《科学》（20190517出版）一周论文导读

翻译 | 宗华

Science, 17 May 2019, Vol. 364, No. 6441

《科学》2019年5月17日，第6441期364卷

健康Health

Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway

通过抑制MYC-WWP1抑制通路重新激活PTEN肿瘤抑制因子用于癌症治疗

▲ 作者：Yu-Ru Lee, Ming Chen, Jonathan D. Lee, et al

▲ 链接：

https://science.sciencemag.org/content/364/6441/eaau0159

▲ 摘要：

长期以来，科学家致力于通过激活肿瘤抑制因子治疗人类癌症，但该策略一直难以实现。

PTEN是一种重要的肿瘤抑制磷酸酶，其二聚体结构活跃于细胞膜上。泛素E3连接酶WWP1的多泛素化，可抑制PTEN的二聚化、膜募集及其功能。无论是基因消融还是药物抑制WWP1，都会触发PTEN的活化并释放抑肿瘤活性。

WWP1似乎是一个直接的MYC（MYC原癌基因）靶基因，在MYC驱动的肿瘤发生中起关键作用。

我们发现，十字花科蔬菜中的化合物——吲哚-3-甲醇是一种天然有效的WWP1抑制剂。因此，我们的发现揭示了一种通过PTEN活化预防和治疗癌症的潜在治疗策略。

▲ Abstract

Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain–containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either geneticablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. WWP1 appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.

Single-cell genomics identifies cell type–specific molecular changes in autism

单细胞基因组学辨别出自闭症细胞类型特异性分子变化

▲ 作者：Dmitry Velmeshev, Lucas Schirmer, Diane Jung, et al

▲ 链接：

https://science.sciencemag.org/content/364/6441/685

▲ 摘要：

尽管自闭症具有临床和遗传异质性，但大量基因表达研究表明，自闭症患者新皮质的变化集中在共同的基因和通路上。然而，直接评估自闭症患者大脑中的特定细胞类型直到最近才成为可能。

我们利用来自自闭症患者皮质组织的单核RNA测序，辨别出同自闭症相关的特定细胞类型的转录组改变。我们发现，在自闭症患者中，上层兴奋性神经元的突触信号和小胶质细胞的分子状态优先受到影响。

此外，我们的结果表明，皮质—皮质投射神经元中特定基因群的失调与自闭症的临床严重程度有关。这些发现表明，上层皮层回路的分子变化与自闭症的行为表现有关。

▲ Abstract

Despite the clinical and genetic heterogeneity of autism, bulk gene expression studies show that changes in theneocortex of autism patients converge on common genes and pathways. However, direct assessment of specific cell types in the brain affected by autism has not been feasible until recently. We used single-nucleus RNA sequencing of cortical tissue from patients with autism to identify autism-associated transcriptomic changes in specific cell types. We found that synaptic signaling of upper-layer excitatory neurons and the molecular state of microglia are preferentially affected in autism. Moreover, our results show that dysregulation of specific groups of genes in cortico-cortical projection neurons correlates with clinical severity of autism. These findings suggest that molecular changes in upper-layer cortical circuits are linked to behavioral manifestations of autism.

 

物理/天文

Physics/Astronomy

Quantum gas microscopy of Rydberg macrodimers

量子气体显微镜用于里德伯宏二聚体观测

▲ 作者：Simon Hollerith, Johannes Zeiher, Jun Rui, et al

▲ 链接：

https://science.sciencemag.org/content/364/6441/664

▲ 摘要：

典型双原子分子的亚纳米尺寸阻碍了对其组分的直接光学获取。里德伯宏二聚体——两个高度激发的里德伯原子的束缚态——以原子间距离很容易超过光学波长为特征。

我们报告了对光学晶格的超冷铷原子气体中此类分子的直接微观观测结果，并对其特征进行了详细描述。此类分子的键长约0.7微米，相当于小细菌的大小，与晶格的对角线距离相匹配。

通过对初始二维原子阵列中原子对的激活，我们获得了50多个振动共振。利用我们的空间分辨探测，我们通过相关原子损耗观测到宏二聚体，并通过选择振动状态，展示了对分子排列的控制。

我们的结果允许对里德伯相互作用潜力进行严格测试，并突出了量子气体显微镜在分子物理学中的潜力。

▲ Abstract

The subnanoscale size of typical diatomic molecules hinders direct optical access to their constituents. Rydberg macrodimers—boundstates of two highly excited Rydberg atoms—feature interatomic distances easily exceeding optical wave lengths. We report the direct microscopic observation and detailed characterization of such molecules in a gas of ultracold rubidium atomsin an optical lattice. The bond length of about 0.7 micrometers, comparable to the size of small bacteria, matches the diagonal distance of the lattice. By exciting pairs in the initial two-dimensional atom array, we resolved more than50 vibrational resonances. Using our spatially resolved detection, we observed the macrodimers by correlated atom loss and demonstrated control of the molecular alignment by the choice of the vibrational state. Our results allowfor rigorous testing of Rydberg interaction potentials and highlight the potential of quantum gas microscopy for molecular physics.

Initial results from the New Horizonsexploration of 2014 MU₆₉, a small Kuiper Belt object

“新视野号”对柯伊伯带小型天体——MU₆₉的初步探测结果

▲ 作者：S. A. Stern, H. A. Weaver, J. R. Spencer, et al

▲ 链接：

https://science.sciencemag.org/content/364/6441/eaaw9771

▲ 摘要：

柯伊伯带是外太阳系的一个遥远区域。2019年1月1日，“新视野号”宇宙飞船飞近(486958)2014 MU₆₉——一个直径约30公里的柯伊伯带冷经典天体。这些物体从未被太阳加热过，因此自形成以来保存得很好。

我们描述了这些相遇观测的初步结果。MU₆₉是一颗二裂片接触双星，具有扁平的形状、离散的地质单元和明显的反照率非均质性。然而，其表面颜色或成分的异质性很少。

同时，没有发现卫星、光环或其他尘埃结构、气体彗发或太阳风相互作用的证据。MU₆₉的起源似乎与卵石云崩溃相一致，随后它的两个裂片低速合并。

▲ Abstract

The Kuiper Belt is a distant region of the outer Solar System. On 1 January 2019, the New Horizons spacecraft flew close to (486958) 2014 MU₆₉, a cold classical Kuiper Belt object approximately 30 kilometers in diameter. Such objects have never been substantially heated by the Sun and are therefore well preserved since their formation. We describe initial results from these encounter observations. MU₆₉ is a bilobed contact binary with a flattened shape, discrete geological units, and noticeable albedo heterogeneity. However, there is little surface color orcompositional heterogeneity. No evidence for satellites, rings or other dust structures, a gas coma, or solar wind interactions was detected. MU₆₉’s origin appears consistent with pebble cloud collapse followed by a low-velocity merger of its two lobes.

生物学Biology

Hierarchical reasoning by neural circuits in the frontal cortex

额叶皮层神经回路的层级推理

▲ 作者：Morteza Sarafyazd, Mehrdad Jazayeri

▲ 链接：

https://science.sciencemag.org/content/364/6441/eaav8911

▲ 摘要：

人类按层级处理信息。在存在层级结构的情况下，失败的来源是不明确的。在一次或多次尝试后，人类通过评估自己的信心解决这种模棱两可。

为理解这一推理策略的神经基础，我们在一项任务中记录了猴子背内侧额叶皮层（DMFC）和前扣带皮层（ACC）的活动。该任务中的消极结果要么由于错误判断了刺激源，要么由于刺激—反应偶然性规则之间隐蔽切换造成。

我们发现，这两个区域都有支持规则转换的证据。进一步的扰动实验表明，ACC在DMFC的下游起作用，并且直接和具体地参与推断隐蔽规则开关。这些结果‏揭示了由皮层回路实现的分层级推理的计算原则。

▲ Abstract

Humans process information hierarchically. In the presence of hierarchies, sources of failures are ambiguous. Humans resolve this ambiguity by assessing their confidence after one or more attempts. To understand the neural basis of this reasoning strategy, we recorded from dorsomedial frontal cortex (DMFC) and anterior cingulate cortex(ACC) of monkeys in a task in which negative outcomes were caused either by misjudging the stimulus or by a covert switch between two stimulus-response contingency rules. We found that both areas harbored a representation of evidence supporting a rule switch. Additional perturbation experiments revealed that ACC functioned down stream of DMFC and was directly and specifically involved in inferring covert rule switches. These results‏ reveal the computational principles of hierarchical reasoning, as implemented by cortical circuits.

Local protein synthesis is a ubiquitous feature of neuronal pre- and postsynaptic compartments

局部蛋白合成是神经元突触前区和突触后区普遍存在的特征

▲ 作者：Anne-Sophie Hafner, Paul G. Donlin-Asp, Beulah Leitch, et al

▲ 链接：

https://science.sciencemag.org/content/364/6441/eaau3644

▲ 摘要：

充分的证据表明，神经元树突中存在信使RNA（mRNAs）定位和蛋白质合成。然而，这些过程在突触前末端的演示是有限的。

我们利用扩展显微镜来分析啮齿类动物神经元中突触前和突触后的细胞间隔。海马体和前脑的突触前末端大多含有mRNA和核糖体。我们对荧光标记的小鼠大脑突触体进行了分类，然后对兴奋性终扣内的数百种mRNA进行了测序。

在进行简单的代谢标记后，超过30%的突触前末端显示出信号，为正在进行的蛋白质合成提供了证据。

我们测试了不同的经典可塑性范式，并且观察到突触前和/或突触后快速翻译的不同模式。因此，突触前末端具有翻译能力，而局部蛋白合成被不同地招募来驱动构成不同可塑性形式基础的区域特异性表型。

▲ Abstract

There is ample evidence for localization of messenger RNAs (mRNAs) and protein synthesis in neuronal dendrites; however, demonstrations of these processes in presynaptic terminals are limited. We used expansion microscopy to resolve pre- and postsynaptic compartments in rodent neurons. Most presynaptic terminals in the hippocampus and forebrain contained mRNA and ribosomes. We sorted fluorescently labeled mouse brain synaptosomes and then sequenced hundreds of mRNA species present within excitatory boutons. After brief metabolic labeling, >30% of all presynaptic terminals exhibited a signal, providing evidence for ongoing protein synthesis. We tested different classic plasticity paradigms and observed distinct patterns of rapid pre-and/or postsynaptic translation. Thus, presynaptic terminals are translationally competent, and local protein synthesis is differentiallyrecruited to drive compartment-specific phenotypes that underlie different forms of plasticity.

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