1 In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target
Robert T. Manguso, Hans W. Pope, Margaret D. Zimmer…John G. Doench & W. Nicholas Haining
（导读 郭思瑶）凭借PD-1检查点阻断的免疫疗法只对小部分癌症患者有效，更多治疗策略有待发现。本研究利用CRISPR–Cas9在小鼠体内可移植肿瘤中进行基因筛选，找出对检查点阻断产生强化或抵抗性的基因。发现多种通路中的基因缺失都可提高肿瘤对免疫疗法的敏感性，其中敲除PTPN2可通过增强干扰素γ介导的抗原呈递和生长抑制效应达到上述效果，该方法有利于筛选预料外通路中的新免疫疗法靶点 。
Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR–Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.
2 Maternal H3K27me3 controls DNA methylation-independent imprinting
Azusa Inoue, Lan Jiang, Falong Lu, Tsukasa Suzuki & Yi Zhang
Mammalian sperm and oocytes have different epigenetic landscapes and are organized in different fashions. After fertilization, the initially distinct parental epigenomes become largely equalized with the exception of certain loci, including imprinting control regions. How parental chromatin becomes equalized and how imprinting control regions escape from this reprogramming is largely unknown. Here we profile parental allele-specific DNase I hypersensitive sites in mouse zygotes and morula embryos, and investigate the epigenetic mechanisms underlying these allelic sites. Integrated analyses of DNA methylome and tri-methylation at lysine 27 of histone H3 (H3K27me3) chromatin immunoprecipitation followed by sequencing identify 76 genes with paternal allele-specific DNase I hypersensitive sites that are devoid of DNA methylation but harbour maternal allele-specific H3K27me3. Interestingly, these genes are paternally expressed in preimplantation embryos, and ectopic removal of H3K27me3 induces maternal allele expression. H3K27me3-dependent imprinting is largely lost in the embryonic cell lineage, but at least five genes maintain their imprinted expression in the extra-embryonic cell lineage. The five genes include all paternally expressed autosomal imprinted genes previously demonstrated to be independent of oocyte DNA methylation. Thus, our study identifies maternal H3K27me3 as a DNA methylation-independent imprinting mechanism.
3 Significant and variable linear polarization during the prompt optical flash of GRB 160625B
E. Troja, V. M. Lipunov, C. G. Mundell…V. Yurkov & N. Gehrels
Newly formed black holes of stellar mass launch collimated outflows (jets) of ionized matter that approach the speed of light. These outflows power prompt, brief and intense flashes of γ-rays known as γ-ray bursts (GRBs), followed by longer-lived afterglow radiation that is detected across the electromagnetic spectrum. Measuring the polarization of the observed GRB radiation provides a direct probe of the magnetic fields in the collimated jets. Rapid-response polarimetric observations of newly discovered bursts have probed the initial afterglow phase1, 2, 3, and show that, minutes after the prompt emission has ended, the degree of linear polarization can be as high as 30 per cent—consistent with the idea that a stable, globally ordered magnetic field permeates the jet at large distances from the central source3. By contrast, optical4, 5, 6 and γ-ray7, 8, 9observations during the prompt phase have led to discordant and often controversial10,11, 12 results, and no definitive conclusions have been reached regarding the origin of the prompt radiation or the configuration of the magnetic field. Here we report the detection of substantial (8.3 ± 0.8 per cent from our most conservative simulation), variable linear polarization of a prompt optical flash that accompanied the extremely energetic and long-lived prompt γ-ray emission from GRB 160625B. Our measurements probe the structure of the magnetic field at an early stage of the jet, closer to its central black hole, and show that the prompt phase is produced via fast-cooling synchrotron radiation in a large-scale magnetic field that is advected from the black hole and distorted by dissipation processes within the jet.
（导读：阿金）新生黑洞将接近光速的电离物质喷射出来，驱动伽马射线暴。利用伽马暴偏振可以直接探测喷流中磁场。本研究在伴随伽马射线暴GRB 160625B的瞬时光学闪中，测得8.3% ± 0.8%的线偏振。该结果显示了喷流早期的磁场结构，并表明伽马暴瞬时阶段的辐射来源于大尺度磁场的快速冷却同步辐射。
4 Neuromorphic computing with nanoscale spintronic oscillators
Jacob Torrejon, Mathieu Riou, Flavio Abreu Araujo…Mark D. Stiles & Julie Grollier
Neurons in the brain behave as nonlinear oscillators, which develop rhythmic activity and interact to process information1. Taking inspiration from this behaviour to realize high-density, low-power neuromorphic computing will require very large numbers of nanoscale nonlinear oscillators. A simple estimation indicates that to fit 108 oscillators organized in a two-dimensional array inside a chip the size of a thumb, the lateral dimension of each oscillator must be smaller than one micrometre. However, nanoscale devices tend to be noisy and to lack the stability that is required to process data in a reliable way. For this reason, despite multiple theoretical proposals2, 3, 4, 5 and several candidates, including memristive6 and superconducting7 oscillators, a proof of concept of neuromorphic computing using nanoscale oscillators has yet to be demonstrated. Here we show experimentally that a nanoscale spintronic oscillator (a magnetic tunnel junction)8, 9 can be used to achieve spoken-digit recognition with an accuracy similar to that of state-of-the-art neural networks. We also determine the regime of magnetization dynamics that leads to the greatest performance. These results, combined with the ability of the spintronic oscillators to interact with each other, and their long lifetime and low energy consumption, open up a path to fast, parallel, on-chip computation based on networks of oscillators.
5 Spontaneous breaking of rotational symmetry in copper oxide superconductors
J. Wu, A. T. Bollinger, X. He & I. Božović
The origin of high-temperature superconductivity in copper oxides and the nature of the ‘normal’ state above the critical temperature are widely debated1, 2, 3. In underdoped copper oxides, this normal state hosts a pseudogap and other anomalous features; and in the overdoped materials, the standard Bardeen–Cooper–Schrieffer description fails4, challenging the idea that the normal state is a simple Fermi liquid. To investigate these questions, we have studied the behaviour of single-crystal La2–xSrxCuO4 films through which an electrical current is being passed. Here we report that a spontaneous voltage develops across the sample, transverse (orthogonal) to the electrical current. The dependence of this voltage on probe current, temperature, in-plane device orientation and doping shows that this behaviour is intrinsic, substantial, robust and present over a broad range of temperature and doping. If the current direction is rotated in-plane by an angle ϕ, the transverse voltage oscillates as sin(2ϕ), breaking the four-fold rotational symmetry of the crystal. The amplitude of the oscillations is strongly peaked near the critical temperature for superconductivity and decreases with increasing doping. We find that these phenomena are manifestations of unexpected in-plane anisotropy in the electronic transport. The films are very thin and epitaxially constrained to be tetragonal (that is, with four-fold symmetry), so one expects a constant resistivity and zero transverse voltage, for every ϕ. The origin of this anisotropy is purely electronic—the so-called electronic nematicity. Unusually, the nematic director is not aligned with the crystal axes, unless a substantial orthorhombic distortion is imposed. The fact that this anisotropy occurs in a material that exhibits high-temperature superconductivity may not be a coincidence.
(导读 晨笛)研究人员在通电流的La2–xSrxCuO4单晶薄膜中发现了广泛存在于各温度、不同掺杂范围的自发横向电压。所通电流方向在面内旋转角度ϕ 后，横向电压大小以sin(2ϕ)的形式发生振荡，打破晶体四重对称。这一电输运的面内各向异性来源于电子向列相，但与晶轴方向无关，这对高温超导或有重要意义。
6 Synergy of synthesis, computation and NMR reveals correct baulamycin structures
Jingjing Wu, Paula Lorenzo, Siying Zhong, Muhammad Ali, Craig P. Butts, Eddie L. Myers & Varinder K. Aggarwal
Small-molecule, biologically active natural products continue to be our most rewarding source of, and inspiration for, new medicines. Sometimes we happen upon such molecules in minute quantities in unique, difficult-to-reach, and often fleeting environments, perhaps never to be discovered again. In these cases, determining the structure of a molecule—including assigning its relative and absolute configurations—is paramount, enabling one to understand its biological activity. Molecules that comprise stereochemically complex acyclic and conformationally flexible carbon chains make such a task extremely challenging. The baulamycins (A and B) serve as a contemporary example. Isolated in small quantities and shown to have promising antimicrobial activity, the structure of the conformationally flexible molecules was determined largely through J-based configurational analysis, but has been found to be incorrect. Our subsequent campaign to identify the true structures of the baulamycins has revealed a powerful method for the rapid structural elucidation of such molecules. Specifically, the prediction of nuclear magnetic resonance (NMR) parameters through density functional theory—combined with an efficient sequence of boron-based synthetic transformations, which allowed an encoded (labelled) mixture of natural-product diastereomers to be prepared—enabled us rapidly to pinpoint and synthesize the correct structures.
7 Global forest loss disproportionately erodes biodiversity in intact landscapes
Matthew G. Betts, Christopher Wolf, William J. Ripple, Ben Phalan, Kimberley A. Millers, Adam Duarte, Stuart H. M. Butchart & Taal Levi
Global biodiversity loss is a critical environmental crisis, yet the lack of spatial data on biodiversity threats has hindered conservation strategies1. Theory predicts that abrupt biodiversity declines are most likely to occur when habitat availability is reduced to very low levels in the landscape (10–30%)2, 3, 4. Alternatively, recent evidence indicates that biodiversity is best conserved by minimizing human intrusion into intact and relatively unfragmented landscapes5. Here we use recently available forest loss data6 to test deforestation effects on International Union for Conservation of Nature Red List categories of extinction risk for 19,432 vertebrate species worldwide. As expected, deforestation substantially increased the odds of a species being listed as threatened, undergoing recent upgrading to a higher threat category and exhibiting declining populations. More importantly, we show that these risks were disproportionately high in relatively intact landscapes; even minimal deforestation has had severe consequences for vertebrate biodiversity. We found little support for the alternative hypothesis that forest loss is most detrimental in already fragmented landscapes. Spatial analysis revealed high-risk hot spots in Borneo, the central Amazon and the Congo Basin. In these regions, our model predicts that 121–219 species will become threatened under current rates of forest loss over the next 30 years. Given that only 17.9% of these high-risk areas are formally protected and only 8.9% have strict protection, new large-scale conservation efforts to protect intact forests7, 8 are necessary to slow deforestation rates and to avert a new wave of global extinctions.
8 A novel mechanism for mechanosensory-based rheotaxis in larval zebrafish
Pablo Oteiza, Iris Odstrcil, George Lauder, Ruben Portugues & Florian Engert
When flying or swimming, animals must adjust their own movement to compensate for displacements induced by the flow of the surrounding air or water1. These flow-induced displacements 位移 can most easily be detected as visual whole-field motion with respect to the animal’s frame of reference2. Despite this, many aquatic animals consistently orient and swim against oncoming flows (a behaviour known as rheotaxis) even in the absence of visual cues3, 4. How animals achieve this task, and its underlying sensory basis, is still unknown. Here we show that, in the absence of visual information, larval zebrafish (Danio rerio) perform rheotaxis by using flow velocity gradients as navigational cues. We present behavioural data that support a novel algorithm based on such local velocity gradients that fish use to avoid getting dragged by flowing water. Specifically, we show that fish use their mechanosensory lateral line to first sense the curl (or vorticity) of the local velocity vector field to detect the presence of flow and, second, to measure its temporal change after swim bouts to deduce flow direction. These results reveal an elegant navigational strategy based on the sensing of flow velocity gradients and provide a comprehensive behavioural algorithm, also applicable for robotic design, that generalizes to a wide range of animal behaviours in moving fluids.
9 Synaptic organization of visual space in primary visual cortex
M. Florencia Iacaruso, Ioana T. Gasler & Sonja B. Hofer
How a sensory stimulus is processed and perceived depends on the surrounding sensory scene. In the visual cortex, contextual signals can be conveyed by an extensive network of intra- and inter-areal excitatory connections that link neurons representing stimulus features separated in visual space1, 2, 3, 4. However, the connectional logic of visual contextual inputs remains unknown; it is not clear what information individual neurons receive from different parts of the visual field, nor how this input relates to the visual features that a neuron encodes, defined by its spatial receptive field. Here we determine the organization of excitatory synaptic inputs responding to different locations in the visual scene by mapping spatial receptive fields in dendritic spines of mouse visual cortex neurons using two-photon calcium imaging. We find that neurons receive functionally diverse inputs from extended regions of visual space. Inputs representing similar visual features from the same location in visual space are more likely to cluster on neighbouring spines. Inputs from visual field regions beyond the receptive field of the postsynaptic neuron often synapse on higher-order dendritic branches. These putative long-range inputs are more frequent and more likely to share the preference for oriented edges with the postsynaptic neuron when the receptive field of the input is spatially displaced along the axis of the receptive field orientation of the postsynaptic neuron. Therefore, the connectivity between neurons with displaced receptive fields obeys a specific rule, whereby they connect preferentially when their receptive fields are co-oriented and co-axially aligned. This organization of synaptic connectivity is ideally suited for the amplification of elongated edges, which are enriched in the visual environment, and thus provides a potential substrate for contour integration and object grouping.
10 Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway
Vasanthi S. Viswanathan, Matthew J. Ryan, Harshil D. Dhruv…Brent R. Stockwell & Stuart L. Schreiber
（导读 韩宇）高间充质细胞状态与多种抗药性相关，但机制尚不清楚。本文从分子层面描述了人类癌细胞系和类器官中这种耐药性高间充质细胞状态，表明其依赖可作为药物靶点的脂质-过氧化物酶途径。抑制该途径可诱导细胞铁死亡（ferroptic cell death），可作为不同间充质细胞状态中耐药性癌细胞的特征。
Plasticity of the cell state has been proposed to drive resistance to multiple classes of cancer therapies, thereby limiting their effectiveness1, 2, 3, 4. A high-mesenchymal cell state observed in human tumours and cancer cell lines has been associated with resistance to multiple treatment modalities across diverse cancer lineages, but the mechanistic underpinning for this state has remained incompletely understood1, 2, 3, 4, 5,6. Here we molecularly characterize this therapy-resistant high-mesenchymal cell state in human cancer cell lines and organoids and show that it depends on a druggable lipid-peroxidase pathway that protects against ferroptosis, a non-apoptotic form of cell death induced by the build-up of toxic lipid peroxides7, 8. We show that this cell state is characterized by activity of enzymes that promote the synthesis of polyunsaturated lipids. These lipids are the substrates for lipid peroxidation by lipoxygenase enzymes8, 9. This lipid metabolism creates a dependency on pathways converging on the phospholipid glutathione peroxidase (GPX4), a selenocysteine-containing enzyme that dissipates lipid peroxides and thereby prevents the iron-mediated reactions of peroxides that induce ferroptotic cell death8. Dependency on GPX4 was found to exist across diverse therapy-resistant states characterized by high expression of ZEB1, including epithelial–mesenchymal transition in epithelial-derived carcinomas, TGFβ-mediated therapy-resistance in melanoma, treatment-induced neuroendocrine transdifferentiation in prostate cancer, and sarcomas, which are fixed in a mesenchymal state owing to their cells of origin. We identify vulnerability to ferroptic cell death induced by inhibition of a lipid peroxidase pathway as a feature of therapy-resistant cancer cells across diverse mesenchymal cell-state contexts.
11 Cysteine protease cathepsin B mediates radiation-induced bystander effects
Yu Peng（彭宇，清华大学）, Man Zhang, Lingjun Zheng…Jau-Song Yu & Ding Xue（薛定，清华大学，科罗拉多大学）
The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation1, 2, 3. Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.
12 Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription
Gloria Jih, Nahid Iglesias, Mark A. Currie…Benjamin A. Garcia & Danesh Moazed
Heterochromatic DNA domains have important roles in the regulation of gene expression and maintenance of genome stability by silencing repetitive DNA elements and transposons. From fission yeast to mammals, heterochromatin assembly at DNA repeats involves the activity of small noncoding RNAs (sRNAs) associated with the RNA interference (RNAi) pathway. Typically, sRNAs, originating from long noncoding RNAs, guide Argonaute-containing effector complexes to complementary nascent RNAs to initiate histone H3 lysine 9 di- and trimethylation (H3K9me2 and H3K9me3, respectively) and the formation of heterochromatin. H3K9me is in turn required for the recruitment of RNAi to chromatin to promote the amplification of sRNA. Yet, how heterochromatin formation, which silences transcription, can proceed by a co-transcriptional mechanism that also promotes sRNA generation remains paradoxical. Here, using Clr4, the fission yeast Schizosaccharomyces pombe homologue of mammalian SUV39H H3K9 methyltransferases, we design active-site mutations that block H3K9me3, but allow H3K9me2 catalysis. We show that H3K9me2 defines a functionally distinct heterochromatin state that is sufficient for RNAi-dependent co-transcriptional gene silencing at pericentromeric DNA repeats. Unlike H3K9me3 domains, which are transcriptionally silent, H3K9me2 domains are transcriptionally active, contain modifications associated with euchromatic transcription, and couple RNAi-mediated transcript degradation to the establishment of H3K9me domains. The two H3K9me states recruit reader proteins with different efficiencies, explaining their different downstream silencing functions. Furthermore, the transition from H3K9me2 to H3K9me3 is required for RNAi-independent epigenetic inheritance of H3K9me domains. Our findings demonstrate that H3K9me2 and H3K9me3 define functionally distinct chromatin states and uncover a mechanism for the formation of transcriptionally permissive heterochromatin that is compatible with its broadly conserved role in sRNA-mediated genome defence.
13 Crystal structures of agonist-bound human cannabinoid receptor CB1
Tian Hua, Kiran Vemuri, Spyros P. Nikas…Raymond C. Stevens & Zhi-Jie Liu（刘志杰，上海科技大学）
（导读 韩宇）CB1是大麻精神活性成分的主要靶标。本文报道了四氢大麻酚（AM11542）和六氢大麻酚（AM841）结合的CB1晶体结构，分辨率分别为2.80 Å和2.95 Å。与拮抗剂结合状态CB1结构的对比，还为受体活化过程中的CB1的结构变化、以及CB1与受体结合的机制提供了更多认识。
The cannabinoid receptor 1 (CB1) is the principal target of the psychoactive constituent of marijuana, the partial agonist Δ9-tetrahydrocannabinol (Δ9-THC)1. Here we report two agonist-bound crystal structures of human CB1 in complex with a tetrahydrocannabinol (AM11542) and a hexahydrocannabinol (AM841) at 2.80 Å and 2.95 Å resolution, respectively. The two CB1–agonist complexes reveal important conformational changes in the overall structure, relative to the antagonist-bound state2, including a 53% reduction in the volume of the ligand-binding pocket and an increase in the surface area of the G-protein-binding region. In addition, a ‘twin toggle switch’ of Phe2003.36 and Trp3566.48 (superscripts denote Ballesteros–Weinstein numbering3) is experimentally observed and appears to be essential for receptor activation. The structures reveal important insights into the activation mechanism of CB1 and provide a molecular basis for predicting the binding modes of Δ9-THC, and endogenous and synthetic cannabinoids. The plasticity of the binding pocket of CB1 seems to be a common feature among certain class A G-protein-coupled receptors. These findings should inspire the design of chemically diverse ligands with distinct pharmacological properties.
14 The lysosomal potassium channel TMEM175 adopts a novel tetrameric architecture
Changkeun Lee, Jiangtao Guo, Weizhong Zeng, Sunghoon Kim, Ji She, Chunlei Cang, Dejian Ren & Youxing Jiang
（导读 韩宇）TMEM175是溶酶体的K+通道，对于维持溶酶体中的膜电位和pH稳定性很重要。本文解析了Chamaesiphon minutus中四聚体TMEM175（CmTMEM175）的晶体结构，其基本结构与经典的K+通道不同，单体间不存在结构域交换。研究还结合突变实验，揭示了其独特的离子选择性机理。
TMEM175 is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability in lysosomes1. It contains two homologous copies of a six-transmembrane-helix (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels2, 3, 4. The prokaryotic TMEM175 channel, which is present in a subset of bacteria and archaea, contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 channel from Chamaesiphon minutus, CmTMEM175, the architecture of which represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family.
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