Acceleration of evolutionary spread by long-range dispersal
Oskar Hallatschek and Daniel S. Fisher
Pathogens, invasive species, rumors, or innovations spread much more quickly around the world nowadays than in previous centuries. The speedup is caused by more frequent long-range dispersal, for example via air traffic. These jumps are crucial because they can generate satellite “outbreaks” at many distant locations, thus rapidly increasing the total rate of spread. We present a simple intuitive argument that captures the resulting spreading patterns. We show (pp. E4911–E4919) that even rare long-range jumps can transform the spread of simple epidemics from wave-like to a very fast type of “metastatic” growth. More generally, our approach can be used to describe how new evolutionary variants spread and thus improves our predictive understanding of the speed of Darwinian adaptation.
Calcium-mediated histone modifications regulate alternative splicing in cardiomyocytes
Alok Sharma, Hieu Nguyen, Cuiyu Geng, Melissa N. Hinman, Guangbin Luo, and Hua Lou
Calcium is an important intracellular second messenger that regulates many biological processes. Many extracellular environmental cues lead to cellular calcium-level changes, which impact on the output of gene expression. In cardiomyocytes, calcium is known to control gene expression at the level of transcription, whereas its role in regulating alternative splicing has not been explored. Our studies demonstrate that in these cells a network of alternatively spliced exons exists, which responds to the altered calcium levels by changing their splicing patterns. Our studies (pp. E4920–E4928) further elucidate an epigenetic regulatory mechanism, triggered by calcium signaling pathways, that leads to histone hyperacetylation along gene bodies, which increases the transcriptional elongation rate of RNA polymerase II and impacts alternative splicing.
Differential gradients of interaction affinities drive efficient targeting and recycling in the GET pathway
Michael E. Rome, Un Seng Chio, Meera Rao, Harry Gristick, and Shu-ou Shan
Ensuring the accuracy of protein interaction cascades is a challenge in many cellular processes. This challenge is faced by the guided entry of tail-anchored (TA) protein (GET) pathway, in which the targeting factor Get3 must sequentially interact with three effector proteins to deliver an essential class of TA proteins to the membrane. Using fluorescence probes that quantitatively interrogate individual Get3–effector interactions, we show here that Get3 adopts discrete conformational states in response to substrate and nucleotide binding; these conformational states allow Get3 to generate differential gradients of interaction energies with distinct effectors, thus driving its cyclic and ordered interaction cascade. These results (pp. E4929–E4935) also explain why multiple effector proteins are needed for TA targeting and uncover a previously unidentified mechanism for recycling Get3 from the membrane.
Liat1, an arginyltransferase-binding protein whose evolution among primates involved changes in the numbers of its 10-residue repeats
Christopher S. Brower, Connor E. Rosen, Richard H. Jones, Brandon C. Wadas, Konstantin I. Piatkov, and Alexander Varshavsky
We describe (pp. E4936–E4945) the discovery and analyses of a previously uncharacterized protein, termed Liat1 (ligand of Ate1), which has been identified because of its interactions with the Ate1 arginyltransferase, a component of the N-end rule pathway of protein degradation. All vertebrates contain proteins similar to mouse Liat1. Remarkably, Liat1 proteins of some primates contain tandem repeats of a 10-residue sequence, whereas Liat1 proteins of other mammals contain a single copy of this motif. Quantities of these repeats are, in general, different in Liat1 of different primates. For example, there are 4, 13, 13, and 17 repeats in the gorilla, orangutan, bonobo, and human Liat1, respectively, suggesting that repeat number changes in this previously uncharacterized protein may contribute to evolution of primates.
Long-range enhancer activity determines Myc sensitivity to Notch inhibitors in T cell leukemia
Yumi Yashiro-Ohtani, Hongfang Wang, Chongzhi Zang, Kelly L. Arnett, Will Bailis, Yugong Ho, Birgit Knoechel, Claudia Lanauze, Lumena Louis, Katherine S. Forsyth, Sujun Chen, Yoonjie Chung, Jonathan Schug, Gerd A. Blobel, Stephen A. Liebhaber, Bradley E. Bernstein, Stephen C. Blacklow, Xiaole Shirley Liu, Jon C. Aster, and Warren S. Pear
The protooncogene c-Myc (Myc) is an oncogenic driver in many cancers, but is difficult to target directly with drugs. An alternative strategy is to use drugs that inhibit factors that regulate Myc expression. Notch drives Myc expression in most T-cell leukemias, but clinical trials of Notch inhibitors have been disappointing, possibly because cells emerge that express Myc in a Notch-independent fashion. Here (pp. E4946–E4953) we identify the genomic switches that regulate Myc expression in the Notch-inhibitor–sensitive and –resistant states. Our findings suggest that Notch inhibitor resistance occurs through a “switch swap” that relieves Notch dependency while increasing dependency on a different factor, bromodomain containing 4 (Brd4). These studies provide a rationale for targeting Myc in T cell leukemias with combinations of Notch and Brd4 inhibitors.
Rapid diversification of five Oryza AA genomes associated with rice adaptation
Qun-Jie Zhang, Ting Zhu, En-Hua Xia, Chao Shi, Yun-Long Liu, Yun Zhang, Yuan Liu, Wen-Kai Jiang, You-Jie Zhao, Shu-Yan Mao, Li-Ping Zhang, Hui Huang, Jun-Ying Jiao, Ping-Zhen Xu, Qiu-Yang Yao, Fan-Chun Zeng, Li-Li Yang, Ju Gao, Da-Yun Tao, Yue-Ju Wang, Jeffrey L. Bennetzen, and Li-Zhi Gao
Asian rice (Oryza sativa) is among the world’s most important crops. The genus Oryza has become a model for the study of plant genome structure, function, and evolution. We have undertaken de novo, full-genome sequence analysis of five diploid AA-genome species that are closely related to O. sativa. These species are native to quite different environments, representing four continents, thus exhibiting very different adaptations. Our studies (pp. E4954–E4962) identify specific genetic changes, in both gene copy number and the degree of diversifying natural selection, that indicate specific genes responsible for these adaptations, particularly in genes related to defense against pathogens and reproductive diversification. This genome discovery and comparative analysis provide a powerful tool for future Oryza study and rice improvement.
Signaling pathways activated by a protease allergen in basophils
Rachel K. Rosenstein, Jelena S. Bezbradica, Shuang Yu, and Ruslan Medzhitov
Helminths and allergens stimulate type 2 immune responses by largely unknown mechanisms. Proteolytic activity is a common feature of many helminths and allergens and can promote activation of the immune system. Signaling pathways activated by these proteases remain poorly characterized and are the focus of this study. Using basophils as model type 2 immune cells, we identified roles for the immunoreceptor tyrosine-based activation motif (ITAM)-containing adaptor Fc receptor γ-chain and calcium signaling in protease-stimulated basophil activation. We suggest models to explain how protease sensing, ITAM signaling, and nuclear factor of activated T cells pathways contribute to produce allergic type 2 responses (pp. E4963–E4971). Elucidation of these signaling pathways and ultimately the identity of protease allergen sensors will be important for the development of pharmacologic strategies to target the initiation of allergic responses.
Excess cholesterol induces mouse egg activation and may cause female infertility
Ayce Yesilaltay, Gregoriy A. Dokshin, Dolores Busso, Li Wang, Dalia Galiani, Tony Chavarria, Eliza Vasile, Linda Quilaqueo, Juan Andrés Orellana, Dalia Walzer, Ruth Shalgi, Nava Dekel, David F. Albertini, Attilio Rigotti, David C. Page, and Monty Krieger
Production of functional sperm and eggs requires a complex process called meiosis. Meiosis in mouse and human eggs pauses at a stage called metaphase II (MII) arrest until fertilization by sperm. After fertilization, eggs released from MII arrest complete meiosis and develop into new individuals. In analyzing the female infertility of genetically altered mice, we discovered that excess cholesterol can trick mouse eggs into behaving as though they were fertilized (released from arrest), thus disrupting the normal synchrony between fertilization and completion of meiosis and rendering them dysfunctional. These findings (pp. E4972–E4980) suggest that abnormal cholesterol metabolism may contribute to some forms of human female infertility.
Metabolic sensor governing bacterial virulence in Staphylococcus aureus
Yue Ding, Xing Liu, Feifei Chen, Hongxia Di, Bin Xu, Lu Zhou, Xin Deng, Min Wu, Cai-Guang Yang, and Lefu Lan
Staphylococcus aureus is one of the most successful and adaptable human pathogens and is a major cause of hospital-acquired infections. Here (pp. E4981–E4990) we provide insight into how S. aureus uses the catabolite control protein E (CcpE) to sense its intracellular metabolic status and to regulate its virulence-associated properties. We define a key circuit of the virulence regulatory network of S. aureus and emphasize that metabolic status may be a critical element governing the virulence of this pathogen. Understanding the role of metabolites in virulence factor expression ultimately may contribute to the development of novel strategies to combat this dreaded infectious disease.
Cells infected with herpes simplex virus 1 export to uninfected cells exosomes containing STING, viral mRNAs, and microRNAs
Maria Kalamvoki, Te Du, and Bernard Roizman
The stimulator of IFN genes (STING) is an important innate immune response to infection by herpes simplex virus 1 (HSV-1). STING’s impact may be deduced from the observation that HSV-1 replicates significantly better in normal immortalized cells depleted of STING. Nevertheless, published evidence shows that STING is stabilized by the virus in infected cells, and this report shows that STING is exported from infected cells in exosomes along with viral microRNAs (miRNAs) and mRNAs. Some miRNAs have been reported to suppress reactivation of latent virus. The results (pp. E4991–E4996) suggest that HSV-1 in special circumstances may control the spread of infection from cell to cell and support the hypothesis that HSV-1 controls its virulence to enable effective person-to-person transmission.
Decreased segregation of brain systems across the healthy adult lifespan
Micaela Y. Chan, Denise C. Park, Neil K. Savalia, Steven E. Petersen, and Gagan S. Wig
The brain is a large-scale network, not unlike many social or technological networks. Just like social networks, brain networks contain subnetworks or systems of highly related or interacting nodes (in the case of brains, nodes may represent neurons or brain areas). Using functional MRI to measure functional correlations between brain areas during periods of rest, we describe differences in brain network organization in a large group of individuals sampled across the healthy adult lifespan (20–89 y). We characterize a measure of system segregation, reflecting the degree to which the systems share connections among one another (pp. E4997–E5006). Increasing age is accompanied by decreasing segregation of brain systems. Importantly, system segregation is predictive of measures of long-term memory function, independent of age.
Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice
Hai-Ying Zhang, Ming Gao, Qing-Rong Liu, Guo-Hua Bi, Xia Li, Hong-Ju Yang, Eliot L. Gardner, Jie Wu, and Zheng-Xiong Xi
Although early studies suggested that cannabinoid CB2 receptors (CB2Rs) are absent in the brain, this view has been challenged by recent findings of significant brain CB2R involvement in several dopamine (DA)-related CNS disorders. The cellular mechanisms underlying these actions are unclear, however. Using multiple approaches, we found that CB2R genes and receptors are expressed in midbrain DA neurons, and that activation of CB2Rs inhibits DA neuronal firing and i.v. cocaine self-administration. These findings (pp. E5007–E5015) not only challenge the long-held view that brain CB2Rs are not expressed in neurons, but also suggest that neuronal CB2Rs modulate DA neuronal activity and DA-regulated behavior. Thus, brain CB2Rs may constitute a new therapeutic target in medication development for treatment of a number of CNS disorders.