Weak lasing in one-dimensional polariton superlattices
Long Zhang, Wei Xie, Jian Wang, Alexander Poddubny, Jian Lu, Yinglei Wang, Jie Gu, Wenhui Liu, Dan Xu, Xuechu Shen, Yuri G. Rubo (Юрiй Рубо), Boris L. Altshuler, Alexey V. Kavokin, and Zhanghai Chen
Bose–Einstein condensation of polaritons in periodically modulated cavities is a very interesting fundamental effect of the physics of many-body systems. It is also promising for application in solid-state lighting and information communication technologies. By a simple microassembling method, we created (pp. E1516–E1519) periodically modulated polariton condensates at room temperature, and observed the stabilization of the coherent condensate due to the spontaneous symmetry-breaking transition. This manifests a previously unidentified type of phase transition, leading to a novel state of matter: the weak lasing state. The optical imaging in both direct and reciprocal space provides clear evidence for the weak lasing in the specific range of the pumping intensities.
Early Roman military fortifications and the origin of Trieste, Italy
Federico Bernardini, Giacomo Vinci, Jana Horvat, Angelo De Min, Emanuele Forte, Stefano Furlani, Davide Lenaz, Michele Pipan, Wenke Zhao, Alessandro Sgambati, Michele Potleca, Roberto Micheli, Andrea Fragiacomo, and Claudio Tuniz
Archaeological evidence from the Trieste area (Italy), revealed by airborne remote sensing and geophysical surveys, provides one of the earliest examples of Roman military fortifications (pp. E1520–E1529). They are the only ones identified in Italy so far. Their origin is most likely related to the first year of the second Roman war against the Histri in 178 B.C., reported by Livy, but the sites were in use, perhaps not continuously, at least until the mid first century B.C. The main identified San Rocco military camp is the best candidate for the site of the first Trieste.
TALE nickase-mediated SP110 knockin endows cattle with increased resistance to tuberculosis
Haibo Wu, Yongsheng Wang, Yan Zhang, Mingqi Yang, Jiaxing Lv, Jun Liu, and Yong Zhang
Bovine tuberculosis is a chronic infectious disease that affects a broad range of mammalian hosts. It is a serious threat to agriculture in many less-developed countries. In this study (pp. E1530–E1539), we introduced a mutation to the FokI of the right hand of wild-type transcription activator-like effector nuclease and established a transcription activator-like effector nickase system that creates single-strand breaks in the genome. Then we used this system to add the mouse gene SP110 to a specific location in the bovine genome and created transgenic cattle with increased resistance to tuberculosis. Our results contribute to the control and prevention of bovine tuberculosis and provide a previously unidentified insight into breeding animals for disease resistance.
Glucocorticoid receptor interacts with PNRC2 in a ligand-dependent manner to recruit UPF1 for rapid mRNA degradation
Hana Cho, Ok Hyun Park, Joori Park, Incheol Ryu, Jeonghan Kim, Jesang Ko, and Yoon Ki Kim
Glucocorticoid receptor (GR) belongs to the nuclear receptor superfamily and functions as a transcription factor. GR regulates various physiological processes, including cell proliferation, energy homeostasis, and inflammation. In this study (pp. E1540–E1549), we provide molecular evidence for the role of GR in the regulation of mRNA stability, which we term GR-mediated mRNA decay (GMD). Efficient GMD requires a ligand, a GR loaded onto target mRNA, upstream frameshift 1 (UPF1), and proline-rich nuclear receptor coregulatory protein 2. GMD functions in the chemotaxis of human monocytes by targeting chemokine (C-C motif) ligand 2 mRNA. Thus, we unravel a previously unappreciated role of GR, which is traditionally considered a transcription factor, in posttranscriptional regulation.
The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation
Matthew F. Jones, Toshifumi Hara, Princy Francis, Xiao Ling Li, Sven Bilke, Yuelin Zhu, Marbin Pineda, Murugan Subramanian, Walter F. Bodmer, and Ashish Lal
In the colon, stem cell self-renewal and multipotency is regulated by the polycomb complex protein BMI1, among other genes. Differentiation is regulated by the transcription factor caudal-type homeobox 1 (CDX1), expression of which coincides with repression of BMI1. Colorectal cancer stem cells (CSCs) express BMI1 but not CDX1. Tumors that silence CDX1 have a higher proportion of CSCs and an undifferentiated histology, whereas aberrant CDX1 expression is associated with intestinal metaplasias such as Barrett's esophagus. We have identified (pp. E1550–E1558) microRNA-215 (miR-215) as a target of CDX1 in colon cancer that mediates repression of BMI1. MiR-215 operates downstream of CDX1 to promote differentiation and inhibit stemness. In combination with recent advances in the therapeutic uses of small RNAs, miR-215 could offer a novel method to specifically target CSCs.
Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate
Fuguo Wu, Tadeusz J. Kaczynski, Santhosh Sethuramanujam, Renzhong Li, Varsha Jain, Malcolm Slaughter, and Xiuqian Mu
Despite the progress made during the last two decades regarding the generation of retinal cell types, the mechanisms by which a retinal progenitor cell decides to adopt a particular cell type remain unclear. Using a binary knockin-transgenic system, we show (pp. E1559–E1568) that two factors, POU domain, class 4, transcription factor 2 (Pou4f2) and insulin gene enhancer protein 1 (Isl1), specify the retinal ganglion cell (RGC) fate and activate the whole gene-expression program required for ganglion cell differentiation. This study, for the first time to our knowledge, defines a set of determinant factors for any retinal cell type, offering significant insight into how cellular diversity is achieved in the central nervous system. It also provides guidance for generating RGCs in vitro for therapeutic purposes.
Equation-free mechanistic ecosystem forecasting using empirical dynamic modeling
Hao Ye, Richard J. Beamish, Sarah M. Glaser, Sue C. H. Grant, Chih-hao Hsieh, Laura J. Richards, Jon T. Schnute, and George Sugihara
The conventional parametric approach to modeling relies on hypothesized equations to approximate mechanistic processes. Although there are known limitations in using an assumed set of equations, parametric models remain widely used to test for interactions, make predictions, and guide management decisions. Here (pp. E1569–E1576), we show that these objectives are better addressed using an alternative equation-free approach, empirical dynamic modeling (EDM). Applied to Fraser River sockeye salmon, EDM models (i) recover the mechanistic relationship between the environment and population biology that fisheries models dismiss as insignificant, (ii) produce significantly better forecasts compared with contemporary fisheries models, and (iii) explicitly link control parameters (spawning abundance) and ecosystem objectives (future recruitment), producing models that are suitable for current management frameworks.
Spatial proximity of homologous alleles and long noncoding RNAs regulate a switch in allelic gene expression
Kalliopi Stratigi, Manouela Kapsetaki, Michalis Aivaliotis, Terrence Town, Richard A. Flavell, and Charalampos G. Spilianakis
In diploid organisms, trans-allelic interactions control gene expression, providing a tight spatial and temporal level of transcription regulation. Although homologous trans-allelic interactions are quite abundant in various organisms such as Drosophila, plants, and fungi, they have not been widely reported in mammals. This article (pp. E1577–E1586) demonstrates that such a trans-allelic association is evident in mammals and involves the homologous spatial proximity of Tnfα alleles as a prerequisite for the biallelic expression of the Tnfα gene. We believe the phenomenon we describe here provides mechanistic insights for the regulation of gene allelic expression and mRNA dosage control necessary for fine-tuning physiological processes in mammals.
Myosin VI regulates gene pairing and transcriptional pause release in T cells
Cornelia E. Zorca, Lark Kyun Kim, Yoon Jung Kim, Matthew R. Krause, Daniel Zenklusen, Charalampos G. Spilianakis, and Richard A. Flavell
Our study (pp. E1587–E1593) examines an important aspect of adaptive immunity, namely, the process of effector T-cell activation, which leads to the enhanced expression of lineage-specific cytokine genes upon T-cell receptor (TCR) re-engagement. We found that the TNF locus undergoes TCR-induced homologous allelic pairing, which correlates with biallelic expression and requires a molecular motor, myosin VI. Furthermore, we identified a role for myosin VI in mediating the transition of RNA polymerase II (RNAPII) from pausing to productive elongation at cytokine and other related loci. We propose that homologous pairing and RNAPII pause release ensure a rapid and synchronous transcriptional response in effector T cells following antigen re-exposure.
Combinatorial proteomic analysis of intercellular signaling applied to the CD28 T-cell costimulatory receptor
Ruijun Tian, Haopeng Wang, Gerald D. Gish, Evangelia Petsalaki, Adrian Pasculescu, Yu Shi, Marianne Mollenauer, Richard D. Bagshaw, Nir Yosef, Tony Hunter, Anne-Claude Gingras, Arthur Weiss, and Tony Pawson
Intracellular signaling during complex cell–cell interactions, such as between immune cells, provides essential cues leading to cell responses. Global characterization of these signaling events is critical for systematically exploring and understanding how they eventually control cell fate. However, proteome-wide characterization of intercellular signaling under physiologically relevant conditions involving multiple interacting receptors during cell–cell interactions remains challenging. We developed (pp. E1594–E1603) an integrated proteomic strategy for quantitatively profiling intercellular-signaling events mediated by protein phosphorylation and protein–protein interaction. We applied this approach to determine the influence of a single receptor-ligand pair during T-cell stimulation by blocking the interaction of the CD28 costimulatory receptor with its ligand. This approach is generally applicable to other transmembrane receptors involved in signaling during complex cell interactions.
The coreceptor CD4 is expressed in distinct nanoclusters and does not colocalize with T-cell receptor and active protein tyrosine kinase p56lck
Kyung-Ho Roh, Björn F. Lillemeier, Feng Wang, and Mark M. Davis
Immune cell signaling is heavily associated with the spatial organization of molecules. Here (pp. E1604–E1613), we examined the nanoscale organization of coreceptor CD4 and its relative spatial localization to the T-cell receptor and the active form of Src kinase p56lck (Lck), using two different superresolution microscopy techniques photoactivated localization microscopy and direct stochastic optical reconstruction microscopy in both living and fixed cells. With concurrent spatial analyses, we show that neither CD4/T-cell antigen receptor nor CD4/active Lck nanoclusters colocalize but only overlap at the interfaces. In activated T cells, the enhanced clustering of each kind results in increased seclusion from each other. Our observations here in molecular resolution may reveal the general roles that are played by nanoscale organization of critical components in immune cell signaling.
CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction
Christoph Tabeling, Hanpo Yu, Liming Wang, Hannes Ranke, Neil M. Goldenberg, Diana Zabini, Elena Noe, Adrienn Krauszman, Birgitt Gutbier, Jun Yin, Michael Schaefer, Christoph Arenz, Andreas C. Hocke, Norbert Suttorp, Richard L. Proia, Martin Witzenrath, and Wolfgang M. Kuebler
Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism that protects against systemic hypoxemia by redistributing blood flow from poorly to better ventilated areas of the lung, thereby minimizing ventilation-perfusion mismatch. However, in chronic hypoxemia-associated lung disease, HPV contributes to pulmonary hypertension. In this study (pp. E1614–E1623), we provide novel evidence for a dual role of sphingolipids as important signal mediators in HPV, which critically depends on the presence of functional cystic fibrosis (CF) transmembrane conductance regulator (CFTR). CFTR gene mutations cause CF, which is associated with profound pulmonary ventilation-perfusion mismatches. The present findings propel our current understanding of HPV, establish a previously undescribed mechanism for hypoxemia in CF disease, and identify CFTR as a functional contributor to the pathologic changes in hypoxia-associated pulmonary hypertension.
Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn
Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Martin Lang, Ying Huang, HyoungBin F. Oh, Masayuki Matsuo, Maria J. Merino, Masahiro Yao, Yusuke Ito, Mitsuko Furuya, Yasuhiro Iribe, Tatsuhiko Kodama, Eileen Southon, Lino Tessarollo, Kunio Nagashima, Diana C. Haines, W. Marston Linehan, and Laura S. Schmidt
The role of FLCN as a tumor suppressor in kidney cancer has been well documented, whereas the functional roles of folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1 and FNIP2) in kidney are unknown. In this study (pp. E1624–E1631), we demonstrate that double inactivation of Fnip1 and Fnip2 leads to enlarged polycystic kidneys or kidney cancer, which mimics the phenotypes seen in Flcn-deficient kidneys and underscores the significance of Fnip1 and Fnip2 in kidney tumor suppression. Moreover, we found that Fnip1/Fnip2 mRNA ratios differ among organs, which may reflect tissue-specific roles for each Fnip. Our findings define Fnip1 and Fnip2 as critical components of the Flcn complex that are essential for its tumor suppressive function and will aid in the development of novel therapeutics for kidney cancer.
Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity
Yoshitaka Miyagawa, Pietro Marino, Gianluca Verlengia, Hiroaki Uchida, William F. Goins, Shinichiro Yokota, David A. Geller, Osamu Yoshida, Joseph Mester, Justus B. Cohen, and Joseph C. Glorioso
Gene therapy has made significant strides in the treatment and even cure of single-gene defects. However, the maturation of this field will require more sophisticated vehicles capable of cell-selective delivery of large genetic payloads whose regulated expression will restore or enhance cellular functionality. High-capacity herpes simplex virus vectors have the potential to meet these challenges but have been limited by the need to preserve one particularly cytotoxic viral product, infected cell polypeptide 0, to maintain transgene transcriptional activity. Our study (pp. E1632–E1641) describes a vector design that solves this conundrum, thereby promising the near-term availability of viral vectors that can efficiently deliver large or multiple regulated transgenes to a diversity of cells without attendant cytotoxicity.
Neuropeptide Y stimulates autophagy in hypothalamic neurons
Célia A. Aveleira, Mariana Botelho, Sara Carmo-Silva, Jorge F. Pascoal, Marisa Ferreira-Marques, Clévio Nóbrega, Luísa Cortes, Jorge Valero, Lígia Sousa-Ferreira, Ana R. Álvaro, Magda Santana, Sebastian Kügler, Luís Pereira de Almeida, and Cláudia Cavadas
Autophagy impairment is a major hallmark of aging, and any intervention that enhances autophagy is of potential interest to delay aging. However, it was described that the hypothalamus is a brain area with a key role on whole-body aging. In the present study (pp. E1642–E1651), we show that an endogenous molecule produced by the hypothalamus, the neuropeptide Y (NPY), stimulates autophagy in rodent hypothalamus. Because both hypothalamic autophagy and NPY levels decrease with age, a better understanding of hypothalamic neuronal autophagy regulation by NPY may provide new putative therapeutic strategies to ameliorate age-related deteriorations and delay aging.
Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus
Jefferson Menezes, Niége Alves, Sidnei Borges, Rafael Roehrs, Jociane de Carvalho Myskiw, Cristiane Regina Guerino Furini, Ivan Izquierdo, and Pâmela B. Mello-Carpes
A brief exposure to a novel environment was recently shown to enhance the extinction of contextual fear probably through a protein synthesis-dependent process of synaptic tagging and capture in the hippocampus. Here (pp. E1652–E1658) we report that this finding can be generalized to the extinction of another fear-motivated task, one-trial inhibitory avoidance. This generalization is important because extinction is used in exposure therapy to treat posttraumatic stress disorder in humans, and this may derive from various forms of fear-related stress. In addition, here we show that the effect of novelty on fear extinction is dependent on dopamine D1 but not D5 receptors in the hippocampus. These findings could be applicable to the exposure therapy of fear memory disorders.
Heteromerization of chemokine (C-X-C motif) receptor 4 with α1A/B-adrenergic receptors controls α1-adrenergic receptor function
Abhishek Tripathi, P. Geoff Vana, Tanmay S. Chavan, Lioubov I. Brueggemann, Kenneth L. Byron, Nadya I. Tarasova, Brian F. Volkman, Vadim Gaponenko, and Matthias Majetschak
α1-Adrenergic receptors are important for the regulation of vascular function and are targeted clinically for blood pressure control. Here (pp. E1659–E1668), we provide evidence that α1A/B-adrenergic receptors (AR) form heteromeric complexes with chemokine (C-X-C motif) receptor 4 (CXCR4) on the cell surface of vascular smooth muscle cells. We show that disruption of α1A/B-AR:CXCR4 heteromeric complexes inhibits α1-AR–mediated functions in vascular smooth muscle cells and that treatment with CXCR4 agonists enhances the potency of the α1-AR agonist phenylephrine to increase blood pressure. These findings extend the current understanding of the molecular mechanisms regulating α1-AR and provide an example of G protein-coupled receptor heteromerization with important functional implications. Compounds targeting the α1A/B-AR:CXCR4 interaction ould provide an alternative pharmacological approach to modulating blood pressure.
Arrhythmogenesis in a catecholaminergic polymorphic ventricular tachycardia mutation that depresses ryanodine receptor function
Yan-Ting Zhao, Carmen R. Valdivia, Georgina B. Gurrola, Patricia P. Powers, B. Cicero Willis, Richard L. Moss, José Jalife, and Héctor H. Valdivia
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic syndrome characterized by life-threatening cardiac arrhythmias triggered by physical exercise or emotional stress. Although patients with CPVT have no abnormalities in cardiac structure, they present ventricular fibrillation or sudden death as the first symptom. Most CPVT cases are linked to mutations in cardiac ryanodine receptor (RyR2), an intracellular Ca2+ channel that provides the majority of Ca2+ that enables heart contraction. The current mechanism for CPVT arrhythmogenesis requires RyR2 affected by gain-of-function mutations. However, loss-of-function mutations of RyR2 have also been found in CPVT patients. We generated (pp. E1669–E1677) an animal model of CPVT that harbors a loss-of-function mutation that was originally described in humans and elucidated novel mechanisms by which hypoactive RyR2 channels trigger malignant arrhythmias.
Genome-wide analysis of thylakoid-bound ribosomes in maize reveals principles of cotranslational targeting to the thylakoid membrane
Reimo Zoschke and Alice Barkan
Proteins in the chloroplast thylakoid membrane system are derived from both the nuclear and plastid genomes. Mechanisms that localize nucleus-encoded proteins to the thylakoid membrane have been studied intensively, but little is known about the analogous issues for plastid-encoded proteins. This genome-wide, high-resolution analysis of the partitioning of chloroplast ribosomes between membrane and soluble fractions revealed (pp. E1678–E1687) that approximately half of the chloroplast-encoded thylakoid proteins integrate cotranslationally and half integrate posttranslationally. Features in the nascent peptide that underlie these distinct behaviors were revealed by analysis of the position on each mRNA at which elongating ribosomes first become attached to the membrane.