1 Gene bivalency at Polycomb domains regulates cranial neural crest positional identity
Maryline Minoux, Sjoerd Holwerda, Antonio Vitobello, Taro Kitazawa, Hubertus Kohler, Michael B. Stadler, Filippo M. Rijli
The cranial neural crest cells are multipotent cells that provide head skeletogenic mesenchyme and are crucial for craniofacial patterning. We analyzed the chromatin landscapes of mouse cranial neural crest subpopulations in vivo. Early postmigratory subpopulations contributing to distinct mouse craniofacial structures displayed similar chromatin accessibility patterns yet differed transcriptionally. Accessible promoters and enhancers of differentially silenced genes carried H3K27me3/H3K4me2 bivalent chromatin marks embedded in large enhancer of zeste homolog 2–dependent Polycomb domains, indicating transcriptional poising. These postmigratory bivalent chromatin regions were already present in premigratory progenitors. At Polycomb domains, H3K27me3 antagonized H3K4me2 deposition, which was restricted to accessible sites. Thus, bivalent Polycomb domains provide a chromatin template for the regulation of cranial neural crest cell positional identity in vivo, contributing insights into the epigenetic regulation of face morphogenesis.
2 Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq
Andrew S. Venteicher, Itay Tirosh, Christine Hebert…Aviv Regev, Mario L. Suvà
Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)–mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.
M. Ramy El-Maarry, O. Groussin, N. Thomas…F. Scholten, X. Shi
The Rosetta spacecraft spent ~2 years orbiting comet 67P/Churyumov-Gerasimenko, most of it at distances that allowed surface characterization and monitoring at submeter scales. From December 2014 to June 2016, numerous localized changes were observed, which we attribute to cometary-specific weathering, erosion, and transient events driven by exposure to sunlight and other processes. While the localized changes suggest compositional or physical heterogeneity, their scale has not resulted in substantial alterations to the comet’s landscape. This suggests that most of the major landforms were created early in the comet’s current orbital configuration. They may even date from earlier if the comet had a larger volatile inventory, particularly of CO or CO2ices, or contained amorphous ice, which could have triggered activity at greater distances from the Sun.
4 Controlled growth and form of precipitating microsculptures
C. Nadir Kaplan, Wim L. Noorduin, Ling Li, Roel Sadza, Laura Folkertsma, Joanna Aizenberg, L. Mahadevan
Controlled self-assembly of three-dimensional shapes holds great potential for fabrication of functional materials. Their practical realization requires a theoretical framework to quantify and guide the dynamic sculpting of the curved structures that often arise in accretive mineralization. Motivated by a variety of bioinspired coprecipitation patterns of carbonate and silica, we develop a geometrical theory for the kinetics of the growth front that leaves behind thin-walled complex structures. Our theory explains the range of previously observed experimental patterns and, in addition, predicts unexplored assembly pathways. This allows us to design a number of functional base shapes of optical microstructures, which we synthesize to demonstrate their light-guiding capabilities. Overall, our framework provides a way to understand and control the growth and form of functional precipitating microsculptures.
5 Identification of single-site gold catalysis in acetylene hydrochlorination
Grazia Malta, Simon A. Kondrat, Simon J. Freakley…Christopher J. Kiely, Graham J. Hutchings
There remains considerable debate over the active form of gold under operating conditions of a recently validated gold catalyst for acetylene hydrochlorination. We have performed an in situ x-ray absorption fine structure study of gold/carbon (Au/C) catalysts under acetylene hydrochlorination reaction conditions and show that highly active catalysts comprise single-site cationic Au entities whose activity correlates with the ratio of Au(I):Au(III) present. We demonstrate that these Au/C catalysts are supported analogs of single-site homogeneous Au catalysts and propose a mechanism, supported by computational modeling, based on a redox couple of Au(I)-Au(III) species.
Brian Shao, Alex L. Bagdasarian, Stasik Popov, Hosea M. Nelson
Over the past 80 years, phenyl cation intermediates have been implicated in a variety of C–H arylation reactions. Although these examples have inspired several theoretical and mechanistic studies, aryl cation equivalents have received limited attention in organic methodology. Their high-energy, promiscuous reactivity profiles have hampered applications in selective intermolecular processes. We report a reaction design that overcomes these challenges. Specifically, we found that β-silicon–stabilized aryl cation equivalents, generated via silylium-mediated fluoride activation, undergo insertion into sp3 and sp2 C–H bonds. This reaction manifold provides a framework for the catalytic arylation of hydrocarbons, including simple alkanes such as methane. This process uses low loadings of Earth-abundant initiators (1 to 5 mole percent) and occurs under mild conditions (30° to 100°C).
7 Mars’ atmospheric history derived from upper-atmosphere measurements of 38Ar/36Ar
B. M. Jakosky, M. Slipski, M. Benna, P. Mahaffy, M. Elrod, R. Yelle, S. Stone, N. Alsaeed
The history of Mars’ atmosphere is important for understanding the geological evolution and potential habitability of the planet. We determine the amount of gas lost to space through time using measurements of the upper-atmospheric structure made by the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft. We derive the structure of 38Ar/36Ar between the homopause and exobase altitudes. Fractionation of argon occurs as a result of loss of gas to space by pickup-ion sputtering, which preferentially removes the lighter atom. The measurements require that 66% of the atmospheric argon has been lost to space. Thus, a large fraction of Mars’ atmospheric gas has been lost to space, contributing to the transition in climate from an early, warm, wet environment to today’s cold, dry atmosphere.
8 Breathing control center neurons that promote arousal in mice
Kevin Yackle, Lindsay A. Schwarz, Kaiwen Kam, Jordan M. Sorokin, John R. Huguenard, Jack L. Feldman, Liqun Luo, Mark A. Krasnow
Slow, controlled breathing has been used for centuries to promote mental calming, and it is used clinically to suppress excessive arousal such as panic attacks. However, the physiological and neural basis of the relationship between breathing and higher-order brain activity is unknown. We found a neuronal subpopulation in the mouse preBötzinger complex (preBötC), the primary breathing rhythm generator, which regulates the balance between calm and arousal behaviors. Conditional, bilateral genetic ablation of the ~175 Cdh9/Dbx1 double-positive preBötC neurons in adult mice left breathing intact but increased calm behaviors and decreased time in aroused states. These neurons project to, synapse on, and positively regulate noradrenergic neurons in the locus coeruleus, a brain center implicated in attention, arousal, and panic that projects throughout the brain.
(导读 董堃) 长期以来，深呼吸被认为是一种缓解压力、抑制过度兴奋的好方法，然而呼吸和大脑高级功能之间的联系尚未明确。本研究在小鼠前包钦格复合体（preBötC）中发现了一种负责调控镇静和兴奋行为的神经元亚群，并且这些神经元能够投射到蓝斑中的去甲肾上腺能神经元并进行正向调节。
9 Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites
M. Dawidowski, L. Emmanouilidis, V. C. Kalel…M. Sattler, G. M. Popowicz
The parasitic protists of the Trypanosoma genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill Trypanosoma by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an “Achilles’ heel” of the Trypanosoma suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.
10 The whole-soil carbon flux in response to warming
Caitlin E. Hicks Pries, C. Castanha1, R. C. Porras, M. S. Torn
（导读 肖坤）土壤中大量碳元素对气候变化具有巨大潜在影响，而土壤全剖面对气候变暖的响应尚未实测。本研究发现随温度升高，土壤CO2 产出和呼吸作用均增加，不同土壤深度对气候变暖的温度敏感性相似。相比仅加热表层土壤的实验和模型，该方法揭示了更大的呼吸响应。
Soil organic carbon harbors three times as much carbon as Earth’s atmosphere, and its decomposition is a potentially large climate change feedback and major source of uncertainty in climate projections. The response of whole-soil profiles to warming has not been tested in situ. In a deep warming experiment in mineral soil, we found that CO2 production from all soil depths increased with 4°C warming; annual soil respiration increased by 34 to 37%. All depths responded to warming with similar temperature sensitivities, driven by decomposition of decadal-aged carbon. Whole-soil warming reveals a larger soil respiration response than many in situ experiments (most of which only warm the surface soil) and models.
11 Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
Alice O. Kamphorst, Andreas Wieland, Tahseen Nasti…Koichi Araki1, Rafi Ahmed
Programmed cell death–1 (PD-1)–targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.
（导读 峰子）程序性死亡-1(PD-1)靶向治疗对多种癌症有疗效，但共刺激分子在增强T细胞效应中的作用仍未知。本研究通过使用慢性淋巴细胞性脉络丛脑膜炎病毒感染的小鼠模型，发现CD28/B7共刺激通路对CD8 T细胞的再激活及有效的PD-1靶向治疗至关重要。
12 T cell costimulatory receptor CD28 is a primary target for PD-1–mediated inhibition
Enfu Hui, Jeanne Cheung, Jing Zhu…Ira Mellman, Ronald D. Vale
（导读 郭思瑶）程序性死亡受体1（PD-1）是抑制T细胞激活的共抑制受体，是重要的癌症免疫疗法靶标。 通过在生化重组系统里用滴定法测量PD-1信号，研究人员发现PD-1主要通过使CD28信号失活来抑制T细胞功能，显示共激活通路在调节T细胞功能和抗PD-L1/PD-1治疗反应中扮演重要角色。
Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.
Celia Pilar Martinez-Jimenez, Nils Eling, Hung-Chang Chen…John C. Marioni, Duncan T. Odom
（导读 郭思瑶）衰老使生理和细胞功能逐渐退化的分子机制尚不清楚。本研究对年轻与老年小鼠激活与未激活的效应子记忆CD4+ T细胞进行单细胞RNA测序发现，被免疫激活后，年轻小鼠T细胞产生统一性的转录谱改变，但衰老小鼠不同T细胞的转录改变异质性较大。这显示升高的细胞间转录多样性将成为哺乳动物组织衰老的标志。
Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated naïve and effector memory CD4+ T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.
14 On the origins of oxygenic photosynthesis and aerobic respiration in Cyanobacteria
Rochelle M. Soo, James Hemp, Donovan H. Parks, Woodward W. Fischer, Philip Hugenholtz
The origin of oxygenic photosynthesis in Cyanobacteria led to the rise of oxygen on Earth ~2.3 billion years ago, profoundly altering the course of evolution by facilitating the development of aerobic respiration and complex multicellular life. Here we report the genomes of 41 uncultured organisms related to the photosynthetic Cyanobacteria (class Oxyphotobacteria), including members of the class Melainabacteria and a new class of Cyanobacteria (class Sericytochromatia) that is basal to the Melainabacteria and Oxyphotobacteria. All members of the Melainabacteria and Sericytochromatia lack photosynthetic machinery, indicating that phototrophy was not an ancestral feature of the Cyanobacteria and that Oxyphotobacteria acquired the genes for photosynthesis relatively late in cyanobacterial evolution. We show that all three classes independently acquired aerobic respiratory complexes, supporting the hypothesis that aerobic respiration evolved after oxygenic photosynthesis.
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