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Nature 论文导读_0824

时间: 2017年09月05日 | 作者: admin | 来源: 未知
Nature 20170824 1 A randomized synbiotic trial to prevent sepsis among infants in rural India 【生物】一项为预防印度农村新生儿败血症的合生素随机试验 Pinaki Panigrahi, Sailajanandan Parida, Nimai C. Nanda…Nigel P

Nature 20170824

1 A randomized synbiotic trial to prevent sepsis among infants in rural India


Pinaki Panigrahi, Sailajanandan Parida, Nimai C. Nanda…Nigel Paneth & Ira H. Gewolb


(导读 寒雨)败血症每年导致大量新生儿死亡。本研究以安慰剂为对照,对印度农村4,556名婴儿展开口服合生素制剂(植物乳杆菌和低聚果糖的组合)随机试验,监测60天后,发现实验组患败血症和死亡的风险显著下降,血培养败血症和呼吸道感染也明显减少,表明该合生素对新生儿败血症可能是一种有效干预。


Sepsis in early infancy results in one million annual deaths worldwide, most of them in developing countries. No efficient means of prevention is currently available. Here we report on a randomized, double-blind, placebo-controlled trial of an oral synbiotic preparation (Lactobacillus plantarum plus fructooligosaccharide) in rural Indian newborns. We enrolled 4,556 infants that were at least 2,000g at birth, at least 35 weeks of gestation, and with no signs of sepsis or other morbidity, and monitored them for 60 days. We show a significant reduction in the primary outcome (combination of sepsis and death) in the treatment arm (risk ratio 0.60, 95% confidence interval 0.48–0.74), with few deaths (4 placebo, 6 synbiotic). Significant reductions were also observed for culture-positive and culture-negative sepsis and lower respiratory tract infections. These findings suggest that a large proportion of neonatal sepsis in developing countries could be effectively prevented using a synbiotic containing L. plantarum ATCC-202195.


2 Correction of a pathogenic gene mutation in human embryos


Hong Ma, Nuria Marti-Gutierrez, Sang-Wook Park…Sanjiv Kaul & Shoukhrat Mitalipov



Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.



(导读 郭怿暄)基因组编辑具有对生殖细胞突变进行纠正的潜力。本研究通过CRISPR-Cas9技术对人类植入前胚胎MYBPC3基因的杂合突变进行修正,利用母源同源野生型基因作为模板高效地修复了父源的基因突变。对细胞周期的控制有效地避免突变嵌合体的形成。作为植入前胚胎遗传诊断的补充技术,该方法具有巨大潜能,但在投入临床前还需进行多方验证。

3 The primed SNARE–complexin–synaptotagmin complex for neuronal exocytosis


Qiangjun Zhou, Peng Zhou, Austin L. Wang…homas C. Südhof & Axel T. Brunger


Synaptotagmin, complexin, and neuronal SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins mediate evoked synchronous neurotransmitter release, but the molecular mechanisms mediating the cooperation between these molecules remain unclear. Here we determine crystal structures of the primed pre-fusion SNARE–complexin–synaptotagmin-1 complex. These structures reveal an unexpected tripartite interface between synaptotagmin-1 and both the SNARE complex and complexin. Simultaneously, a second synaptotagmin-1 molecule interacts with the other side of the SNARE complex via the previously identified primary interface. Mutations that disrupt either interface in solution also severely impair evoked synchronous release in neurons, suggesting that both interfaces are essential for the primed pre-fusion state. Ca2+ binding to the synaptotagmin-1 molecules unlocks the complex, allows full zippering of the SNARE complex, and triggers membrane fusion. The tripartite SNARE–complexin–synaptotagmin-1 complex at a synaptic vesicle docking site has to be unlocked for triggered fusion to start, explaining the cooperation between complexin and synaptotagmin-1 in synchronizing evoked release on the sub-millisecond timescale.


(导读 吴媛媛)突触结合蛋白Synaptotagmin, complexin神经元SNARE蛋白共同介导神经递质的释放但三者之间的协调控机制尚不清楚。本研究报道了囊泡融合前SNARE–complexin–synaptotagmin-1复合物的晶体结构揭示了synaptotagmin-1SNARE复合体及complexin之间两种重要的交接方式,以及三种蛋白的互作在神经元胞吐作用的重要作用


4 Distinguishing spin-aligned and isotropic black hole populations with gravitational waves


 Will M. Farr, Simon Stevenson, M. Coleman Miller, Ilya Mandel, Ben Farr & Alberto Vecchio






(导读:阿金)直接探测来自双黑洞合并的引力波有助于揭开双黑洞形成之谜。彼此独立的致密天体通过相互作用形成的双黑洞拥有各向同性的,由成对出生的恒星演化而成的双黑洞则拥有特殊取向。本研究分析了已报告的四次双黑洞合并事件的数据,发现在2.4 σ 置信度上,等效自旋没有特殊取向。



The direct detection of gravitational waves from merging binary black holes opens up a window into the environments in which binary black holes form. One signature of such environments is the angular distribution 角度分布 of the black hole spins. Binary systems that formed through dynamical interactions between already-compact objects are expected to have isotropic spin orientations 各向同性的旋转倾向(that is, the spins of the black holes are randomly oriented with respect to the orbit of the binary system), whereas those that formed from pairs of stars born together are more likely to have spins that are preferentially aligned with the orbit. The best-measured combination of spin parameters for each of the four likely binary black hole detections GW150914, LVT151012, GW151226 and GW170104 is the ‘effective’ spin. Here we report that, if the magnitudes of the black hole spins are allowed to extend to high values, the effective spins for these systems indicate a 0.015 odds ratio against an aligned angular distribution compared to an isotropic one. When considering the effect of ten additional detections, this odds ratio decreases to 2.9×107 against alignment. The existing preference for either an isotropic spin distribution or low spin magnitudes for the observed systems will be confirmed (or overturned) confidently in the near future.



5 Large turbulent reservoirs of cold molecular gas around high-redshift starburst galaxies


 E. Falgarone, M. A. Zwaan, B. Godard…I. Oteo& F. Walter






(导读 阿金)分析星暴星系中的甲基炔CH+有助于了解活动星系核反馈和星系成长间的相互影响。本研究报道了6个高红移(2.5)的透镜星暴星系光谱中的CH+的辐射、吸收谱线,发现辐射谱线产生于热星系风带来的强力冲击波,而吸收谱线表明高涡度冷气体的存在。结果暗示控制恒星形成的星系反馈延长了星暴阶段。


Starburst galaxies at the peak of cosmic star formation are among the most extreme star-forming engines in the Universe, producing stars over about 100 million years. The star-formation rates of these galaxies, which exceed 100 solar masses per year, require large reservoirs of cold molecular gas to be delivered to their cores, despite strong feedback from stars or active galactic nuclei. Consequently, starburst galaxies are ideal for studying the interplay between this feedback and the growth of a galaxy. The methylidyne cation, CH+, is a most useful molecule for such studies because it cannot form in cold gas without suprathermal energy input, so its presence indicates dissipation of mechanical energy or strong ultraviolet irradiation. Here we report the detection of CH+ (J=1–0) emission and absorption lines in the spectra 光谱 of six lensed starburst galaxies at redshifts near 2.5. This line has such a high critical density for excitation that it is emitted only in very dense gas, and is absorbed in low-density gas. We find that the CH+ emission lines, which are broader than 1,000 kilometres per second, originate in dense shock waves powered by hot galactic winds. The CH+ absorption lines reveal highly turbulent reservoirs of cool (about 100 kelvin), low-density gas, extending far (more than 10 kiloparsecs) outside the starburst galaxies (which have radii of less than 1 kiloparsec). We show that the galactic winds sustain turbulence in the 10-kiloparsec-scale environments of the galaxies, processing these environments into multiphase, gravitationally bound reservoirs. However, the mass outflow rates are found to be insufficient to balance the star-formation rates. Another mass input is therefore required for these reservoirs, which could be provided by ongoing mergers or cold-stream accretion. Our results suggest that galactic feedback, coupled jointly to turbulence and gravity, extends the starburst phase of a galaxy instead of quenching it.


6 Epitaxy of advanced nanowire quantum devices


Sasa Gazibegovic, Diana Car, Hao Zhang…Chris J. Palmstrøm & Erik P. A. M. Bakkers







Semiconductor nanowires are ideal for realizing various low-dimensional quantum devices. In particular, topological phases of matter hosting non-Abelian quasiparticles (such as anyons) can emerge when a semiconductor nanowire with strong spin–orbit coupling is brought into contact with a superconductor. To exploit the potential of non-Abelian anyons—which are key elements of topological quantum computing—fully, they need to be exchanged in a well-controlled braiding operation. Essential hardware for braiding is a network of crystalline nanowires coupled to superconducting islands. Here we demonstrate a technique for generic bottom-up synthesis of complex quantum devices with a special focus on nanowire networks with a predefined number of superconducting islands. Structural analysis confirms the high crystalline quality of the nanowire junctions, as well as an epitaxial superconductor–semiconductor interface. Quantum transport measurements of nanowire ‘hashtags’ reveal Aharonov–Bohm and weak-antilocalization effects, indicating a phase-coherent system with strong spin–orbit coupling. In addition, a proximity-induced hard superconducting gap (with vanishing sub-gap conductance) is demonstrated in these hybrid superconductor–semiconductor nanowires, highlighting the successful materials development necessary for a first braiding experiment. Our approach opens up new avenues for the realization of epitaxial three-dimensional quantum architectures which have the potential to become key components of various quantum devices.


7 Molecular magnetic hysteresis at 60 kelvin in dysprosocenium


Conrad A. P. Goodwin, Fabrizio Ortu, Daniel Reta, Nicholas F. Chilton & David P. Mills







Lanthanides have been investigated extensively for potential applications in quantum information processing and high-density data storage at the molecular and atomic scale. Experimental achievements include reading and manipulating single nuclear spins, exploiting atomic clock transitions for robust qubits and, most recently, magnetic data storage in single atoms. Single-molecule magnets exhibit magnetic hysteresis of molecular origin—a magnetic memory effect and a prerequisite of data storage—and so far lanthanide examples have exhibited this phenomenon at the highest temperatures. However, in the nearly 25 years since the discovery of single-molecule magnets, hysteresis temperatures have increased from 4 kelvin to only about 14 kelvin using a consistent magnetic field sweep rate of about 20 oersted per second, although higher temperatures have been achieved by using very fast sweep rates(for example, 30 kelvin with 200 oersted per second). Here we report a hexa-tert-butyldysprosocenium complex—[Dy(Cpttt)2][B(C6F5)4], with Cpttt={C5H2tBu3-1,2,4} and tBu=C(CH3)3—which exhibits magnetic hysteresis at temperatures of up to 60 kelvin at a sweep rate of 22 oersted per second. We observe a clear change in the relaxation dynamics at this temperature, which persists in magnetically diluted samples, suggesting that the origin of the hysteresis is the localized metal–ligand vibrational modes that are unique to dysprosocenium. Ab initio calculations of spin dynamics demonstrate that magnetic relaxation at high temperatures is due to local molecular vibrations. These results indicate that, with judicious molecular design, magnetic data storage in single molecules at temperatures above liquid nitrogen should be possible.


8 Minimal geological methane emissions during the Younger Dryas–Preboreal abrupt warming event


Vasilii V. Petrenko, Andrew M. Smith, Hinrich Schaefer…Ray F. Weiss & Jeffrey P. Severinghaus





(导读:阿金)本研究通过冰核测量数据表明从新仙女木期至前北方期的温暖间隔期(约11,600 年前)地质甲烷排放量平均不超過1540万吨/年,说明目前地质甲烷排放量被高估而人为化石甲烷排放量被低估,同时证明当时大气甲烷的增加来自湿地排放,但不排除未来源自古碳库的大量甲烷排放。


Methane (CH4) is a powerful greenhouse gas and plays a key part in global atmospheric chemistry. Natural geological emissions (fossil methane vented naturally from marine and terrestrial seeps and mud volcanoes) are thought to contribute around 52 teragrams of methane per year to the global methane source, about 10 per cent of the total, but both bottom-up methods (measuring emissions) and top-down approaches (measuring atmospheric mole fractions and isotopes) for constraining these geological emissions have been associated with large uncertainties. Here we use ice core measurements to quantify the absolute amount of radiocarbon-containing methane (14CH4) in the past atmosphere and show that geological methane emissions were no higher than 15.4 teragrams per year (95 per cent confidence), averaged over the abrupt warming event that occurred between the Younger Dryas and Preboreal intervals, approximately 11,600 years ago. Assuming that past geological methane emissions were no lower than today, our results indicate that current estimates of today’s natural geological methane emissions (about 52 teragrams per year) are too high and, by extension, that current estimates of anthropogenic fossil methane emissions are too low. Our results also improve on and confirm earlier findings that the rapid increase of about 50 per cent in mole fraction of atmospheric methane at the Younger Dryas–Preboreal event was driven by contemporaneous methane from sources such as wetlands; our findings constrain the contribution from old carbon reservoirs (marine methane hydrates, permafrost and methane trapped under ice) to 19 per cent or less (95 per cent confidence). To the extent that the characteristics of the most recent deglaciation and the Younger Dryas–Preboreal warming are comparable to those of the current anthropogenic warming, our measurements suggest that large future atmospheric releases of methane from old carbon sources are unlikely to occur.





9 Mutation predicts 40 million years of fly wing evolution


David Houle, Geir H. Bolstad, Kim van der Linde & Thomas F. Hansen



Mutation enables evolution, but the idea that adaptation is also shaped by mutational variation is controversial. Simple evolutionary hypotheses predict such a relationship if the supply of mutations constrains evolution, but it is not clear that constraints exist, and, even if they do, they may be overcome by long-term natural selection. Quantification of the relationship between mutation and phenotypic divergence among species will help to resolve these issues. Here we use precise data on over 50,000 Drosophilid fly wings to demonstrate unexpectedly strong positive relationships between variation produced by mutation, standing genetic variation, and the rate of evolution over the last 40 million years. Our results are inconsistent with simple constraint hypotheses because the rate of evolution is very low relative to what both mutational and standing variation could allow. In principle, the constraint hypothesis could be rescued if the vast majority of mutations are so deleterious that they cannot contribute to evolution, but this also requires the implausible assumption that deleterious mutations have the same pattern of effects as potentially advantageous ones. Our evidence for a strong relationship between mutation and divergence in a slowly evolving structure challenges the existing models of mutation in evolution.


(导读 郭怿暄)进化制约假说认为,基因突变量会制约进化的速率,但此假说备受争议。本研究观察了超过5万只果蝇科动物的翅膀脉络,发现由突变产生的变异、既有遗传差异、以及过去4000万年的进化率三者间存在极强的正相关关系但观测到的进化速率显著低于基因差异所允许的速率,这对制约假说提出了挑战。



10 Stromal R-spondin orchestrates gastric epithelial stem cells and gland homeostasis


Michael Sigal, Catriona Y. Logan, Marta Kapalczynska…Manuel R. Amieva & Thomas F. Meyer


(导读 寒雨)胃病原幽门螺杆菌(H. pylori )可以激活胃干细胞并加快上皮更新,而Wnt信号在干细胞识别和上皮再生中有重要作用。本研究发现H. pylori 感染可以增加基质R-spondin 3的表达,从而扩增快速增值的Axin2阳性细胞群,从而造成过度增殖和腺体增生。微环境基质细胞控制和改变上皮细胞动态的能力帮助维持组织再生和稳态的平衡。

The constant regeneration of stomach epithelium is driven by long-lived stem cells123, but the mechanism that regulates their turnover is not well understood. We have recently found that the gastric pathogen Helicobacter pylori can activate gastric stem cells and increase epithelial turnover4, while Wnt signalling is known to be important for stem cell identity and epithelial regeneration in several tissues5. Here we find that antral Wnt signalling, marked by the classic Wnt target gene Axin2, is limited to the base and lower isthmus of gastric glands, where the stem cells reside. Axin2 is expressed by Lgr5+ cells, as well as adjacent, highly proliferative Lgr5 cells that are able to repopulate entire glands, including the base, upon depletion of the Lgr5+ population. Expression of both Axin2 and Lgr5 requires stroma-derived R-spondin 3 produced by gastric myofibroblasts proximal to the stem cell compartment. Exogenous R-spondin administration expands and accelerates proliferation of Axin2+/Lgr5but not Lgr5+ cells. Consistent with these observations, H. pylori infection increases stromal R-spondin 3 expression and expands the Axin2+ cell pool to cause hyperproliferation and gland hyperplasia. The ability of stromal niche cells to control and adapt epithelial stem cell dynamics constitutes a sophisticated mechanism that orchestrates epithelial regeneration and maintenance of tissue integrity.


11 Polylox barcoding reveals haematopoietic stem cell fates realized in vivo


Weike Pei, Thorsten B. Feyerabend, Jens Rössler…Thomas Höfer & Hans-Reimer Rodewald




(导读 郭思瑶)对复杂器官和组织在单个细胞水平的发育解读仍是挑战。为此,科学家研发出一种新型细胞标记,即基于Cre–loxP人工重组DNA位点,可广泛应用于内源性条形码标记。其技术核心是利用位点特异性重组进行基因打靶 。利用该技术追踪细胞起源,证明了多能干细胞开始的分层发育树确实存在于造血系统。

Developmental deconvolution of complex organs and tissues at the level of individual cells remains challenging. Non-invasive genetic fate mapping1 has been widely used, but the low number of distinct fluorescent marker proteins limits its resolution. Much higher numbers of cell markers have been generated using viral integration sites, viral barcodes3, and strategies based on transposons4 and CRISPR–Cas9 genome editing5; however, temporal and tissue-specific induction of barcodes in situ has not been achieved. Here we report the development of an artificial DNA recombination locus (termed Polylox) that enables broadly applicable endogenous barcoding based on the Cre–loxP recombination system67Polyloxrecombination in situ reaches a practical diversity of several hundred thousand barcodes, allowing tagging of single cells. We have used this experimental system, combined with fate mapping, to assess haematopoietic stem cell (HSC) fates in vivo. Classical models of haematopoietic lineage specification assume a tree with few major branches. More recently, driven in part by the development of more efficient single-cell assays and improved transplantation efficiencies, different models have been proposed, in which unilineage priming may occur in mice and humans at the level of HSCs8910. We have introduced barcodes into HSC progenitors in embryonic mice, and found that the adult HSC compartment is a mosaic of embryo-derived HSC clones, some of which are unexpectedly large. Most HSC clones gave rise to multilineage or oligolineage fates, arguing against unilineage priming, and suggesting coherent usage of the potential of cells in a clone. The spreading of barcodes, both after induction in embryos and in adult mice, revealed a basic split between common myeloid–erythroid development and common lymphocyte development, supporting the long-held but contested view of a tree-like haematopoietic structure.


12 cGAS surveillance of micronuclei links genome instability to innate immunity


Karen J. Mackenzie, Paula Carroll, Carol-Anne Martin…Martin A. M. Reijns & Andrew P. Jackson




(导读 郭思瑶)细胞质内双链DNA感应器环状GMP–AMP合成酶(cGAS)可在自体免疫紊乱和DNA损伤时被激活。科学家利用活细胞激光显微解剖和单细胞转录组技术,他们发现形成微核的细胞内会诱导干扰素刺激基因的表达。微核是一种重要的免疫调节DNA,通过cGAS识别微核可能是一种细胞自体免疫监督机制。

DNA is strictly compartmentalized within the nucleus to prevent autoimmunity1; despite this, cyclic GMP–AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage23456. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis7, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.


13 Mitotic progression following DNA damage enables pattern recognition within micronuclei


Shane M. Harding, Joseph L. Benci, Jerome Irianto, Dennis E. Discher, Andy J. Minn & Roger A. Greenberg




(导读 郭思瑶)癌症的毒性疗法之后免疫细胞会延迟到达,其过程尚不清楚。科学家发现双链DNA断裂后的有丝分裂进程会形成微核作为模式识别受体环状GMP–AMP合成酶(cGAS)的储存库。抑制癌细胞有丝分裂进展或模式识别的丢失会阻止微核形成,从而减少免疫反应。这说明细胞周期的短暂调控是结合毒性药物和免疫检查点抑制剂时要考虑的一项重要因素。

Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy1. A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP–AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)–cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.


14 CDK4/6 inhibition triggers anti-tumour immunity

【生物】抑制CDK4 / 6触发抗肿瘤免疫

Shom Goel, Molly J. DeCristo, April C. Watt…Sandra S. McAllister & Jean J. Zhao




(导读 郭思瑶)细胞周期蛋白依赖性激酶46 (CDK4/6)是细胞周期的重要驱动力,是恶性肿瘤形成和生长所必须的。科学家利用乳腺癌和其他实体癌小鼠模型发现选择性CDK4/6抑制剂不仅抑制癌细胞分裂进程,还促进抗肿瘤免疫反应。其主要通过增加癌细胞抗原呈递和减少调节性T淋巴细胞增殖来实现。这为抗肿瘤治疗提供了新思路。

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies12. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours34. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells5. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.



15 Vaccine-driven pharmacodynamic dissection and mitigation of fenethylline psychoactivity


Cody J. Wenthur, Bin Zhou & Kim D. Janda


Fenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and ‘pharmacoterrorism’ in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system. Although the psychoactive properties of fenethylline have been reported to differ from those of other synthetic stimulants, the in vivo chemical complexity it manifests upon ingestion has impeded efforts to unambiguously identify the specific species responsible for these effects. Here we develop a ‘dissection through vaccination’ approach, called DISSECTIV, to mitigate the psychoactive effects of fenethylline and show that its rapid-onset and distinct psychoactive properties are facilitated by functional synergy between theophylline and amphetamine. Our results demonstrate that incremental vaccination against a single chemical species within a multi-component mixture can be used to uncover emergent properties arising from polypharmacological activity. We anticipate that DISSECTIV will be used to expose unidentified active chemical species and resolve pharmacodynamic interactions within other chemically complex systems, such as those found in counterfeit or illegal drug preparations, post-metabolic tissue samples and natural product extracts.

(导读 卓思琪)苯甲锡林是合成神经兴奋剂,其体内代谢带来的化学复杂度对药理学研究带来了阻碍。本文开发了“疫苗接种分析”(DISSECTIV)方法可缓和苯甲锡林的神经作用,并以此发现苯甲锡林的神经作用由茶碱和苯丙胺协同作用产生。通过增加针对某一化学物质的疫苗接种,可发现多向药理学活性带来的变化。研究者希望DISSECTIV能用于开发化学物质的未知活性,并解决其与复杂化学系统在药效上的相互作用。


16 Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure


Xiangyu Liu, Seungkirl Ahn, Alem W. Kahsai…Robert J. Lefkowitz & Brian K. Kobilka


(导读 寒雨)β受体阻滞剂是最常用的药物之一,Cmpd-15是第一个别构β-受体阻滞剂。本文报道了与Cmpd-15PA结合的β2AR的结构,Cmpd-15PA结合在跨膜螺旋1267的胞内端与胞内环1以及螺旋8形成的底物口袋将该结构与活化/非活化状态下β2AR结构进行对比,进一步揭示了Cmpd-15调节激动剂的结合亲和力和信号传导的机制。


G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β2 adrenergic receptor (β2AR) that was recently isolated from a DNA-encoded small-molecule library1. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the β2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the β2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.