1 UBE2O remodels the proteome during terminal erythroid differentiation
Anthony T. Nguyen, Miguel A. Prado, Paul J. Schmidt…Mark D. Fleming, Daniel Finley
During terminal differentiation, the global protein complement is remodeled, as epitomized by erythrocytes, whose cytosol is ~98% globin. The erythroid proteome undergoes a rapid transition at the reticulocyte stage; however, the mechanisms driving programmed elimination of preexisting cytosolic proteins are unclear. We found that a mutation in the murine Ube2o gene, which encodes a ubiquitin-conjugating enzyme induced during erythropoiesis, results in anemia. Proteomic analysis suggested that UBE2O is a broad-spectrum ubiquitinating enzyme that remodels the erythroid proteome. In particular, ribosome elimination, a hallmark of reticulocyte differentiation, was defective in Ube2o−/− mutants. UBE2O recognized ribosomal proteins and other substrates directly, targeting them to proteasomes for degradation. Thus, in reticulocytes, the induction of ubiquitinating factors may drive the transition from a complex to a simple proteome.
2 UBE2O is a quality control factor for orphans of multiprotein complexes
Kota Yanagitani, Szymon Juszkiewicz, Ramanujan S. Hegde
Many nascent proteins are assembled into multiprotein complexes of defined stoichiometry. Imbalances in the synthesis of individual subunits result in orphans. How orphans are selectively eliminated to maintain protein homeostasis is poorly understood. Here, we found that the conserved ubiquitin-conjugating enzyme UBE2O directly recognized juxtaposed basic and hydrophobic patches on unassembled proteins to mediate ubiquitination without a separate ubiquitin ligase. In reticulocytes, where UBE2O is highly up-regulated, unassembled α-globin molecules that failed to assemble with β-globin were selectively ubiquitinated by UBE2O. In nonreticulocytes, ribosomal proteins that did not engage nuclear import factors were targets for UBE2O. Thus, UBE2O is a self-contained quality control factor that comprises substrate recognition and ubiquitin transfer activities within a single protein to efficiently target orphans of multiprotein complexes for degradation.
3 Mechanochemical unzipping of insulating polyladderene to semiconducting polyacetylene
Zhixing Chen, Jaron A. M. Mercer, Xiaolei Zhu…Noah Z. Burns, Yan Xia（夏岩，斯坦福大学）
Biological systems sense and respond to mechanical stimuli in a complex manner. In an effort to develop synthetic materials that transduce mechanical force into multifold changes in their intrinsic properties, we report on a mechanochemically responsive nonconjugated polymer that converts to a conjugated polymer via an extensive rearrangement of the macromolecular structure in response to force. Our design is based on the facile mechanochemical unzipping of polyladderene, a polymer inspired by a lipid natural product structure and prepared via direct metathesis polymerization. The resultant polyacetylene block copolymers exhibit long conjugation length and uniform trans-configuration and self-assemble into semiconducting nanowires. Calculations support a tandem unzipping mechanism of the ladderene units.
4 Direct atomic-level insight into the active sites of a high-performance PGM-free ORR catalyst
Hoon T. Chung, David A. Cullen, Drew Higgins…Karren L. More, Piotr Zelenay
Platinum group metal–free (PGM-free) metal-nitrogen-carbon catalysts have emerged as a promising alternative to their costly platinum (Pt)–based counterparts in polymer electrolyte fuel cells (PEFCs) but still face some major challenges, including (i) the identification of the most relevant catalytic site for the oxygen reduction reaction (ORR) and (ii) demonstration of competitive PEFC performance under automotive-application conditions in the hydrogen (H2)–air fuel cell. Herein, we demonstrate H2-air performance gains achieved with an iron-nitrogen-carbon catalyst synthesized with two nitrogen precursors that developed hierarchical porosity. Current densities recorded in the kinetic region of cathode operation, at fuel cell voltages greater than ~0.75 V, were the same as those obtained with a Pt cathode at a loading of 0.1 milligram of Pt per centimeter squared. The proposed catalytic active site, carbon-embedded nitrogen-coordinated iron (FeN4), was directly visualized with aberration-corrected scanning transmission electron microscopy, and the contributions of these active sites associated with specific lattice-level carbon structures were explored computationally.
5 Revealing hidden antiferromagnetic correlations in doped Hubbard chains via string correlators
Timon A. Hilker, Guillaume Salomon, Fabian Grusdt…Immanuel Bloch, Christian Gross
Topological phases, like the Haldane phase in spin-1 chains, defy characterization through local order parameters. Instead, nonlocal string order parameters can be employed to reveal their hidden order. Similar diluted magnetic correlations appear in doped one-dimensional lattice systems owing to the phenomenon of spin-charge separation. Here we report on the direct observation of such hidden magnetic correlations via quantum gas microscopy of hole-doped ultracold Fermi-Hubbard chains. The measurement of nonlocal spin-density correlation functions reveals a hidden finite-range antiferromagnetic order, a direct consequence of spin-charge separation. Our technique, which measures nonlocal order directly, can be readily extended to higher dimensions to study the complex interplay between magnetic order and density fluctuations.
Martin W. Scheeler, Wim M. van Rees, Hridesh Kedia, Dustin Kleckner, William T. M. Irvine
Helicity, a topological measure of the intertwining of vortices in a fluid flow, is a conserved quantity in inviscid fluids but can be dissipated by viscosity in real flows. Despite its relevance across a range of flows, helicity in real fluids remains poorly understood because the entire quantity is challenging to measure. We measured the total helicity of thin-core vortex tubes in water. For helical vortices that are stretched or compressed by a second vortex, we found conservation of total helicity. For an isolated helical vortex, we observed evolution toward and maintenance of a constant helicity state after the dissipation of twist helicity by viscosity. Our results show that helicity can remain constant even in a viscous fluid and provide an improved basis for understanding and manipulating helicity in real flows.
7 Large-amplitude transfer motion of hydrated excess protons mapped by ultrafast 2D IR spectroscopy
Fabian Dahms, Benjamin P. Fingerhut, Erik T. J. Nibbering, Ehud Pines, Thomas Elsaesser
Solvation and transport of excess protons in aqueous systems play a fundamental role in acid-base chemistry and biochemical processes. We mapped ultrafast proton excursions along the proton transfer coordinate by means of two-dimensional infrared spectroscopy, both in bulk water and in a Zundel cation (H5O2)+ motif selectively prepared in acetonitrile. Electric fields from the environment and stochastic hydrogen bond motions induce fluctuations of the proton double-minimum potential. Within the lifetime of a particular hydration geometry, the proton explores a multitude of positions on a sub-100-femtosecond time scale. The proton transfer vibration is strongly damped by its 20- to 40-femtosecond population decay. Our results suggest a central role of Zundel-like geometries in aqueous proton solvation and transport.
过剩质子的溶剂化与转移在酸碱化学与生化过程中起重要作用。本研究借助二维红外光谱成像，在体相水和乙腈中选择性制备 Zundel 阳离子 (H5O2)+ 两种环境下，沿着质子转移坐标绘制了质子运动路径。研究结果表明了类-Zundel 几何构型在水溶液质子溶剂化和运输中的重要作用。
8 Winter storms drive rapid phenotypic, regulatory, and genomic shifts in the green anole lizard
Shane C. Campbell-Staton, Zachary A. Cheviron, Nicholas Rochette, Julian Catchen, Jonathan B. Losos, Scott V. Edwards
Extreme environmental perturbations offer opportunities to observe the effects of natural selection in wild populations. During the winter of 2013–2014, the southeastern United States endured an extreme cold event. We used thermal performance, transcriptomics, and genome scans to measure responses of lizard populations to storm-induced selection. We found significant increases in cold tolerance at the species’ southern limit. Gene expression in southern survivors shifted toward patterns characteristic of northern populations. Comparing samples before and after the extreme winter, 14 genomic regions were differentiated in the surviving southern population; four also exhibited signatures of local adaptation across the latitudinal gradient and implicate genes involved in nervous system function. Together, our results suggest that extreme winter events can rapidly produce strong selection on natural populations at multiple biological levels that recapitulate geographic patterns of local adaptation.
（导读 郭思瑶）极端环境变化展示了自然选择对野生种群的影响。2013-2014年冬天，美国东南部遭遇了极寒天气。科研人员利用热力性能，转录组和基因组分析了蜥蜴种群， 发现南部种群耐寒极限大幅提高，南部幸存蜥蜴的基因表达向北部种群的基因特征靠拢。这说明极端气候事件可以迅速对自然种群产生极大的选择作用。
9 The microbial metabolite desaminotyrosine protects from influenza through type I interferon
Ashley L. Steed, George P. Christophi, Gerard E. Kaiko…Deborah J. Lenschow, Thaddeus S. Stappenbeck
The microbiota is known to modulate the host response to influenza infection through as-yet-unclear mechanisms. We hypothesized that components of the microbiota exert effects through type I interferon (IFN), a hypothesis supported by analysis of influenza in a gain-of-function genetic mouse model. Here we show that a microbially associated metabolite, desaminotyrosine (DAT), protects from influenza through augmentation of type I IFN signaling and diminution of lung immunopathology. A specific human-associated gut microbe, Clostridium orbiscindens,produced DAT and rescued antibiotic-treated influenza-infected mice. DAT protected the host by priming the amplification loop of type I IFN signaling. These findings show that specific components of the enteric microbiota have distal effects on responses to lethal infections through modulation of type I IFN.
（导读 郭思瑶）肠道微生物群可调节宿主对流感的应答，其机制尚不清楚。通过流感病毒在功能获得性小鼠模型中的分析，科学家发现人类肠道细菌Clostridium orbiscindens的代谢产物脱氨基酪氨酸(DAT)可以通过I型干扰素信号调节减少肺部损伤。DAT通过I型干扰素放大环路来保护宿主。该发现确定了肠道菌群对于感染进行应答的具体成分。
10 Chemogenetics revealed: DREADD occupancy and activation via converted clozapine
Juan L. Gomez, Jordi Bonaventura, Wojciech Lesniak…Antonello Bonci, Michael Michaelides
(导读 马欢) DREADD(designer receptors exclusively activated by designer drugs)的应用建立在特定受体可由特定药物n-氧化氯氮平（CNO）专一激活的假设下，然而其在体的作用机制尚未得到证实。本文作者通过放射性配体受体占有率测量和体内正电子发射断层扫描发现脑中表达的DREADD 被CNO代谢物氯氮平而非其本身激活。
The chemogenetic technology DREADD (designer receptors exclusively activated by designer drugs) is widely used for remote manipulation of neuronal activity in freely moving animals. DREADD technology posits the use of “designer receptors,” which are exclusively activated by the “designer drug” clozapine N-oxide (CNO). Nevertheless, the in vivo mechanism of action of CNO at DREADDs has never been confirmed. CNO does not enter the brain after systemic drug injections and shows low affinity for DREADDs. Clozapine, to which CNO rapidly converts in vivo, shows high DREADD affinity and potency. Upon systemic CNO injections, converted clozapine readily enters the brain and occupies central nervous system–expressed DREADDs, whereas systemic subthreshold clozapine injections induce preferential DREADD-mediated behaviors.
11 Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy
Robert W. Myers, Hong-Ping Guan, Juliann Ehrhart…Daniel M. Kemp, Iyassu K. Sebhat
5′-Adenosine monophosphate–activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722–mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
12 Genomic estimation of complex traits reveals ancient maize adaptation to temperate North America
Kelly Swarts, Rafal M. Gutaker, Bruce Benz…Edward S. Buckler, Hernán A. Burbano
By 4000 years ago, people had introduced maize to the southwestern United States; full agriculture was established quickly in the lowland deserts but delayed in the temperate highlands for 2000 years. We test if the earliest upland maize was adapted for early flowering, a characteristic of modern temperate maize. We sequenced fifteen 1900-year-old maize cobs from Turkey Pen Shelter in the temperate Southwest. Indirectly validated genomic models predicted that Turkey Pen maize was marginally adapted with respect to flowering, as well as short, tillering, and segregating for yellow kernel color. Temperate adaptation drove modern population differentiation and was selected in situ from ancient standing variation. Validated prediction of polygenic traits improves our understanding of ancient phenotypes and the dynamics of environmental adaptation.
（导读 郭思瑶）4000年前，玉米被引入美国西南部，很快成为西南部低地的主要农作物，但直到 2000后才年才进入温带高地。科研人员对1900年前该地玉米棒基因组进行测序，发现其已为适应环境在花期，发芽和分枝上的发生改变。对温度的适应驱动了当代种群分化。这有利于加深我们对古代表型和环境适应动态变化的理解。
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