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时间: 2017年04月10日 | 作者: admin | 来源: Nature
审校:半夏 访冬 金庄维 赵维杰 【天文学】 A retrograde co-orbital asteroid of Jupiter 与 木星 共轨的 逆行小行星 Paul Wiegert, Martin Connors Christian Veillet http://www.nature.com/nature/journal/v543/n7647/full/


审校:半夏 访冬 金庄维 赵维杰



A retrograde co-orbital asteroid of Jupiter


Paul Wiegert, Martin Connors & Christian Veillet


(导读 吴媛媛)  天文学家于2015年发现了小行星2015 BZ509但当时并未确定其轨道。本研究报道了对2015 BZ509的观察、分析结果,证其与木星共轨并且逆行该状态稳定地持续了约一百万年。暗示与行星共轨的逆行小行星可能比人们之前预测的更加普遍。


Recent theoretical work in celestial mechanics has revealed that an asteroid may orbit stably in the same region as a planet, despite revolving around the Sun in the sense opposite to that of the planet itself. Asteroid 2015 BZ509 was discovered in 2015, but with too much uncertainty in its measured orbit to establish whether it was such a retrograde co-orbital body. Here we report observations and analysis that demonstrates that asteroid 2015 BZ509 is indeed a retrograde co-orbital asteroid of the planet Jupiter. We find that 2015 BZ509 has long-term stability, having been in its current, resonant state for around a million years. This is long enough to preclude precise calculation of the time or mechanism of its injection to its present state, but it may be a Halley-family comet that entered the resonance through an interaction with Saturn. Retrograde co-orbital asteroids of Jupiter and other planets may be more common than previously expected.



Functional materials discovery using energy–structure–function maps


Angeles Pulido, Linjiang Chen, Tomasz Kaczorowsk…Andrew I. Cooper & Graeme M. Day



(导读 张奕林)  设计分子晶体需要与设计宏观材料不同的设计思路。本文结合计算晶体结构预测与性质预测,建了能量-结构-功能图。该图描述候选分子的各种可能结构及其性质。借助这一关系图我们预言了一高孔隙率固体材料,其密度在现有分子晶体中最低。

Molecular crystals cannot be designed in the same manner as macroscopic objects, because they do not assemble according to simple, intuitive rules. Their structures result from the balance of many weak interactions, rather than from the strong and predictable bonding patterns found in metal–organic frameworks and covalent organic frameworks. Hence, design strategies that assume a topology or other structural blueprint will often fail. Here we combine computational crystal structure prediction and property prediction to build energy–structure–function maps that describe the possible structures and properties that are available to a candidate molecule. Using these maps, we identify a highly porous solid, which has the lowest density reported for a molecular crystal so far. Both the structure of the crystal and its physical properties, such as methane storage capacity and guest-molecule selectivity, are predicted using the molecular structure as the only input. More generally, energy–structure–function maps could be used to guide the experimental discovery of materials with any target function that can be calculated from predicted crystal structures, such as electronic structure or mechanical properties.


Ultra-selective high-flux membranes from directly synthesized zeolite nanosheets


Mi Young Jeon, Donghun Kim, Prashant Kumar…J. Ilja Siepmann & Michael Tsapatsis


(导读 王腾)  具有MFI结构的沸石作为选择性催化剂或吸附剂广泛应用但其成本很高。研究人员使用纳米晶种生长法(高产量、低成本)合成了具有超高长径比且厚度仅为5nm2.5个单位晶胞)的MFI纳米片可用于制造纤薄且无缺陷的涂层,有效覆盖多孔基底,并可通过制造具有超选择性高通量的MFI分离膜。


A zeolite with structure type MFI is an aluminosilicate or silicate material that has a three-dimensionally connected pore network, which enables molecular recognition in the size range 0.5–0.6 nm. These micropore dimensions are relevant for many valuable chemical intermediates, and therefore MFI-type zeolites are widely used in the chemical industry as selective catalysts or adsorbents. As with all zeolites, strategies to tailor them for specific applications include controlling their crystal size and shape. Nanometre-thick MFI crystals (nanosheets) have been introduced in pillared and self-pillared (intergrown) architectures, offering improved mass-transfer characteristics for certain adsorption and catalysis applications. Moreover, single (non-intergrown and non-layered) nanosheets have been used to prepare thin membranes that could be used to improve the energy efficiency of separation processes. However, until now, single MFI nanosheets have been prepared using a multi-step approach based on the exfoliation of layered MFI, followed by centrifugation to remove non-exfoliated particles. This top-down method is time-consuming, costly and low-yield and it produces fragmented nanosheets with submicrometre lateral dimensions. Alternatively, direct (bottom-up) synthesis could produce high-aspect-ratio zeolite nanosheets, with improved yield and at lower cost. Here we use a nanocrystal-seeded growth method triggered by a single rotational intergrowth to synthesize high-aspect-ratio MFI nanosheets with a thickness of 5 nanometres (2.5 unit cells). These high-aspect-ratio nanosheets allow the fabrication of thin and defect-free coatings that effectively cover porous substrates. These coatings can be intergrown to produce high-flux and ultra-selective MFI membranes that compare favourably with other MFI membranes prepared from existing MFI materials (such as exfoliated nanosheets or nanocrystals).



A low-spin Fe(III) complex with 100-ps ligand-to-metal charge transfer photoluminescence


Pavel Chábera, Yizhu Liu, Om Prakash…Petter Persson & Kenneth Wärnmark


(导读 肖坤)  在光敏剂、发光器件等应用中,为了保证电荷转移态的长寿命,一般难以将过渡金属配合物中的贵金属替换为廉价金属。研究人员设计出一种低自旋Fe(iii)配合物,具有100ps的配体-金属电荷转移态寿命及室温下光致发光的特性。该研究暗示采用合理设计或许可以将铁基材料用于发光器件和光敏剂。


Transition-metal complexes are used as photosensitizers, in light-emitting diodes, for biosensing and in photocatalysis. A key feature in these applications is excitation from the ground state to a charge-transfer state; the long charge-transfer-state lifetimes typical for complexes of ruthenium and other precious metals are often essential to ensure high performance. There is much interest in replacing these scarce elements with Earth-abundant metals, with iron and copper being particularly attractive owing to their low cost and non-toxicity. But despite the exploration of innovative molecular designs, it remains a formidable scientific challenge to access Earth-abundant transition-metal complexes with long-lived charge-transfer excited states. No known iron complexes are considered photoluminescent at room temperature, and their rapid excited-state deactivation precludes their use as photosensitizers. Here we present the iron complex [Fe(btz)3]3+ (where btz is 3,3′-dimethyl-1,1′-bis(p-tolyl)-4,4′-bis(1,2,3-triazol-5-ylidene)), and show that the superior σ-donor and π-acceptor electron properties of the ligand stabilize the excited state sufficiently to realize a long charge-transfer lifetime of 100 picoseconds (ps) and room-temperature photoluminescence. This species is a low-spin Fe(III) d5 complex, and emission occurs from a long-lived doublet ligand-to-metal charge-transfer (2LMCT) state that is rarely seen for transition-metal complexes. The absence of intersystem crossing, which often gives rise to large excited-state energy losses in transition-metal complexes, enables the observation of spin-allowed emission directly to the ground state and could be exploited as an increased driving force in photochemical reactions on surfaces. These findings suggest that appropriate design strategies can deliver new iron-based materials for use as light emitters and photosensitizers.



Capacity shortfalls hinder the performance of marine protected areas globally


David A. Gill, Michael B. Mascia, Gabby N. Ahmadia…Stephen Woodley & Helen E. Fox


(导读 肖坤)  为保护海洋资源,全球海洋保护区(MPA)设立日益增多,而其管理状况和成效尚不明确。研究人员建立了一套全球MPA管理状况和鱼类种群数据库对MPA进行评估,发现虽然71%的MPA起到积极作用,但人力资金支持不足对保护成效造成严重制约,一味扩张面积会导致保护成效欠佳。


Marine protected areas (MPAs) are increasingly being used globally to conserve marine resources. However, whether many MPAs are being effectively and equitably managed, and how MPA management influences substantive outcomes remain unknown. We developed a global database of management and fish population data (433 and 218 MPAs, respectively) to assess: MPA management processes; the effects of MPAs on fish populations; and relationships between management processes and ecological effects. Here we report that many MPAs failed to meet thresholds for effective and equitable management processes, with widespread shortfalls in staff and financial resources. Although 71% of MPAs positively influenced fish populations, these conservation impacts were highly variable. Staff and budget capacity were the strongest predictors of conservation impact: MPAs with adequate staff capacity had ecological effects 2.9 times greater than MPAs with inadequate capacity. Thus, continued global expansion of MPAs without adequate investment in human and financial capacity is likely to lead to sub-optimal conservation outcomes.



Groundwater depletion embedded in international food trade


Carole Dalin, Yoshihide Wada, Thomas Kastner & Michael J. Puma




(导读 郭思瑶)  基于全球用于特定农作物的不可再生地下水数据和全球贸易数据,研究人员发现灌溉用水中大约11%的不可再生地下水用于国际食品贸易,突显了全球食品与水安全危机。该研究有利于全球食品生产的可持续发展与地下水资源的有效管理。


Recent hydrological modelling and Earth observations have located and quantified alarming rates of groundwater depletion worldwide. This depletion is primarily due to water withdrawals for irrigation, but its connection with the main driver of irrigation, global food consumption, has not yet been explored. Here we show that approximately eleven per cent of non-renewable groundwater use for irrigation is embedded in international food trade, of which two-thirds are exported by Pakistan, the USA and India alone. Our quantification of groundwater depletion embedded in the world’s food trade is based on a combination of global, crop-specific estimates of non-renewable groundwater abstraction and international food trade data. A vast majority of the world’s population lives in countries sourcing nearly all their staple crop imports from partners who deplete groundwater to produce these crops, highlighting risks for global food and water security. Some countries, such as the USA, Mexico, Iran and China, are particularly exposed to these risks because they both produce and import food irrigated from rapidly depleting aquifers. Our results could help to improve the sustainability of global food production and groundwater resource management by identifying priority regions and agricultural products at risk as well as the end consumers of these products.


Transboundary health impacts of transported global air pollution and international trade


Qiang Zhang(张强,清华大学)... Steven J. Davis(加利福尼亚大学)... Jintai Lin(林金泰,北京大学)… Kebin He(贺克斌,清华大学) & Dabo Guan




(导读 郭思瑶)  国际贸易正在导致排放与污染的全球化。研究人员估计了不同地域PM2.5造成的过早死亡,结果发现22%的相关死亡与货物跨国消耗有关。这显示了国际贸易相关的PM2.5污染造成跨国界的健康影响要比长距离大气污染物输送造成的影响更严重。


Millions of people die every year from diseases caused by exposure to outdoor air pollution. Some studies have estimated premature mortality related to local sources of air pollution, but local air quality can also be affected by atmospheric transport of pollution from distant sources. International trade is contributing to the globalization of emission and pollution as a result of the production of goods (and their associated emissions) in one region for consumption in another region. The effects of international trade on air pollutant emissions, air quality and health have been investigated regionally, but a combined, global assessment of the health impacts related to international trade and the transport of atmospheric air pollution is lacking. Here we combine four global models to estimate premature mortality caused by fine particulate matter (PM2.5) pollution as a result of atmospheric transport and the production and consumption of goods and services in different world regions. We find that, of the 3.45 million premature deaths related to PM2.5 pollution in 2007 worldwide, about 12 per cent (411,100 deaths) were related to air pollutants emitted in a region of the world other than that in which the death occurred, and about 22 per cent (762,400 deaths) were associated with goods and services produced in one region for consumption in another. For example, PM2.5pollution produced in China in 2007 is linked to more than 64,800 premature deaths in regions other than China, including more than 3,100 premature deaths in western Europe and the USA; on the other hand, consumption in western Europe and the USA is linked to more than 108,600 premature deaths in China. Our results reveal that the transboundary health impacts of PM2.5 pollution associated with international trade are greater than those associated with long-distance atmospheric pollutant transport.



The true tempo of evolutionary radiation and decline revealed on the Hawaiian archipelago


Jun Y. Lim & Charles R. Marshall


(导读 逸轩)  利用化石和分子系统发生解释类群进化动态略有不足,我们利用地质知悉模型研究夏威夷地区岛屿面积与物种丰富度变化关系,发现地方类群在辐射进化中物种积累速度先快后慢。结果显示景观动态如何驱动大时间尺度进化,并预计许多其他现存类群也处于相似的进化衰退。

Establishing the relationship between rates of change in species richness and biotic and abiotic environmental change is a major goal of evolutionary biology. Although exquisite fossil and geological records provide insight in rare cases, most groups lack high-quality fossil records. Consequently, biologists typically rely on molecular phylogenies to study the diversity dynamics of clades, usually by correlating changes in diversification rate with environmental or trait shifts. However, inferences drawn from molecular phylogenies can be limited owing to the challenge of accounting for extinct species, making it difficult to accurately determine the underlying diversity dynamics that produce them. Here, using a geologically informed model of the relationship between changing island area and species richness for the Hawaiian archipelago, we infer the rates of species richness change for 14 endemic groups over their entire evolutionary histories without the need for fossil data, or molecular phylogenies. We find that these endemic clades underwent evolutionary radiations characterized by initially increasing rates of species accumulation, followed by slow-downs. In fact, for most groups on most islands, their time of evolutionary expansion has long past, and they are now undergoing previously unrecognized long-term evolutionary decline. Our results show how landscape dynamism can drive evolutionary dynamics over broad timescales, including driving species loss that is not readily detected using molecular phylogenies, or without a rich fossil record. We anticipate that examination of other clades where the relationship between environmental change and species richness change can be quantified will reveal that many other living groups have also experienced similarly complex evolutionary trajectories, including long-term and ongoing evolutionary decline.



Neural ensemble dynamics underlying a long-term associative memory


Benjamin F. Grewe, Jan Gründemann, Lacey J. Kitch…Andreas Lüthi & Mark J. Schnitzer


(导读 卓思琪)  神经集成编码联想记忆的方式尚未可知。本文研究了小鼠在畏惧学习和畏惧消除过程中基底外侧杏仁核神经元的Ca2+动态变化,发现畏惧条件可双向调节单个细胞对条件刺激(CS)的响应,这使响应CS的神经集成表征趋于非条件刺激(US)表征。CS-US联合的强度可以用来预测小鼠的行为调节水平。


The brain’s ability to associate different stimuli is vital for long-term memory, but how neural ensembles encode associative memories is unknown. Here we studied how cell ensembles in the basal and lateral amygdala encode associations between conditioned and unconditioned stimuli (CS and US, respectively). Using a miniature fluorescence microscope, we tracked the Ca2+dynamics of ensembles of amygdalar neurons during fear learning and extinction over 6 days in behaving mice. Fear conditioning induced both up- and down-regulation of individual cells’ CS-evoked responses. This bi-directional plasticity mainly occurred after conditioning, and reshaped the neural ensemble representation of the CS to become more similar to the US representation. During extinction training with repetitive CS presentations, the CS representation became more distinctive without reverting to its original form. Throughout the experiments, the strength of the ensemble-encoded CS–US association predicted the level of behavioural conditioning in each mouse. These findings support a supervised learning model in which activation of the US representation guides the transformation of the CS representation.


Mapping of a non-spatial dimension by the hippocampal–entorhinal circuit


Dmitriy Aronov, Rhino Nevers & David W. Tank


(导读 董堃)  海马和内嗅皮层在空间导航任务中的神经活动被认为和定位、速度以及对界限的揣测有关。然而本研究利用大鼠行为学实验证实,海马-内嗅皮层神经环路不仅在空间导航中发挥重要作用,在多种记忆主导的行为活动中也占有一席之地,这对理解复杂的认知过程具有重要意义。

During spatial navigation, neural activity in the hippocampus and the medial entorhinal cortex (MEC) is correlated to navigational variables such as location, head direction, speed, and proximity to boundaries. These activity patterns are thought to provide a map-like representation of physical space. However, the hippocampal–entorhinal circuit is involved not only in spatial navigation, but also in a variety of memory-guided behaviours. The relationship between this general function and the specialized spatial activity patterns is unclear. A conceptual framework reconciling these views is that spatial representation is just one example of a more general mechanism for encoding continuous, task-relevant variables. Here we tested this idea by recording from hippocampal and entorhinal neurons during a task that required rats to use a joystick to manipulate sound along a continuous frequency axis. We found neural representation of the entire behavioural task, including activity that formed discrete firing fields at particular sound frequencies. Neurons involved in this representation overlapped with the known spatial cell types in the circuit, such as place cells and grid cells. These results suggest that common circuit mechanisms in the hippocampal–entorhinal system are used to represent diverse behavioural tasks, possibly supporting cognitive processes beyond spatial navigation.


A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer


Felipe de Sousa e Melo, Antonina V. Kurtova, Jonathan M. Harnoss…Robert Piskol & Frederic J. de Sauvage


导读 Nature自然科研  肿瘤干细胞被认为是肿瘤进展和转移的驱动力并可能成为控制癌症转移的靶点。,但在多数癌症中还未找到确凿的实验证据。本研究发现在结肠癌中, Lgr5是肿瘤干细胞的标志物。Lgr5+干细胞的去除限制了肿瘤的生长以及肝脏转移灶的形成和生长。


Cancer stem cells (CSCs) have been hypothesized to represent the driving force behind tumour progression and metastasis, making them attractive cancer targets. However, conclusive experimental evidence for their functional relevance is still lacking for most malignancies. Here we show that the leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) identifies intestinal CSCs in mouse tumours engineered to recapitulate the clinical progression of human colorectal cancer. We demonstrate that selective Lgr5+ cell ablation restricts primary tumour growth, but does not result in tumour regression. Instead, tumours are maintained by proliferative Lgr5 cells that continuously attempt to replenish the Lgr5+ CSC pool, leading to rapid re-initiation of tumour growth upon treatment cessation. Notably, CSCs are critical for the formation and maintenance of liver metastasis derived from colorectal cancers. Together, our data highlight distinct CSC dependencies for primary versus metastasic tumour growth, and suggest that targeting CSCs may represent a therapeutic opportunity for managing metastatic disease.


LACTB is a tumour suppressor that modulates lipid metabolism and cell state


Zuzana Keckesova,   Joana Liu Donaher,  Jasmine De Cock…Jean E. Vance     & Robert A. Weinberg




导读 郭思瑶  研究人员通过检测瘤细胞与正常分化细胞基因表达谱的不同,并进行小鼠与人类的体内、体外实验,发现线粒体蛋白LACTB有抑制乳腺癌细胞扩增的潜力。其机制包含乳腺癌细胞线粒体脂质代谢和分化程序的改变,这涉及线粒体磷酸酯丝氨酸脱羧酶水平的降低。这项研究揭示了肿瘤抑制的新机制。


Post-mitotic, differentiated cells exhibit a variety of characteristics that contrast with those of actively growing neoplastic cells, such as the expression of cell-cycle inhibitors and differentiation factors. We hypothesized that the gene expression profiles of these differentiated cells could reveal the identities of genes that may function as tumour suppressors. Here we show, using in vitro and in vivo studies in mice and humans, that the mitochondrial protein LACTB potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial phosphatidylserine decarboxylase, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. These observations uncover a novel mitochondrial tumour suppressor and demonstrate a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells, thereby revealing a previously undescribed mechanism of tumour suppression.





Somatic mutations reveal asymmetric cellular dynamics in the early human embryo


Young Seok Ju, Inigo Martincorena, Moritz Gerstung…Peter J. Campbell & Michael R. Stratton


(导读 峰子)  发生于胚胎早期的体细胞突变会复制到成人体细胞中,可能导致多种疾病或异常。本研究运用全基因组测序,对241位成人的血液细胞进行测序,鉴定出163个早期胚胎突变并对其进行分析,为早期人类胚胎发生的体细胞突变率、突变过程及突变发展提供见解。


Somatic cells acquire mutations throughout the course of an individual’s life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.




Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens


Michael S. Khodadoust, Niclas Olsson, Lisa E. Wagar…Joshua E. Elias & Ash A. Alizadeh


(导读 峰子)  目前,肿瘤抗原的发现与鉴定仍是一项较大的挑战。本研究报道了一种基因组学与蛋白质组学结合的方法,从17名套细胞淋巴瘤患者体内鉴定出了由MHC复合体呈现于癌细胞表面的新抗原,这些抗原能够被识别并激活CD4+T细胞,进而特异性杀死肿瘤细胞。该工作为开发个性化免疫疗法提供了理论基础。


Cancer somatic mutations can generate neoantigens that distinguish malignant from normal cells. However, the personalized identification and validation of neoantigens remains a major challenge. Here we discover neoantigens in human mantle-cell lymphomas by using an integrated genomic and proteomic strategy that interrogates tumour antigen peptides presented by major histocompatibility complex (MHC) class I and class II molecules. We applied this approach to systematically characterize MHC ligands from 17 patients. Remarkably, all discovered neoantigenic peptides were exclusively derived from the lymphoma immunoglobulin heavy- or light-chain variable regions. Although we identified MHC presentation of private polymorphic germline alleles, no mutated peptides were recovered from non-immunoglobulin somatically mutated genes. Somatic mutations within the immunoglobulin variable region were almost exclusively presented by MHC class II. We isolated circulating CD4+ T cells specific for immunoglobulin-derived neoantigens and found these cells could mediate killing of autologous lymphoma cells. These results demonstrate that an integrative approach combining MHC isolation, peptide identification, and exome sequencing is an effective platform to uncover tumour neoantigens. Application of this strategy to human lymphoma implicates immunoglobulin neoantigens as targets for lymphoma immunotherapy.



Effective combinatorial immunotherapy for castration-resistant prostate cancer


Xin Lu, James W. Horner, Erin Paul…Y. Alan Wang & Ronald A. DePinho


(导读 峰子)  转移性去势抵抗性前列腺癌(mCRPC)对使用针对CTLA4PD1/PD-L1抗体的免疫检查点阻断疗法具有较大抗性,本研究使用mCRPC嵌合体小鼠模型,发现当髓源性抑制细胞(MDSC)靶向疗法与免疫检查点阻断疗法相结合时,两者显示出强大的协同效应,为临床治疗mCRPC提供了一种潜在的治疗方案。


A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b+Gr1+) promote tumour initiation and progression. These observations prompted us to hypothesize that robust immunotherapy responses in mCRPC may be elicited by the combined actions of immune checkpoint blockade agents together with targeted agents that neutralize MDSCs yet preserve T-cell function. Here we develop a novel chimaeric mouse model of mCRPC to efficiently test combination therapies in an autochthonous setting. Combination of anti-CTLA4 and anti-PD1 engendered only modest efficacy. Targeted therapy against mCRPC-infiltrating MDSCs, using multikinase inhibitors such as cabozantinib and BEZ235, also showed minimal anti-tumour activities. Strikingly, primary and metastatic CRPC showed robust synergistic responses when immune checkpoint blockade was combined with MDSC-targeted therapy. Mechanistically, combination therapy efficacy stemmed from the upregulation of interleukin-1 receptor antagonist and suppression of MDSC-promoting cytokines secreted by prostate cancer cells. These observations illuminate a clinical path hypothesis for combining immune checkpoint blockade with MDSC-targeted therapies in the treatment of mCRPC.



The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1


Andrew A. Wylie, Joseph Schoepfer, Wolfgang Jahnke…Nicholas J. Keen & William R. Sellers


(导读 峰子)  慢性髓样白血病由BCR-ABL1融合癌蛋白驱动,针对催化位点的ABL1激酶抑制剂已取得良好疗效,但容易产生抗性,约50%的病人愈后复发。本研究报道了临床试验ABL1变构抑制剂ABL001,该药靶向ABL1的肉豆蔻酰口袋而致其失活,ABL001与催化性抑制剂nilotinib的联用可完全控制疾病,且终止治疗后无复发。


Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR–ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.



Energy transduction and alternating access of the mammalian ABC transporter P-glycoprotein


Brandy Verhalen, Reza Dastvan, Sundarapandian Thangapandian…Emad Tajkhorshid & Hassane S. Mchaourab



(导读 峰子)  ATP结合盒(ABC)转运蛋白利用ATP水解能量进行底物运输的结构动态未知。本研究利用电子-电子双共振及分子动力学模拟描述了此过程中鼠ABC外排性转运体P-糖蛋白(Pgp)与ATP和底物交替结合的构象循环,阐明了Pgp中核苷酸结合结构域和跨膜结构域的构象改变,揭示了ABC转运蛋白底物转出中的结构变化。


ATP binding cassette (ABC) transporters of the exporter class harness the energy of ATP hydrolysis in the nucleotide-binding domains (NBDs) to power the energetically uphill efflux of substrates by a dedicated transmembrane domain (TMD). Although numerous investigations have described the mechanism of ATP hydrolysis and defined the architecture of ABC exporters, a detailed structural dynamic understanding of the transduction of ATP energy to the work of substrate translocation remains elusive. Here we used double electron–electron resonance and molecular dynamics simulations to describe the ATP- and substrate-coupled conformational cycle of the mouse ABC efflux transporter P-glycoprotein (Pgp; also known as ABCB1), which has a central role in the clearance of xenobiotics and in cancer resistance to chemotherapy. Pairs of spin labels were introduced at residues selected to track the putative inward-facing to outward-facing transition. Our findings illuminate how ATP energy is harnessed in the NBDs in a two-stroke cycle and elucidate the consequent conformational motion that reconfigures the TMD, two critical aspects of Pgp transport mechanism. Along with a fully atomistic model of the outward-facing conformation in membranes, the insight into Pgp conformational dynamics harmonizes mechanistic and structural data into a novel perspective on ATP-coupled transport and reveals mechanistic divergence within the efflux class of ABC transporters.