication p.442
ミトコンドリアでのタンパク質翻訳速度には本来的に変動が見られる。この変動が、寿命と相関していることが見いだされた。このことは、代謝的変化の長寿への影響に対して統一的な機序が働いている可能性を示唆している。
doi: 10.1038/497442a
デングウイルス：2種類の宿主、2つの構造
Dengue virus: Two hosts, two structures p.443
蚊の細胞内で28°Cで増殖したデングウイルスは、極めて秩序立った構造を持っている。だが、37°Cで増殖したデングウイルスはもっと秩序性が低下した構造を持っているとわかり、ヒトの免疫系はこのウイルスを我々が以前に考えていたようなやり方で認識している訳ではないことが示唆された。
doi: 10.1038/497443a
構造生物学：状況を利用して成功しているちっちゃな酵素
Structural biology: Tiny enzyme uses context to succeed p.445
酵素であるジアシルグリセロールキナーゼが手持ちの数少ないアミノ酸残基を使って、膜と結合するための係留索と活性部位をどのようにして形成するのかは、長らく謎とされてきた。結晶構造から、それが「親しい同僚」からのちょっとした助けによってなされることが明らかになった。
doi: 10.1038/nature12245
物理化学：マイクロ波を使って検出された掌性
Physical chemistry: Handedness detected by microwaves p.446
分子の掌性、つまりキラリティーを測定し、決定する従来の方法は、いずれも同じ理論的概念に基づいていた。今回、こうした枠組みから離れた方法が報告された。
doi: 10.1038/497446b
材料科学：二兎を追う方がいい場合
Materials science: When two is better than one p.448
エアロゲルには多くの応用が考えられるが、弾性が乏しいことが一般に問題となっている。カーボンナノチューブとグラフェンの相乗的組織化によって、多機能性で超軽量、かつ極めて弾性に富んだエアロゲルが作られた。
doi: 10.1038/497448a
DNA複製：四重鎖という障害を通り越す
DNA replication: Driving past four-stranded snags p.449
グアニン四重鎖のような珍しいDNA構造は、DNA複製を停止させて、細胞にとって悲惨な結果をもたらすことがある。酵素のPif1ヘリカーゼファミリーは、このような構造を効率よく解きほぐすために進化してきた。
doi: 10.1038/nature12244
Articles
老化：保存された寿命関連機構としてのミトコンドリア–核タンパク質不均衡
Mitonuclear protein imbalance as a conserved longevity mechanism p.451
Mitochondrial ribosomal proteins have been identified as longevity regulators in C. elegans and mammalian systems, their role in longevity is linked to mitonuclear protein imbalance and the mitochondrial unfolded protein response.
doi: 10.1038/nature12188
細胞：Pif1ファミリーのヘリカーゼはグアニン四重鎖モチーフで生じるゲノム不安定性を抑制する
Pif1 family helicases suppress genome instability at G-quadruplex motifs p.458
In vitro and in vivo, the yeast Pif1 helicase is able to unwind four-stranded G-quadruplex (G4) DNA efficiently and suppress the genomic instability that occurs at such structures; these G4 maintenance activities are conserved among evolutionarily diverse Pif1 family helicases, including human PIF1, demonstrating the importance of this activity throughout evolution.
doi: 10.1038/nature12149
Letters
宇宙：高磁気レイノルズ数におけるせん断駆動ダイナモ波
Shear-driven dynamo waves at high magnetic Reynolds number p.463
Astrophysical magnetic fields often display remarkable organization, despite being generated by dynamo action driven by turbulent flows at high conductivity. An example is the eleven-year solar cycle, which shows spatial coherence over the entire solar surface. The difficulty in understanding the emergence of this large-scale organization is that whereas at low conductivity (measured by the magnetic Reynolds number, Rm) dynamo fields are well organized, at high Rm their structure is dominated by rapidly varying small-scale fluctuations. This arises because the smallest scales have the highest rate of strain, and can amplify magnetic field most efficiently. Therefore most of the effort to find flows whose large-scale dynamo properties persist at high Rm has been frustrated. Here we report high-resolution simulations of a dynamo that can generate organized fields at high Rm; indeed, the generation mechanism, which involves the interaction between helical flows and shear, only becomes effective at large Rm. The shear does not enhance generation at large scales, as is commonly thought; instead it reduces generation at small scales. The solution consists of propagating dynamo waves, whose existence was postulated more than 60 years ago and which have since been used to model the solar cycle.
doi: 10.1038/nature12177
宇宙：高伝導率の磁気流体力学乱流における磁力線凍結の破壊
Flux-freezing breakdown in high-conductivity magnetohydrodynamic turbulence p.466
The idea of ‘frozen-in’ magnetic field lines for ideal plasmas is useful to explain diverse astrophysical phenomena, for example the shedding of excess angular momentum from protostars by twisting of field lines frozen into the interstellar medium. Frozen-in field lines, however, preclude the rapid changes in magnetic topology observed at high conductivities, as in solar flares. Microphysical plasma processes are a proposed explanation of the observed high rates, but it is an open question whether such processes can rapidly reconnect astrophysical flux structures much greater in extent than several thousand ion gyroradii. An alternative explanation is that turbulent Richardson advection brings field lines implosively together from distances far apart to separations of the order of gyroradii. Here we report an analysis of a simulation of magnetohydrodynamic turbulence at high conductivity that exhibits Richardson dispersion. This effect of advection in rough velocity fields, which appear non-differentiable in space, leads to line motions that are completely indeterministic or ‘spontaneously stochastic’, as predicted in analytical studies. The turbulent breakdown of standard flux freezing at scales greater than the ion gyroradius can explain fast reconnection of very large-scale flux structures, both observed (solar flares and coronal mass ejections) and predicted (the inner heliosheath, accretion disks, γ-ray bursts and so on). For laminar plasma flows with smooth velocity fields or for low turbulence intensity, stochastic flux freezing reduces to the usual frozen-in condition.
doi: 10.1038/nature12128
物理：紫外光の全角度負屈折および能動平面レンズ効果
All-angle negative refraction and active flat lensing of ultraviolet light p.470
Decades ago, Veselago predicted that a material with simultaneously negative electric and magnetic polarization responses would yield a ‘left-handed’ medium in which light propagates with opposite phase and energy velocities—a condition described by a negative refractive index. He proposed that a flat slab of left-handed material possessing an isotropic refractive index of −1 could act like an imaging lens in free space. Left-handed materials do not occur naturally, and it has only recently become possible to achieve a left-handed response using metamaterials, that is, electromagnetic structures engineered on subwavelength scales to elicit tailored polarization responses. So far, left-handed responses have typically been implemented using resonant metamaterials composed of periodic arrays of unit cells containing inductive–capacitive resonators and conductive wires. Negative refractive indices that are isotropic in two or three dimensions at microwave frequencies have been achieved in resonant metamaterials with centimetre-scale features. Scaling the left-handed response to higher frequencies, such as infrared or visible, has been done by shrinking critical dimensions to submicrometre scales by means of top-down nanofabrication. This miniaturization has, however, so far been achieved at the cost of reduced unit-cell symmetry, yielding a refractive index that is negative along only one axis. Moreover, lithographic scaling limits have so far precluded the fabrication of resonant metamaterials with left-handed responses at frequencies beyond the visible. Here we report the experimental implementation of a bulk metamaterial with a left-handed response to ultraviolet light. The structure, based on stacked plasmonic waveguides, yields an omnidirectional left-handed response for transverse magnetic polarization characterized by a negative refractive index. By engineering the structure to have a refractive index close to −1 over a broad angular range, we achieve Veselago flat lensing, in free space, of arbitrarily shaped, two-dimensional objects beyond the near field. We further demonstrate active, all-optical modulation of the image transferred by the flat lens.
doi: 10.1038/nature12158
化学：マイクロ波分光法によるキラル分子のエナンチオマー特異的検出
Enantiomer-specific detection of chiral molecules via microwave spectroscopy p.475
Chirality plays a fundamental part in the activity of biological molecules and broad classes of chemical reactions, but detecting and quantifying it remains challenging. The spectroscopic methods of choice are usually circular dichroism and vibrational circular dichroism, methods that are forbidden in the electric dipole approximation. The resultant weak effects produce weak signals, and thus require high sample densities. In contrast, nonlinear techniques probing electric-dipole-allowed effects have been used for sensitive chiral analyses of liquid samples. Here we extend this class of approaches by carrying out nonlinear resonant phase-sensitive microwave spectroscopy of gas phase samples in the presence of an adiabatically switched non-resonant orthogonal electric field; we use this technique to map the enantiomer-dependent sign of an electric dipole Rabi frequency onto the phase of emitted microwave radiation. We outline theoretically how this results in a sensitive and species-selective method for determining the chirality of cold gas-phase molecules, and implement it experimentally to distinguish between the S and R enantiomers of 1,2-propanediol and their racemic mixture. This technique produces a large and definitive signature of chirality, and has the potential to determine the chirality of multiple species in a mixture.
doi: 10.1038/nature12150
気候：熱帯域平均上昇流の増加が引き起こす成層圏の準2年周期振動の弱化
Weakened stratospheric quasibiennial oscillation driven by increased tropical mean upwelling p.478
The zonal wind in the tropical stratosphere switches between prevailing easterlies and westerlies with a period of about 28 months. In the lowermost stratosphere, the vertical structure of this quasibiennial oscillation (QBO) is linked to the mean upwelling, which itself is a key factor in determining stratospheric composition. Evidence for changes in the QBO have until now been equivocal, raising questions as to the extent of stratospheric circulation changes in a global warming context. Here we report an analysis of near-equatorial radiosonde observations for 1953–2012, and reveal a long-term trend of weakening amplitude in the zonal wind QBO in the tropical lower stratosphere. The trend is particularly notable at the 70-hectopascal pressure level (an altitude of about 19 kilometres), where the QBO amplitudes dropped by roughly one-third over the period. This trend is also apparent in the global warming simulations of the four models in the Coupled Model Intercomparison Project Phase 5 (CMIP5) that realistically simulate the QBO. The weakening is most reasonably explained as resulting from a trend of increased mean tropical upwelling in the lower stratosphere. Almost all comprehensive climate models have projected an intensifying tropical upwelling in global warming scenarios, but attempts to estimate changes in the upwelling by using observational data have yielded ambiguous, inconclusive or contradictory results. Our discovery of a weakening trend in the lower-stratosphere QBO amplitude provides strong support for the existence of a long-term trend of enhanced upwelling near the tropical tropopause.
doi: 10.1038/nature12140
神経科学：聴覚皮質の皮質線条体ニューロンは聴覚弁別の際に決定を駆動する
Corticostriatal neurons in auditory cortex drive decisions during auditory discrimination p.482
The neural pathways by which information about the acoustic world reaches the auditory cortex are well characterized, but how auditory representations are transformed into motor commands is not known. Here we use a perceptual decision-making task in rats to study this transformation. We demonstrate the role of corticostriatal projection neurons in auditory decisions by manipulating the activity of these neurons in rats performing an auditory frequency-discrimination task. Targeted channelrhodopsin-2 (ChR2)-mediated stimulation of corticostriatal neurons during the task biased decisions in the direction predicted by the frequency tuning of the stimulated neurons, whereas archaerhodopsin-3 (Arch)-mediated inactivation biased decisions in the opposite direction. Striatal projections are widespread in cortex and may provide a general mechanism for the control of motor decisions by sensory cortex.
doi: 10.1038/nature12077
神経科学：主嗅覚系における嫌悪感をもたらすにおいの重複しないコード化
Non-redundant coding of aversive odours in the main olfactory pathway p.486
Many species are critically dependent on olfaction for survival. In the main olfactory system of mammals, odours are detected by sensory neurons that express a large repertoire of canonical odorant receptors and a much smaller repertoire of trace amine-associated receptors (TAARs). Odours are encoded in a combinatorial fashion across glomeruli in the main olfactory bulb, with each glomerulus corresponding to a specific receptor. The degree to which individual receptor genes contribute to odour perception is unclear. Here we show that genetic deletion of the olfactory Taar gene family, or even a single Taar gene (Taar4), eliminates the aversion that mice display to low concentrations of volatile amines and to the odour of predator urine. Our findings identify a role for the TAARs in olfaction, namely, in the high-sensitivity detection of innately aversive odours. In addition, our data reveal that aversive amines are represented in a non-redundant fashion, and that individual main olfactory receptor genes can contribute substantially to odour perception.
doi: 10.1038/nature12114
生理：Sema3Aは感覚神経支配を介して骨量を調節する
Sema3A regulates bone-mass accrual through sensory innervations p.490
Semaphorin 3A (Sema3A) is a diffusible axonal chemorepellent that has an important role in axon guidance. Previous studies have demonstrated that Sema3a−/− mice have multiple developmental defects due to abnormal neuronal innervations. Here we show in mice that Sema3A is abundantly expressed in bone, and cell-based assays showed that Sema3A affected osteoblast differentiation in a cell-autonomous fashion. Accordingly, Sema3a−/− mice had a low bone mass due to decreased bone formation. However, osteoblast-specific Sema3A-deficient mice (Sema3acol1−/− and Sema3aosx−/− mice) had normal bone mass, even though the expression of Sema3A in bone was substantially decreased. In contrast, mice lacking Sema3A in neurons (Sema3asynapsin−/− and Sema3anestin−/− mice) had low bone mass, similar to Sema3a−/− mice, indicating that neuron-derived Sema3A is responsible for the observed bone abnormalities independent of the local effect of Sema3A in bone. Indeed, the number of sensory innervations of trabecular bone was significantly decreased in Sema3asynapsin−/− mice, whereas sympathetic innervations of trabecular bone were unchanged. Moreover, ablating sensory nerves decreased bone mass in wild-type mice, whereas it did not reduce the low bone mass in Sema3anestin−/− mice further, supporting the essential role of the sensory nervous system in normal bone homeostasis. Finally, neuronal abnormalities in Sema3a−/− mice, such as olfactory development, were identified in Sema3asynasin−/− mice, demonstrating that neuron-derived Sema3A contributes to the abnormal neural development seen in Sema3a−/− mice, and indicating that Sema3A produced in neurons regulates neural development in an autocrine manner. This study demonstrates that Sema3A regulates bone remodelling indirectly by modulating sensory nerve development, but not directly by acting on osteoblasts.
doi: 10.1038/nature12115
免疫：ヒトヘルペスウイルス感染におけるCD8αα+皮膚常在性T細胞による免疫監視
Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection p.494
Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown that CD8+ T cells persist in genital skin and mucosa at the dermal–epidermal junction (DEJ)—the portal of neuronal release of reactivating virus—for prolonged time periods after herpes lesions are cleared. The phenotype and function of this persistent CD8+ T-cell population remain unknown. Here, using cell-type-specific laser capture microdissection, transcriptional profiling and T-cell antigen receptor β-chain (TCRβ) genotyping on sequential genital skin biopsies, we show that CD8αα+ T cells are the dominant resident population of DEJ CD8+ T cells that persist at the site of previous HSV-2 reactivation. CD8αα+ T cells located at the DEJ lack chemokine-receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCR β-chain repertoire reveals that the DEJ CD8αα+ T cells are oligoclonal with diverse usage of TCR variable-β genes, which differ from those commonly described for mucosa-associated invariant T cells and natural killer T cells. Dominant clonotypes are shown to overlap among multiple recurrences over a period of two-and-a-half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8αα+ T cells. These studies indicate that DEJ CD8αα+ T cells are tissue-resident cells that seem to have a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8αα+ T cells may be a critical component for developing effective vaccines against skin and mucosal infections.
doi: 10.1038/nature12110
医学：TLR4アンタゴニストのエリトランは致死的なインフルエンザ感染からマウスを防御する
The TLR4 antagonist Eritoran protects mice from lethal influenza infection p.498
There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4−/− mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)—a potent, well-tolerated, synthetic TLR4 antagonist—blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
doi: 10.1038/nature12118
発生：マイクロRNA miR-235は芽細胞の休眠と栄養状態とを結びつける
The microRNA miR-235 couples blast-cell quiescence to the nutritional state p.503
The coordination of stem- and blast-cell behaviours, such as self-renewal, differentiation and quiescence, with physiological changes underlies growth, regeneration and tissue homeostasis. Germline stem and somatic blast cells in newly hatched Caenorhabditis elegans larvae can suspend postembryonic development, which consists of diverse cellular events such as migration, proliferation and differentiation, until the nutritional state becomes favourable (termed L1 diapause). Although previous studies showed that the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway regulates this developmental quiescence, the detailed mechanism by which the IIS pathway enables these multipotent cells to respond to nutrient availability is unknown. Here we show in C. elegans that the microRNA (miRNA) miR-235, a sole orthologue of mammalian miR-92 from the oncogenic miR-17-92 cluster, acts in the hypodermis and glial cells to arrest postembryonic developmental events in both neuroblasts and mesoblasts. Expression of mir-235 persists during L1 diapause, and decreases upon feeding in a manner dependent on the IIS pathway. Upregulation of one of the miR-235 targets, nhr-91, which encodes an orthologue of mammalian germ cell nuclear factor, is responsible for defects caused by loss of the miRNA. Our findings establish a novel role of a miR-92 orthologue in coupling blast-cell behaviours to the nutritional state.
doi: 10.1038/nature12117
細胞：ラミンA/Cとエメリンは、アクチンの動態を変化させることにより、MKL1–SRF活性を調節する
Lamin A/C and emerin regulate MKL1–SRF activity by modulating actin dynamics p.507
Laminopathies, caused by mutations in the LMNA gene encoding the nuclear envelope proteins lamins A and C, represent a diverse group of diseases that include Emery–Dreifuss muscular dystrophy (EDMD), dilated cardiomyopathy (DCM), limb-girdle muscular dystrophy, and Hutchison–Gilford progeria syndrome. Most LMNA mutations affect skeletal and cardiac muscle by mechanisms that remain incompletely understood. Loss of structural function and altered interaction of mutant lamins with (tissue-specific) transcription factors have been proposed to explain the tissue-specific phenotypes. Here we report in mice that lamin-A/C-deficient (Lmna−/−) and LmnaN195K/N195K mutant cells have impaired nuclear translocation and downstream signalling of the mechanosensitive transcription factor megakaryoblastic leukaemia 1 (MKL1), a myocardin family member that is pivotal in cardiac development and function. Altered nucleo-cytoplasmic shuttling of MKL1 was caused by altered actin dynamics in Lmna−/− and LmnaN195K/N195K mutant cells. Ectopic expression of the nuclear envelope protein emerin, which is mislocalized in Lmna mutant cells and also linked to EDMD and DCM, restored MKL1 nuclear translocation and rescued actin dynamics in mutant cells. These findings present a novel mechanism that could provide insight into the disease aetiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.
doi: 10.1038/nature12105
生化学：シャペロンが介在するプロテアソーム組み立ての際に起こる再構成
Reconfiguration of the proteasome during chaperone-mediated assembly p.512
The proteasomal ATPase ring, comprising Rpt1–Rpt6, associates with the heptameric α-ring of the proteasome core particle (CP) in the mature proteasome, with the Rpt carboxy-terminal tails inserting into pockets of the α-ring. Rpt ring assembly is mediated by four chaperones, each binding a distinct Rpt subunit. Here we report that the base subassembly of the Saccharomyces cerevisiae proteasome, which includes the Rpt ring, forms a high-affinity complex with the CP. This complex is subject to active dissociation by the chaperones Hsm3, Nas6 and Rpn14. Chaperone-mediated dissociation was abrogated by a non-hydrolysable ATP analogue, indicating that chaperone action is coupled to nucleotide hydrolysis by the Rpt ring. Unexpectedly, synthetic Rpt tail peptides bound α-pockets with poor specificity, except for Rpt6, which uniquely bound the α2/α3-pocket. Although the Rpt6 tail is not visualized within an α-pocket in mature proteasomes, it inserts into the α2/α3-pocket in the base–CP complex and is important for complex formation. Thus, the Rpt–CP interface is reconfigured when the lid complex joins the nascent proteasome to form the mature holoenzyme.
doi: 10.1038/nature12123
遺伝：LGR4遺伝子のナンセンス変異は複数のヒト疾患や他の形質と関連する
Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits p.517
Low bone mineral density (BMD) is used as a parameter of osteoporosis. Genome-wide association studies of BMD have hitherto focused on BMD as a quantitative trait, yielding common variants of small effects that contribute to the population diversity in BMD. Here we use BMD as a dichotomous trait, searching for variants that may have a direct effect on the risk of pathologically low BMD rather than on the regulation of BMD in the healthy population. Through whole-genome sequencing of Icelandic individuals, we found a rare nonsense mutation within the leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) gene (c.376C>T) that is strongly associated with low BMD, and with osteoporotic fractures. This mutation leads to termination of LGR4 at position 126 and fully disrupts its function. The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Interestingly, the phenotype of carriers of the c.376C>T mutation overlaps that of Lgr4 mutant mice.
doi: 10.1038/nature12124
構造生物学：膜内在ジアシルグリセロールキナーゼの結晶構造
Crystal structure of the integral membrane diacylglycerol kinase p.521
Diacylglycerol kinase catalyses the ATP-dependent phosphorylation of diacylglycerol to phosphatidic acid for use in shuttling water-soluble components to membrane-derived oligosaccharide and lipopolysaccharide in the cell envelope of Gram-negative bacteria. For half a century, this 121-residue kinase has served as a model for investigating membrane protein enzymology, folding, assembly and stability. Here we present crystal structures for three functional forms of this unique and paradigmatic kinase, one of which is wild type. These reveal a homo-trimeric enzyme with three transmembrane helices and an amino-terminal amphiphilic helix per monomer. Bound lipid substrate and docked ATP identify the putative active site that is of the composite, shared site type. The crystal structures rationalize extensive biochemical and biophysical data on the enzyme. They are, however, at variance with a published solution NMR model in that domain swapping, a key feature of the solution form, is not observed in the crystal structures.
doi: 10.1038/nature12179
