Editorials
ヒトの脳のシミュレーションを目指すヨーロッパの大規模計画は、神経科学に狙い以上の成果をもたらすだろう。
Head start p.5
Europe’s mega-project to simulate the human brain has much to offer neuroscience research — whether or not it delivers on its central promise.
doi: 10.1038/503005a
文化遺産の保護、保存を研究する科学者に対し、各国政府は支援を強化すべきだ。
Historic work p.6
Governments need to strengthen support for scientists who preserve our cultural heritage.
doi: 10.1038/503006a
大量の極小ビーズの挙動から、さまざまな生物に見られる集団運動の謎が明らかになるだろう。
Follow the crowd p.6
The behaviour of millions of minuscule beads reveals some secrets of collective motion.
doi: 10.1038/503006b
News
X線望遠鏡が、ヨーロッパの宇宙開発計画の優先順位第1位に。
X-rays top space agenda p.13
European agency selects mission themes, with X-ray telescope the biggest winner.
doi: 10.1038/503013a
精密な遺伝子編集によるトランスジェニックサルに、動物モデルとしての期待が。
Precision gene editing paves way for transgenic monkeys p.14
Despite political challenges, engineered primates could be better disease models than mice.
doi: 10.1038/503014a
2004年に始まった米国本土の地震計アレイ観測は、今年ほぼ終了し、来年にはアラスカへ。
US seismic array eyes its final frontier p.16
Moveable sensor grid will begin monitoring Alaska next summer.
doi: 10.1038/503016a
長年決着がつかなかったリンネのゾウ標本の分類が、プロテオミクス解析から明らかに。
Proteins help solve taxonomy riddle p.18
Proteomic technique proves that 300-year-old Linnaean elephant was wrongly classified.
doi: 10.1038/503018a
生物兵器拡散を防ぐためのEUの規制が感染症研究を難しくすると、科学者から懸念が。
Pathogen-research laws queried p.19
Scientists fear EU biosafety rules could complicate publication of work on infectious diseases.
doi: 10.1038/503019a
News Features
神経科学：脳を新たな角度から
Neuroscience: New angles on the brain p.21
神経回路を調べるさまざまな技術によって、ヒトの認知の研究は大きく進歩しつつある。
doi: 10.1038/503021a
神経科学：スマート接続
Neuroelectronics: Smart connections p.22
ヒトのニューロンが、省エネ高性能の新しいコンピューターチップのヒントになる。
doi: 10.1038/503022a
神経科学：ブレインストーム
Neurotechnology: Brain storm p.26
オバマ政権の打ち出したBRAIN計画がどのようなものになるか、神経科学者たちの取り組みが進んでいる。
doi: 10.1038/503026a
News & Views
神経科学：ニューロンの結合を作り出す
Neuroscience: Sculpting neuronal connectivity p.42
ニューロンでは、転写プログラムが抑制性の入力に対して、ニューロン内の領域ごとに異なる調節を行っていることが分かってきた。これは、神経回路では経験依存性の「可塑性」を獲得するための意外なスイッチが協調的に働いていることを示している。
doi: 10.1038/503042a
応用物理学：順調に進む
Applied physics: On a roll p.43
転がる粒子の集団は、走路の中では一方向性のまとまった動きを示すことが分かっている。理論的モデル作製によって流体力学的効果と静電気的効果がこうしたふるまいを促進していることが示唆された。
doi: 10.1038/503043a
進化生態学：珍しさが恋しさを募らせる
Evolutionary ecology: Novelty makes the heart grow fonder p.44
グッピーについての研究で「希少雄効果」、すなわち強い配偶者選択を受ける形質で変異が維持されるという謎を説明するためにずっと以前に考えられた仮説に対して、これまでで最も明確な証拠が得られた。
doi: 10.1038/nature12701
神経科学：何をどういう風になすべきか
Neuroscience: What to do and how p.45
意思決定は周囲の環境によって変わると考えられる。サル脳の前前頭皮質の解析から、ニューロン集団レベルでの動的な過程がこうした挙動を制御していることが示された。
doi: 10.1038/503045a
気候科学：当時は不確か、現在は的外れ
Climate science: Uncertain then, irrelevant now p.47
気候へのエアロゾルの影響の推定値の不確実性は、過去の汚染されていない大気についての知識が不十分であることに由来する。そのため、このような影響の解明がさらに進んでも、現在の気候の理解には考えられているほど役に立たない可能性が出てきた。
doi: 10.1038/503047a
心理学：青年期の脳について良い知らせと悪い知らせ
Psychology: Good and bad news on the adolescent brain p.48
リスクについての悪い知らせを聞くと、人は有害な事象に対する自己の脆弱性の評価を変えるものだが、未熟な若者は年長者に比べてその評価の正確性が低い。この知見は、若者がとる危険な行動への対応に関係してくると考えられる。
doi: 10.1038/nature12704
Reviews
神経科学：皮質ニューロンの接続性と感覚の符号化
Cortical connectivity and sensory coding p.51
The sensory cortex contains a wide array of neuronal types, which are connected together into complex but partially stereotyped circuits. Sensory stimuli trigger cascades of electrical activity through these circuits, causing specific features of sensory scenes to be encoded in the firing patterns of cortical populations. Recent research is beginning to reveal how the connectivity of individual neurons relates to the sensory features they encode, how differences in the connectivity patterns of different cortical cell classes enable them to encode information using different strategies, and how feedback connections from higher-order cortex allow sensory information to be integrated with behavioural context.
doi: 10.1038/nature12654
医学：グルコース恒常性および糖尿病における脳と膵島との協調
Cooperation between brain and islet in glucose homeostasis and diabetes p.59
Although a prominent role for the brain in glucose homeostasis was proposed by scientists in the nineteenth century, research throughout most of the twentieth century focused on evidence that the function of pancreatic islets is both necessary and sufficient to explain glucose homeostasis, and that diabetes results from defects of insulin secretion, action or both. However, insulin-independent mechanisms, referred to as ‘glucose effectiveness’, account for roughly 50% of overall glucose disposal, and reduced glucose effectiveness also contributes importantly to diabetes pathogenesis. Although mechanisms underlying glucose effectiveness are poorly understood, growing evidence suggests that the brain can dynamically regulate this process in ways that improve or even normalize glycaemia in rodent models of diabetes. Here we present evidence of a brain-centred glucoregulatory system (BCGS) that can lower blood glucose levels via both insulin-dependent and -independent mechanisms, and propose a model in which complex and highly coordinated interactions between the BCGS and pancreatic islets promote normal glucose homeostasis. Because activation of either regulatory system can compensate for failure of the other, defects in both may be required for diabetes to develop. Consequently, therapies that target the BCGS in addition to conventional approaches based on enhancing insulin effects may have the potential to induce diabetes remission, whereas targeting just one typically does not.
doi: 10.1038/nature12709
Articles
気候：間接強制力の不確実性に対する自然起源のエアロゾルの大きな寄与
Large contribution of natural aerosols to uncertainty in indirect forcing p.67
It has been assumed that a better understanding of the effects of anthropogenic aerosols will greatly reduce the large uncertainties associated with our predictions of the radiative forcing effects of aerosols on climate; however, this study shows that nearly half of the uncertainty in the radiative effect of aerosols on clouds derives from uncertainties in pre-industrial natural aerosols.
doi: 10.1038/nature12674
神経科学：SHANK3の過剰発現は独特な薬理遺伝学的性質を伴う躁病的行動を引き起こす
SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties p.72
Mouse and human studies reveal that incorrect gene dosage of SHANK3 (a gene linked to some human neuropsychiatric disorders, including autism spectrum disorder) is associated with behavioural abnormalities including mania, possibly because of actin regulation problems in excitatory/inhibitory synapses.
doi: 10.1038/nature12630
神経科学：前前頭皮質での反復性動態による文脈依存的な神経演算
Context-dependent computation by recurrent dynamics in prefrontal cortex p.78
This study shows that in monkeys making context-dependent decisions, task-relevant and task-irrelevant signals are confusingly intermixed in single units of the prefrontal cortex, but are readily understood in the framework of a dynamical process unfolding at the level of the population; a recurrently connected neural network model reproduces key features of the data and suggests a novel mechanism for selection and integration of task-relevant evidence towards a decision.
doi: 10.1038/nature12742
構造生物学：ドーパミン輸送体のX線構造により明らかになった抗うつ剤の作用機構
X-ray structure of dopamine transporter elucidates antidepressant mechanism p.85
The X-ray crystal structure of the Drosophila dopamine transporter bound to the antidepressant drug nortriptyline is presented, providing the first crystal structure of a eukaryotic neurotransmitter sodium symporter.
doi: 10.1038/nature12533
Letters
ナノテクノロジー：レーザー駆動誘電体マイクロ構造における電子加速の実証
Demonstration of electron acceleration in a laser-driven dielectric microstructure p.91
The enormous size and cost of current state-of-the-art accelerators based on conventional radio-frequency technology has spawned great interest in the development of new acceleration concepts that are more compact and economical. Micro-fabricated dielectric laser accelerators (DLAs) are an attractive approach, because such dielectric microstructures can support accelerating fields one to two orders of magnitude higher than can radio-frequency cavity-based accelerators. DLAs use commercial lasers as a power source, which are smaller and less expensive than the radio-frequency klystrons that power today’s accelerators. In addition, DLAs are fabricated via low-cost, lithographic techniques that can be used for mass production. However, despite several DLA structures having been proposed recently, no successful demonstration of acceleration in these structures has so far been shown. Here we report high-gradient (beyond 250 MeV m−1) acceleration of electrons in a DLA. Relativistic (60-MeV) electrons are energy-modulated over 563 ± 104 optical periods of a fused silica grating structure, powered by a 800-nm-wavelength mode-locked Ti:sapphire laser. The observed results are in agreement with analytical models and electrodynamic simulations. By comparison, conventional modern linear accelerators operate at gradients of 10–30 MeV m−1, and the first linear radio-frequency cavity accelerator was ten radio-frequency periods (one metre) long with a gradient of approximately 1.6 MeV m−1 (ref. 5). Our results set the stage for the development of future multi-staged DLA devices composed of integrated on-chip systems. This would enable compact table-top accelerators on the MeV–GeV (106–109 eV) scale for security scanners and medical therapy, university-scale X-ray light sources for biological and materials research, and portable medical imaging devices, and would substantially reduce the size and cost of a future collider on the multi-TeV (1012 eV) scale.
doi: 10.1038/nature12664
応用物理学：運動性コロイド集団における巨視的方向性運動の出現
Emergence of macroscopic directed motion in populations of motile colloids p.95
From the formation of animal flocks to the emergence of coordinated motion in bacterial swarms, populations of motile organisms at all scales display coherent collective motion. This consistent behaviour strongly contrasts with the difference in communication abilities between the individuals. On the basis of this universal feature, it has been proposed that alignment rules at the individual level could solely account for the emergence of unidirectional motion at the group level. This hypothesis has been supported by agent-based simulations. However, more complex collective behaviours have been systematically found in experiments, including the formation of vortices, fluctuating swarms, clustering and swirling. All these (living and man-made) model systems (bacteria, biofilaments and molecular motors, shaken grains and reactive colloids) predominantly rely on actual collisions to generate collective motion. As a result, the potential local alignment rules are entangled with more complex, and often unknown, interactions. The large-scale behaviour of the populations therefore strongly depends on these uncontrolled microscopic couplings, which are extremely challenging to measure and describe theoretically. Here we report that dilute populations of millions of colloidal rolling particles self-organize to achieve coherent motion in a unique direction, with very few density and velocity fluctuations. Quantitatively identifying the microscopic interactions between the rollers allows a theoretical description of this polar-liquid state. Comparison of the theory with experiment suggests that hydrodynamic interactions promote the emergence of collective motion either in the form of a single macroscopic ‘flock’, at low densities, or in that of a homogenous polar phase, at higher densities. Furthermore, hydrodynamics protects the polar-liquid state from the giant density fluctuations that were hitherto considered the hallmark of populations of self-propelled particles. Our experiments demonstrate that genuine physical interactions at the individual level are sufficient to set homogeneous active populations into stable directed motion.
doi: 10.1038/nature12673
化学：仮想磁気鋳型によって誘導されるコロイド集合
Colloidal assembly directed by virtual magnetic moulds p.99
Interest in assemblies of colloidal particles has long been motivated by their applications in photonics, electronics, sensors and microlenses. Existing assembly schemes can position colloids of one type relatively flexibly into a range of desired structures, but it remains challenging to produce multicomponent lattices, clusters with precisely controlled symmetries and three-dimensional assemblies. A few schemes can efficiently produce complex colloidal structures, but they require system-specific procedures. Here we show that magnetic field microgradients established in a paramagnetic fluid can serve as ‘virtual moulds’ to act as templates for the assembly of large numbers (∼108) of both non-magnetic and magnetic colloidal particles with micrometre precision and typical yields of 80 to 90 per cent. We illustrate the versatility of this approach by producing single-component and multicomponent colloidal arrays, complex three-dimensional structures and a variety of colloidal molecules from polymeric particles, silica particles and live bacteria and by showing that all of these structures can be made permanent. In addition, although our magnetic moulds currently resemble optical traps in that they are limited to the manipulation of micrometre-sized objects, they are massively parallel and can manipulate non-magnetic and magnetic objects simultaneously in two and three dimensions.
doi: 10.1038/nature12591
地球：マントル深部条件における溶融した玄武岩の構造変化
Structural change in molten basalt at deep mantle conditions p.104
Silicate liquids play a key part at all stages of deep Earth evolution, ranging from core and crust formation billions of years ago to present-day volcanic activity. Quantitative models of these processes require knowledge of the structural changes and compression mechanisms that take place in liquid silicates at the high pressures and temperatures in the Earth’s interior. However, obtaining such knowledge has long been impeded by the challenging nature of the experiments. In recent years, structural and density information for silica glass was obtained at record pressures of up to 100 GPa (ref. 1), a major step towards obtaining data on the molten state. Here we report the structure of molten basalt up to 60 GPa by means of in situ X-ray diffraction. The coordination of silicon increases from four under ambient conditions to six at 35 GPa, similar to what has been reported in silica glass. The compressibility of the melt after the completion of the coordination change is lower than at lower pressure, implying that only a high-order equation of state can accurately describe the density evolution of silicate melts over the pressure range of the whole mantle. The transition pressure coincides with a marked change in the pressure-evolution of nickel partitioning between molten iron and molten silicates, indicating that melt compressibility controls siderophile-element partitioning.
doi: 10.1038/nature12668
進化生物学：野生グッピー個体群で見られる希少な雄の配偶優位性
Mating advantage for rare males in wild guppy populations p.108
To understand the processes that maintain genetic diversity is a long-standing challenge in evolutionary biology, with implications for predicting disease resistance, response to environmental change, and population persistence. Simple population genetic models are not sufficient to explain the high levels of genetic diversity sometimes observed in ecologically important traits. In guppies (Poecilia reticulata), male colour pattern is both diverse and heritable, and is arguably one of the most extreme examples of morphological polymorphism known. Negative frequency-dependent selection (NFDS), a form of selection in which genotypes are favoured when they are rare, can potentially maintain such extensive polymorphism, but few experimental studies have confirmed its operation in nature. Here we use highly replicated experimental manipulations of natural populations to show that males with rare colour patterns have higher reproductive fitness, demonstrating NFDS mediated by sexual selection. Rare males acquired more mates and sired more offspring compared to common males and, as previously reported, had higher rates of survival. Orange colour, implicated in other studies of sexual selection in guppies, did predict male reproductive success, but only in one of three populations. These data support the hypothesis that NFDS maintains diversity in the colour patterns of male guppies through two selective agents, mates and predators. Similar field-based manipulations of genotype frequencies could provide a powerful approach to reveal the underlying ecological and behavioural mechanisms that maintain genetic and phenotypic diversity.
doi: 10.1038/nature12717
神経科学：食欲を抑制する神経回路の遺伝学的な同定
Genetic identification of a neural circuit that suppresses appetite p.111
Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin, as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively. Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice. However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic and pharmacogenetic tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.
doi: 10.1038/nature12596
神経科学：樹状突起の発火はin vivoで皮質ニューロンにおける刺激選択性を高める
Dendritic spikes enhance stimulus selectivity in cortical neurons in vivo p.115
Neuronal dendrites are electrically excitable: they can generate regenerative events such as dendritic spikes in response to sufficiently strong synaptic input. Although such events have been observed in many neuronal types, it is not well understood how active dendrites contribute to the tuning of neuronal output in vivo. Here we show that dendritic spikes increase the selectivity of neuronal responses to the orientation of a visual stimulus (orientation tuning). We performed direct patch-clamp recordings from the dendrites of pyramidal neurons in the primary visual cortex of lightly anaesthetized and awake mice, during sensory processing. Visual stimulation triggered regenerative local dendritic spikes that were distinct from back-propagating action potentials. These events were orientation tuned and were suppressed by either hyperpolarization of membrane potential or intracellular blockade of NMDA (N-methyl-d-aspartate) receptors. Both of these manipulations also decreased the selectivity of subthreshold orientation tuning measured at the soma, thus linking dendritic regenerative events to somatic orientation tuning. Together, our results suggest that dendritic spikes that are triggered by visual input contribute to a fundamental cortical computation: enhancing orientation selectivity in the visual cortex. Thus, dendritic excitability is an essential component of behaviourally relevant computations in neurons.
doi: 10.1038/nature12600
神経科学：活動依存的な転写因子NPAS4は領域特異的な抑制を調節する
The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition p.121
A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials and prevent the generation of dendritic calcium spikes. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinatesthe redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.
doi: 10.1038/nature12743
免疫：インテグリン調節療法は強皮症マウスモデルでの繊維形成や自己免疫を防止する
Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma p.126
In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell–matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell–matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.
doi: 10.1038/nature12614
細胞生物学：インテグリンシグナル伝達の方向切り替えスイッチと新しい抗血栓形成戦略
A directional switch of integrin signalling and a new anti-thrombotic strategy p.131
Integrins have a critical role in thrombosis and haemostasis. Antagonists of the platelet integrin αIIbβ3 are potent anti-thrombotic drugs, but also have the life-threatening adverse effect of causing bleeding. It is therefore desirable to develop new antagonists that do not cause bleeding. Integrins transmit signals bidirectionally. Inside-out signalling activates integrins through a talin-dependent mechanism. Integrin ligation mediates thrombus formation and outside-in signalling, which requires Gα13 and greatly expands thrombi. Here we show that Gα13 and talin bind to mutually exclusive but distinct sites within the integrin β3 cytoplasmic domain in opposing waves. The first talin-binding wave mediates inside-out signalling and also ligand-induced integrin activation, but is not required for outside-in signalling. Integrin ligation induces transient talin dissociation and Gα13 binding to an EXE motif (in which X denotes any residue), which selectively mediates outside-in signalling and platelet spreading. The second talin-binding wave is associated with clot retraction. An EXE-motif-based inhibitor of Gα13–integrin interaction selectively abolishes outside-in signalling without affecting integrin ligation, and suppresses occlusive arterial thrombosis without affecting bleeding time. Thus, we have discovered a new mechanism for the directional switch of integrin signalling and, on the basis of this mechanism, designed a potent new anti-thrombotic drug that does not cause bleeding.
doi: 10.1038/nature12613
細胞生物学：ジストログリカン上のLARGEグリカンが、マトリックスを支える調節可能な足場として機能し、ジストロフィーを防いでいる
LARGE glycans on dystroglycan function as a tunable matrix scaffold to prevent dystrophy p.136
The dense glycan coat that surrounds every cell is essential for cellular development and physiological function, and it is becoming appreciated that its composition is highly dynamic. Post-translational addition of the polysaccharide repeating unit [-3-xylose-α1,3-glucuronic acid-β1-]n by like-acetylglucosaminyltransferase (LARGE) is required for the glycoprotein dystroglycan to function as a receptor for proteins in the extracellular matrix. Reductions in the amount of [-3-xylose-α1,3-glucuronic acid-β1-]n (hereafter referred to as LARGE-glycan) on dystroglycan result in heterogeneous forms of muscular dystrophy. However, neither patient nor mouse studies has revealed a clear correlation between glycosylation status and phenotype. This disparity can be attributed to our lack of knowledge of the cellular function of the LARGE-glycan repeat. Here we show that coordinated upregulation of Large and dystroglycan in differentiating mouse muscle facilitates rapid extension of LARGE-glycan repeat chains. Using synthesized LARGE-glycan repeats we show a direct correlation between LARGE-glycan extension and its binding capacity for extracellular matrix ligands. Blocking Large upregulation during muscle regeneration results in the synthesis of dystroglycan with minimal LARGE-glycan repeats in association with a less compact basement membrane, immature neuromuscular junctions and dysfunctional muscle predisposed to dystrophy. This was consistent with the finding that patients with increased clinical severity of disease have fewer LARGE-glycan repeats. Our results reveal that the LARGE-glycan of dystroglycan serves as a tunable extracellular matrix protein scaffold, the extension of which is required for normal skeletal muscle function.
doi: 10.1038/nature12605
構造生物学：生体アミン輸送体に対する多様な抗うつ剤の作用の構造基盤
Structural basis for action by diverse antidepressants on biogenic amine transporters p.141
The biogenic amine transporters (BATs) regulate endogenous neurotransmitter concentrations and are targets for a broad range of therapeutic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin–noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs). Because eukaryotic BATs are recalcitrant to crystallographic analysis, our understanding of the mechanism of these inhibitors and antidepressants is limited. LeuT is a bacterial homologue of BATs and has proven to be a valuable paradigm for understanding relationships between their structure and function. However, because only approximately 25% of the amino acid sequence of LeuT is in common with that of BATs, and as LeuT is a promiscuous amino acid transporter, it does not recapitulate the pharmacological properties of BATs. Indeed, SSRIs and TCAs bind in the extracellular vestibule of LeuT and act as non-competitive inhibitors of transport. By contrast, multiple studies demonstrate that both TCAs and SSRIs are competitive inhibitors for eukaryotic BATs and bind to the primary binding pocket. Here we engineered LeuT to harbour human BAT-like pharmacology by mutating key residues around the primary binding pocket. The final LeuBAT mutant binds the SSRI sertraline with a binding constant of 18 nM and displays high-affinity binding to a range of SSRIs, SNRIs and a TCA. We determined 12 crystal structures of LeuBAT in complex with four classes of antidepressants. The chemically diverse inhibitors have a remarkably similar mode of binding in which they straddle transmembrane helix (TM) 3, wedge between TM3/TM8 and TM1/TM6, and lock the transporter in a sodium- and chloride-bound outward-facing open conformation. Together, these studies define common and simple principles for the action of SSRIs, SNRIs and TCAs on BATs.
doi: 10.1038/nature12648
