ALBERT

Description: Separation and purification are critical industrial processes for separating components of chemical mixtures, and these processes account for about half of industrial energy usage (1). Gas mixtures of compounds with very similar physical properties are particularly difficult to separate. On pages 137 and 141 of this issue, Cadiau et al. (2) and Cui et al. (3), respectively, show that microporous materials can be designed to have high adsorption capacity and selectivity for particular hydrocarbons, enabling energy-efficient separation. Author: Jerry Y. S. Lin

Description: Biomass-degrading microorganisms use lytic polysaccharide monooxygenase (LPMO) enzymes to help digest cellulose, chitin, and starch. By cleaving otherwise inaccessible crystalline cellulose chains, these enzymes provide access to hydrolytic enzymes. LPMOs are of interest to biotechnology because efficient depolymerization of cellulose is a major bottleneck for the production of biologically based chemicals and fuels. On page 1098 of this issue, Kracher et al. (1) compare LPMO-reducing substrates in fungi from different taxonomic groups and lifestyles, based on both biochemical and genomic evidence. The results provide insights into reductive activation of LPMO that are important for developing more efficient industrial enzymes for lignocellulose biorefineries. Author: Angel T. Martínez

Description: Author: Marc S. Lavine

Description: An empirical observation of a relationship between a striking feature of electronic transmission through a π-system, destructive quantum interference (QI), on one hand, and the stability of diradicals on the other, leads to the proof of a general theorem that relates the two. Subject to a number of simplifying assumptions,...

Description: The comment and response concerning the report of oxidation of methane to methanol by water (Reports, 5 May 2017, p. 523) do not fully capture the implications of thermodynamic limitations. A nonisothermal process in which each cycle requires a large temperature swing and permits only substoichiometric methane conversion surely could not be carried out on any practical scale.

Description: Labinger argues that stepwise reaction of methane with water to produce methanol and hydrogen will never be commercially feasible because of its substoichiometric basis with respect to the active site and the requirement of a large temperature swing. This comment is not touching any new ground, beyond describing the thermodynamic feasibility, thermal cycling, and the role of water as discussed previously. Most important, it does not have a solid numerical basis.

Description: Vinyl carbocations have been the subject of extensive experimental and theoretical studies over the past five decades. Despite this long history in chemistry, the utility of vinyl cations in chemical synthesis has been limited, with most reactivity studies focusing on solvolysis reactions or intramolecular processes. Here we report synthetic and mechanistic studies of vinyl cations generated through silylium–weakly coordinating anion catalysis. We find that these reactive intermediates undergo mild intermolecular carbon-carbon bond–forming reactions, including carbon-hydrogen (C–H) insertion into unactivated sp 3 C–H bonds and reductive Friedel-Crafts reactions with arenes. Moreover, we conducted computational studies of these alkane C–H functionalization reactions and discovered that they proceed through nonclassical, ambimodal transition structures. This reaction manifold provides a framework for the catalytic functionalization of hydrocarbons using simple ketone derivatives.

Description: It is commonly assumed that recognition and discrimination of chirality, both in nature and in artificial systems, depend solely on spatial effects. However, recent studies have suggested that charge redistribution in chiral molecules manifests an enantiospecific preference in electron spin orientation. We therefore reasoned that the induced spin polarization may affect enantiorecognition through exchange interactions. Here we show experimentally that the interaction of chiral molecules with a perpendicularly magnetized substrate is enantiospecific. Thus, one enantiomer adsorbs preferentially when the magnetic dipole is pointing up, whereas the other adsorbs faster for the opposite alignment of the magnetization. The interaction is not controlled by the magnetic field per se, but rather by the electron spin orientations, and opens prospects for a distinct approach to enantiomeric separations.

Description: Theory has established the importance of geometric phase (GP) effects in the adiabatic dynamics of molecular systems with a conical intersection connecting the ground- and excited-state potential energy surfaces, but direct observation of their manifestation in chemical reactions remains a major challenge. Here, we report a high-resolution crossed molecular beams study of the H + HD -〉 H 2 + D reaction at a collision energy slightly above the conical intersection. Velocity map ion imaging revealed fast angular oscillations in product quantum state–resolved differential cross sections in the forward scattering direction for H 2 products at specific rovibrational levels. The experimental results agree with adiabatic quantum dynamical calculations only when the GP effect is included.

Description: The chemistry of the carbonyl group is essential to modern organic synthesis. The preparation of substituted, enantioenriched 1,3- or 1,5-dicarbonyls is well developed, as their disconnection naturally follows from the intrinsic polarity of the carbonyl group. By contrast, a general enantioselective access to quaternary stereocenters in acyclic 1,4-dicarbonyl systems remains an unresolved problem, despite the tremendous importance of 2,3-substituted 1,4-dicarbonyl motifs in natural products and drug scaffolds. Here we present a broad enantioselective and stereodivergent strategy to access acyclic, polysubstituted 1,4-dicarbonyls via acid-catalyzed [3,3]-sulfonium rearrangement starting from vinyl sulfoxides and ynamides. The stereochemistry at sulfur governs the absolute sense of chiral induction, whereas the double bond geometry dictates the relative configuration of the final products.

Description: With the recent soaring production of natural gas, the use of methane and other light hydrocarbon feedstocks as starting materials in synthetic transformations is becoming increasingly economically attractive, although it remains chemically challenging. We report the development of photocatalytic C–H amination, alkylation, and arylation of methane, ethane, and higher alkanes under visible light irradiation at ambient temperature. High catalytic efficiency (turnover numbers up to 2900 for methane and 9700 for ethane) and selectivity were achieved using abundant, inexpensive cerium salts as photocatalysts. Ligand-to-metal charge transfer excitation generated alkoxy radicals from simple alcohols that in turn acted as hydrogen atom transfer catalysts. The mixed-phase gas/liquid reaction was adapted to continuous flow, enabling the efficient use of gaseous feedstocks in scalable photocatalytic transformations.

Description: Intrigued by the potential of nanoscale machines, scientists have long attempted to control molecular motion. We monitored the individual 0.7-nanometer steps of a single molecular hopper as it moved in an electric field along a track in a nanopore controlled by a chemical ratchet. The hopper demonstrated characteristics desired in a moving molecule: defined start and end points, processivity, no chemical fuel requirement, directional motion, and external control. The hopper was readily functionalized to carry cargos. For example, a DNA molecule could be ratcheted along the track in either direction, a prerequisite for nanopore sequencing.

Description: Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]–based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

Description: Here we report an anomalous porous molecular crystal built of C–H···N-bonded double-layered roof-floor components and wall components of a segregatively interdigitated architecture. This complicated porous structure consists of only one type of fully aromatic multijoint molecule carrying three identical dipyridylphenyl wedges. Despite its high symmetry, this molecule accomplishes difficult tasks by using two of its three wedges for roof-floor formation and using its other wedge for wall formation. Although a C–H···N bond is extremely labile, the porous crystal maintains its porosity until thermal breakdown of the C–H···N bonds at 202°C occurs, affording a nonporous polymorph. Though this nonporous crystal survives even at 325°C, it can retrieve the parent porosity under acetonitrile vapor. These findings show how one can translate simplicity into ultrahigh complexity.

Description: Some of the simplest and most powerful carbon-carbon bond forming strategies take advantage of readily accessible ubiquitous motifs: carbonyls and olefins. Here we report a fundamentally distinct mode of reactivity between carbonyls and olefins that differs from established acid-catalyzed carbonyl-ene, Prins, and carbonyl-olefin metathesis reaction paths. A range of epsilon, zeta-unsaturated ketones undergo Brønsted acid–catalyzed intramolecular cyclization to provide tetrahydrofluorene products via the formation of two new carbon-carbon bonds. Theoretical calculations and accompanying mechanistic studies suggest that this carbocyclization reaction proceeds through the intermediacy of a transient oxetane formed by oxygen atom transfer. The complex polycyclic frameworks in this product class appear as common substructures in organic materials, bioactive natural products, and recently developed pharmaceuticals.

Description: Alkene aminoarylation with a single, bifunctional reagent is a concise synthetic strategy. We report a catalytic protocol for the addition of arylsulfonylacetamides across electron-rich alkenes with complete anti-Markovnikov regioselectivity and excellent diastereoselectivity to provide 2,2-diarylethylamines. In this process, single-electron alkene oxidation enables carbon-nitrogen bond formation to provide a key benzylic radical poised for a Smiles-Truce 1,5-aryl shift. This reaction is redox-neutral, exhibits broad functional group compatibility, and occurs at room temperature with loss of sulfur dioxide. As this process is driven by visible light, uses readily available starting materials, and demonstrates convergent synthesis, it is well suited for use in a variety of synthetic endeavors.

Description: Photocatalysis based on optically active, "plasmonic" metal nanoparticles has emerged as a promising approach to facilitate light-driven chemical conversions under far milder conditions than thermal catalysis. However, an understanding of the relation between thermal and electronic excitations has been lacking. We report the substantial light-induced reduction of the thermal activation barrier for ammonia decomposition on a plasmonic photocatalyst. We introduce the concept of a light-dependent activation barrier to account for the effect of light illumination on electronic and thermal excitations in a single unified picture. This framework provides insight into the specific role of hot carriers in plasmon-mediated photochemistry, which is critically important for designing energy-efficient plasmonic photocatalysts.

Description: Single-electron reduction of a carbonyl to a ketyl enables access to a polarity-reversed platform of reactivity for this cornerstone functional group. However, the synthetic utility of the ketyl radical is hindered by the strong reductants necessary for its generation, which also limit its reactivity to net reductive mechanisms. We report a strategy for net redox-neutral generation and reaction of ketyl radicals. The in situ conversion of aldehydes to α-acetoxy iodides lowers their reduction potential by more than 1 volt, allowing for milder access to the corresponding ketyl radicals and an oxidative termination event. Upon subjecting these iodides to a dimanganese decacarbonyl precatalyst and visible light irradiation, an atom transfer radical addition (ATRA) mechanism affords a broad scope of vinyl iodide products with high Z -selectivity.

Description: Reactions that form a product with the same reactive functionality as that of one of the starting compounds frequently end in oligomerization. As a salient example, selective aldol coupling of the smallest, though arguably most useful, enolizable aldehyde, acetaldehyde, with just one partner substrate has proven to be extremely challenging. Here, we report a highly enantioselective Mukaiyama aldol reaction with the simple triethylsilyl (TES) and tert -butyldimethylsilyl (TBS) enolates of acetaldehyde and various aliphatic and aromatic acceptor aldehydes. The reaction is catalyzed by recently developed, strongly acidic imidodiphosphorimidates (IDPi), which, like enzymes, display a confined active site but, like small-molecule catalysts, have a broad substrate scope. The process is scalable, fast, efficient (0.5 to 1.5 mole % catalyst loading), and greatly simplifies access to highly valuable silylated acetaldehyde aldols.

Description: Single-molecule magnets (SMMs) containing only one metal center may represent the lower size limit for molecule-based magnetic information storage materials. Their current drawback is that all SMMs require liquid-helium cooling to show magnetic memory effects. We now report a chemical strategy to access the dysprosium metallocene cation [(Cp i Pr5 )Dy(Cp*)] + (Cp i Pr5 , penta-iso-propylcyclopentadienyl; Cp *, pentamethylcyclopentadienyl), which displays magnetic hysteresis above liquid-nitrogen temperatures. An effective energy barrier to reversal of the magnetization of U eff = 1541 wave number is also measured. The magnetic blocking temperature of T B = 80 kelvin for this cation overcomes an essential barrier toward the development of nanomagnet devices that function at practical temperatures.

Description: The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467030/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467030/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thi, Emily P -- Mire, Chad E -- Lee, Amy C H -- Geisbert, Joan B -- Zhou, Joy Z -- Agans, Krystle N -- Snead, Nicholas M -- Deer, Daniel J -- Barnard, Trisha R -- Fenton, Karla A -- MacLachlan, Ian -- Geisbert, Thomas W -- U19 AI109711/AI/NIAID NIH HHS/ -- U19AI109711/AI/NIAID NIH HHS/ -- England -- Nature. 2015 May 21;521(7552):362-5. doi: 10.1038/nature14442. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada. ; 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901685" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jun 4;522(7554):6. doi: 10.1038/522006a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040858" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roth, Anna -- Diederichs, Sven -- England -- Nature. 2015 May 14;521(7551):170-1. doi: 10.1038/521170a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RNA Biology and Cancer Division, German Cancer Research Center, and at the Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25971508" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geddes, Linda -- England -- Nature. 2015 Nov 5;527(7576):22-5. doi: 10.1038/527022a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536940" target="_blank"〉PubMed〈/a〉

Description: Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720437/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindemans, Caroline A -- Calafiore, Marco -- Mertelsmann, Anna M -- O'Connor, Margaret H -- Dudakov, Jarrod A -- Jenq, Robert R -- Velardi, Enrico -- Young, Lauren F -- Smith, Odette M -- Lawrence, Gillian -- Ivanov, Juliet A -- Fu, Ya-Yuan -- Takashima, Shuichiro -- Hua, Guoqiang -- Martin, Maria L -- O'Rourke, Kevin P -- Lo, Yuan-Hung -- Mokry, Michal -- Romera-Hernandez, Monica -- Cupedo, Tom -- Dow, Lukas E -- Nieuwenhuis, Edward E -- Shroyer, Noah F -- Liu, Chen -- Kolesnick, Richard -- van den Brink, Marcel R M -- Hanash, Alan M -- HHSN272200900059C/PHS HHS/ -- K08 HL115355/HL/NHLBI NIH HHS/ -- K08-HL115355/HL/NHLBI NIH HHS/ -- K99 CA176376/CA/NCI NIH HHS/ -- K99-CA176376/CA/NCI NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P01-CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30-CA008748/CA/NCI NIH HHS/ -- R01 AI080455/AI/NIAID NIH HHS/ -- R01 AI100288/AI/NIAID NIH HHS/ -- R01 AI101406/AI/NIAID NIH HHS/ -- R01 HL069929/HL/NHLBI NIH HHS/ -- R01 HL125571/HL/NHLBI NIH HHS/ -- R01-AI080455/AI/NIAID NIH HHS/ -- R01-AI100288/AI/NIAID NIH HHS/ -- R01-AI101406/AI/NIAID NIH HHS/ -- R01-HL069929/HL/NHLBI NIH HHS/ -- R01-HL125571/HL/NHLBI NIH HHS/ -- U19 AI116497/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):560-4. doi: 10.1038/nature16460. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands. ; Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, Australia. ; Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Cancer Biology &Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. ; Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649819" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lynch, Michael -- England -- Nature. 2015 Jul 23;523(7561):414-6. doi: 10.1038/nature14634. Epub 2015 Jul 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Indiana University, Bloomington, Indiana 47405, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26176917" target="_blank"〉PubMed〈/a〉

Description: In Drosophila, just as in vertebrates, changes in external temperature are encoded by bidirectional opponent thermoreceptor cells: some cells are excited by warming and inhibited by cooling, whereas others are excited by cooling and inhibited by warming. The central circuits that process these signals are not understood. In Drosophila, a specific brain region receives input from thermoreceptor cells. Here we show that distinct genetically identified projection neurons (PNs) in this brain region are excited by cooling, warming, or both. The PNs excited by cooling receive mainly feed-forward excitation from cool thermoreceptors. In contrast, the PNs excited by warming ('warm-PNs') receive both excitation from warm thermoreceptors and crossover inhibition from cool thermoreceptors through inhibitory interneurons. Notably, this crossover inhibition elicits warming-evoked excitation, because warming suppresses tonic activity in cool thermoreceptors. This in turn disinhibits warm-PNs and sums with feed-forward excitation evoked by warming. Crossover inhibition could cancel non-thermal activity (noise) that is positively correlated among warm and cool thermoreceptor cells, while reinforcing thermal activity which is anti-correlated. Our results show how central circuits can combine signals from bidirectional opponent neurons to construct sensitive and robust neural codes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Wendy W -- Mazor, Ofer -- Wilson, Rachel I -- R01 DC008174/DC/NIDCD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 19;519(7543):353-7. doi: 10.1038/nature14170. Epub 2015 Mar 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA. ; 1] Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA [2] Harvard NeuroDiscovery Center, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25739502" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Broadfoot, Marla -- England -- Nature. 2015 Aug 20;524(7565):275. doi: 10.1038/nature.2015.18187.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26289186" target="_blank"〉PubMed〈/a〉

Description: The regulated release of anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that alpha-MSH is an agonist that couples the receptor to the Galphas signalling pathway, while AgRP binds competitively to block alpha-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by alpha-MSH and AgRP can be mediated independently of Galphas signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of alpha-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383680/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ghamari-Langroudi, Masoud -- Digby, Gregory J -- Sebag, Julien A -- Millhauser, Glenn L -- Palomino, Rafael -- Matthews, Robert -- Gillyard, Taneisha -- Panaro, Brandon L -- Tough, Iain R -- Cox, Helen M -- Denton, Jerod S -- Cone, Roger D -- 5R01 DK082884-03/DK/NIDDK NIH HHS/ -- DK020593/DK/NIDDK NIH HHS/ -- F31 DK102343/DK/NIDDK NIH HHS/ -- P30 DK020593/DK/NIDDK NIH HHS/ -- R01 DK064265/DK/NIDDK NIH HHS/ -- R01 DK070332/DK/NIDDK NIH HHS/ -- R01DK064265/DK/NIDDK NIH HHS/ -- R01DK070332/DK/NIDDK NIH HHS/ -- R25 GM059994/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):94-8. doi: 10.1038/nature14051. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. ; Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA. ; 1] Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37208, USA. ; King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK. ; 1] Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600267" target="_blank"〉PubMed〈/a〉

Description: Wing polyphenism is an evolutionarily successful feature found in a wide range of insects. Long-winged morphs can fly, which allows them to escape adverse habitats and track changing resources, whereas short-winged morphs are flightless, but usually possess higher fecundity than the winged morphs. Studies on aphids, crickets and planthoppers have revealed that alternative wing morphs develop in response to various environmental cues, and that the response to these cues may be mediated by developmental hormones, although research in this area has yielded equivocal and conflicting results about exactly which hormones are involved. As it stands, the molecular mechanism underlying wing morph determination in insects has remained elusive. Here we show that two insulin receptors in the migratory brown planthopper Nilaparvata lugens, InR1 and InR2, have opposing roles in controlling long wing versus short wing development by regulating the activity of the forkhead transcription factor Foxo. InR1, acting via the phosphatidylinositol-3-OH kinase (PI(3)K)-protein kinase B (Akt) signalling cascade, leads to the long-winged morph if active and the short-winged morph if inactive. InR2, by contrast, functions as a negative regulator of the InR1-PI(3)K-Akt pathway: suppression of InR2 results in development of the long-winged morph. The brain-secreted ligand Ilp3 triggers development of long-winged morphs. Our findings provide the first evidence of a molecular basis for the regulation of wing polyphenism in insects, and they are also the first demonstration--to our knowledge--of binary control over alternative developmental outcomes, and thus deepen our understanding of the development and evolution of phenotypic plasticity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Hai-Jun -- Xue, Jian -- Lu, Bo -- Zhang, Xue-Chao -- Zhuo, Ji-Chong -- He, Shu-Fang -- Ma, Xiao-Fang -- Jiang, Ya-Qin -- Fan, Hai-Wei -- Xu, Ji-Yu -- Ye, Yu-Xuan -- Pan, Peng-Lu -- Li, Qiao -- Bao, Yan-Yuan -- Nijhout, H Frederik -- Zhang, Chuan-Xi -- England -- Nature. 2015 Mar 26;519(7544):464-7. doi: 10.1038/nature14286. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Rice Biology and Ministry of Agriculture Key Laboratory of Agricultural Entomology, Institute of Insect Sciences, Zhejiang University, Hangzhou 310058, China. ; Department of Biology, Duke University, Durham, North Carolina 27708, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25799997" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zaret, Kenneth S -- England -- Nature. 2015 Aug 13;524(7564):165-6. doi: 10.1038/nature15201. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Regenerative Medicine and Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26245376" target="_blank"〉PubMed〈/a〉

Description: Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-beta plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530583/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530583/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gjoneska, Elizabeta -- Pfenning, Andreas R -- Mathys, Hansruedi -- Quon, Gerald -- Kundaje, Anshul -- Tsai, Li-Huei -- Kellis, Manolis -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 NS078839/NS/NINDS NIH HHS/ -- R01HG004037-07/HG/NHGRI NIH HHS/ -- R01NS078839/NS/NINDS NIH HHS/ -- RC1 HG005334/HG/NHGRI NIH HHS/ -- RC1HG005334/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):365-9. doi: 10.1038/nature14252.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693568" target="_blank"〉PubMed〈/a〉

Description: FOXP3(+) regulatory T cells (Treg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-antigens. This local IL-2 induction of STAT5 phosphorylation in Treg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by Treg cells reduces their regulatory capacity and disrupts their localization in clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells are activated to cytokine production on a regular basis, with physically co-clustering T cell receptor-stimulated Treg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702500/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702500/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Zhiduo -- Gerner, Michael Y -- Van Panhuys, Nicholas -- Levine, Andrew G -- Rudensky, Alexander Y -- Germain, Ronald N -- R37 AI034206/AI/NIAID NIH HHS/ -- R37AI034206/AI/NIAID NIH HHS/ -- T32GM007739/GM/NIGMS NIH HHS/ -- Z01 AI000403-25/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 10;528(7581):225-30. doi: 10.1038/nature16169. Epub 2015 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA. ; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605524" target="_blank"〉PubMed〈/a〉

Description: Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance, while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation. Recently, stem cells have been shown to regulate themselves using an autocrine mechanism. The existence of a 'stem cell niche' was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells. Since then, an increasing body of work has focused on defining stem cell niches. Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells. Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells . Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521991/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521991/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pardo-Saganta, Ana -- Tata, Purushothama Rao -- Law, Brandon M -- Saez, Borja -- Chow, Ryan Dz-Wei -- Prabhu, Mythili -- Gridley, Thomas -- Rajagopal, Jayaraj -- 5P30HL101287-02/HL/NHLBI NIH HHS/ -- R01 HL118185/HL/NHLBI NIH HHS/ -- R01HL118185/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):597-601. doi: 10.1038/nature14553. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA [2] Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; 1] Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, Massachusetts 02138, USA. ; Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147083" target="_blank"〉PubMed〈/a〉

Description: Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383723/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Turner, Tychele N -- Sharma, Kamal -- Oh, Edwin C -- Liu, Yangfan P -- Collins, Ryan L -- Sosa, Maria X -- Auer, Dallas R -- Brand, Harrison -- Sanders, Stephan J -- Moreno-De-Luca, Daniel -- Pihur, Vasyl -- Plona, Teri -- Pike, Kristen -- Soppet, Daniel R -- Smith, Michael W -- Cheung, Sau Wai -- Martin, Christa Lese -- State, Matthew W -- Talkowski, Michael E -- Cook, Edwin -- Huganir, Richard -- Katsanis, Nicholas -- Chakravarti, Aravinda -- 1U24MH081810/MH/NIMH NIH HHS/ -- 5R25MH071584-07/MH/NIMH NIH HHS/ -- MH095867/MH/NIMH NIH HHS/ -- MH19961-14/MH/NIMH NIH HHS/ -- R00 MH095867/MH/NIMH NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 MH060007/MH/NIMH NIH HHS/ -- R01 MH074090/MH/NIMH NIH HHS/ -- R01MH074090/MH/NIMH NIH HHS/ -- R01MH081754/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):51-6. doi: 10.1038/nature14186. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA. ; Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; 1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, Yale University, New Haven, Connecticut 06511, USA. ; Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA. ; National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Autism &Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania 17837, USA. ; University of Illinois at Chicago, Chicago, Illinois 60608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807484" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Feb 26;518(7540):456. doi: 10.1038/518456b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719627" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brown, Laura S -- Lankford, William F -- England -- Nature. 2015 May 21;521(7552):284-5. doi: 10.1038/521284a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Central American Solar Energy Project (CASEP), Charlottesville, Virginia, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993943" target="_blank"〉PubMed〈/a〉

Description: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Twyman-Saint Victor, Christina -- Rech, Andrew J -- Maity, Amit -- Rengan, Ramesh -- Pauken, Kristen E -- Stelekati, Erietta -- Benci, Joseph L -- Xu, Bihui -- Dada, Hannah -- Odorizzi, Pamela M -- Herati, Ramin S -- Mansfield, Kathleen D -- Patsch, Dana -- Amaravadi, Ravi K -- Schuchter, Lynn M -- Ishwaran, Hemant -- Mick, Rosemarie -- Pryma, Daniel A -- Xu, Xiaowei -- Feldman, Michael D -- Gangadhar, Tara C -- Hahn, Stephen M -- Wherry, E John -- Vonderheide, Robert H -- Minn, Andy J -- KL2TR000139/TR/NCATS NIH HHS/ -- P01AI112521/AI/NIAID NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA016520/CA/NCI NIH HHS/ -- P50 CA174523/CA/NCI NIH HHS/ -- P50CA174523/CA/NCI NIH HHS/ -- R01 AI105343/AI/NIAID NIH HHS/ -- R01 CA158186/CA/NCI NIH HHS/ -- R01 CA163739/CA/NCI NIH HHS/ -- R01AI105343/AI/NIAID NIH HHS/ -- R01CA158186/CA/NCI NIH HHS/ -- R01CA163739/CA/NCI NIH HHS/ -- R01CA172651/CA/NCI NIH HHS/ -- T32DK007066/DK/NIDDK NIH HHS/ -- U01AI095608/AI/NIAID NIH HHS/ -- U19 AI082630/AI/NIAID NIH HHS/ -- U19AI082630/AI/NIAID NIH HHS/ -- UL1RR024134/RR/NCRR NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida 33136, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25754329" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bourzac, Katherine -- England -- Nature. 2015 Nov 5;527(7576):S8-9. doi: 10.1038/527S8a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536225" target="_blank"〉PubMed〈/a〉

Description: Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chao -- Spevak, Wayne -- Zhang, Ying -- Burton, Elizabeth A -- Ma, Yan -- Habets, Gaston -- Zhang, Jiazhong -- Lin, Jack -- Ewing, Todd -- Matusow, Bernice -- Tsang, Garson -- Marimuthu, Adhirai -- Cho, Hanna -- Wu, Guoxian -- Wang, Weiru -- Fong, Daniel -- Nguyen, Hoa -- Shi, Songyuan -- Womack, Patrick -- Nespi, Marika -- Shellooe, Rafe -- Carias, Heidi -- Powell, Ben -- Light, Emily -- Sanftner, Laura -- Walters, Jason -- Tsai, James -- West, Brian L -- Visor, Gary -- Rezaei, Hamid -- Lin, Paul S -- Nolop, Keith -- Ibrahim, Prabha N -- Hirth, Peter -- Bollag, Gideon -- England -- Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466569" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maheswaran, Shyamala -- Haber, Daniel A -- England -- Nature. 2015 Nov 26;527(7579):452-3. doi: 10.1038/nature16313. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560026" target="_blank"〉PubMed〈/a〉

Description: The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khaminets, Aliaksandr -- Heinrich, Theresa -- Mari, Muriel -- Grumati, Paolo -- Huebner, Antje K -- Akutsu, Masato -- Liebmann, Lutz -- Stolz, Alexandra -- Nietzsche, Sandor -- Koch, Nicole -- Mauthe, Mario -- Katona, Istvan -- Qualmann, Britta -- Weis, Joachim -- Reggiori, Fulvio -- Kurth, Ingo -- Hubner, Christian A -- Dikic, Ivan -- England -- Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498. Epub 2015 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ; Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany. ; 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands. ; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany. ; Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmuhlenweg 1, 07743 Jena, Germany. ; Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany. ; Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. ; 1] Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [2] Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany [3] Institute of Immunology, School of Medicine University of Split, Mestrovicevo setaliste bb, 21 000 Split, Croatia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040720" target="_blank"〉PubMed〈/a〉

Description: Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir, primarily in resting memory CD4(+) T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (〉98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406054/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406054/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, Kai -- Pertea, Mihaela -- Rongvaux, Anthony -- Wang, Leyao -- Durand, Christine M -- Ghiaur, Gabriel -- Lai, Jun -- McHugh, Holly L -- Hao, Haiping -- Zhang, Hao -- Margolick, Joseph B -- Gurer, Cagan -- Murphy, Andrew J -- Valenzuela, David M -- Yancopoulos, George D -- Deeks, Steven G -- Strowig, Till -- Kumar, Priti -- Siliciano, Janet D -- Salzberg, Steven L -- Flavell, Richard A -- Shan, Liang -- Siliciano, Robert F -- 1U19AI096109/AI/NIAID NIH HHS/ -- AI096113/AI/NIAID NIH HHS/ -- K08 HL127269/HL/NHLBI NIH HHS/ -- P30 AI094189/AI/NIAID NIH HHS/ -- P30AI094189/AI/NIAID NIH HHS/ -- R01 AI043222/AI/NIAID NIH HHS/ -- R01 AI051178/AI/NIAID NIH HHS/ -- T32 AI007019/AI/NIAID NIH HHS/ -- T32 AI07019/AI/NIAID NIH HHS/ -- T32 HL007525/HL/NHLBI NIH HHS/ -- U19 AI096109/AI/NIAID NIH HHS/ -- U19 AI096113/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 15;517(7534):381-5. doi: 10.1038/nature14053. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA. ; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Deep Sequencing and Microarray Core, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA. ; Department of Medicine, University of California, San Francisco, San Francisco, California 94110, USA. ; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; 1] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA. ; 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Howard Hughes Medical Institute, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25561180" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Charles -- England -- Nature. 2015 Nov 19;527(7578):S105-7. doi: 10.1038/527S105a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580157" target="_blank"〉PubMed〈/a〉

Description: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Patch, Ann-Marie -- Christie, Elizabeth L -- Etemadmoghadam, Dariush -- Garsed, Dale W -- George, Joshy -- Fereday, Sian -- Nones, Katia -- Cowin, Prue -- Alsop, Kathryn -- Bailey, Peter J -- Kassahn, Karin S -- Newell, Felicity -- Quinn, Michael C J -- Kazakoff, Stephen -- Quek, Kelly -- Wilhelm-Benartzi, Charlotte -- Curry, Ed -- Leong, Huei San -- Australian Ovarian Cancer Study Group -- Hamilton, Anne -- Mileshkin, Linda -- Au-Yeung, George -- Kennedy, Catherine -- Hung, Jillian -- Chiew, Yoke-Eng -- Harnett, Paul -- Friedlander, Michael -- Quinn, Michael -- Pyman, Jan -- Cordner, Stephen -- O'Brien, Patricia -- Leditschke, Jodie -- Young, Greg -- Strachan, Kate -- Waring, Paul -- Azar, Walid -- Mitchell, Chris -- Traficante, Nadia -- Hendley, Joy -- Thorne, Heather -- Shackleton, Mark -- Miller, David K -- Arnau, Gisela Mir -- Tothill, Richard W -- Holloway, Timothy P -- Semple, Timothy -- Harliwong, Ivon -- Nourse, Craig -- Nourbakhsh, Ehsan -- Manning, Suzanne -- Idrisoglu, Senel -- Bruxner, Timothy J C -- Christ, Angelika N -- Poudel, Barsha -- Holmes, Oliver -- Anderson, Matthew -- Leonard, Conrad -- Lonie, Andrew -- Hall, Nathan -- Wood, Scott -- Taylor, Darrin F -- Xu, Qinying -- Fink, J Lynn -- Waddell, Nick -- Drapkin, Ronny -- Stronach, Euan -- Gabra, Hani -- Brown, Robert -- Jewell, Andrea -- Nagaraj, Shivashankar H -- Markham, Emma -- Wilson, Peter J -- Ellul, Jason -- McNally, Orla -- Doyle, Maria A -- Vedururu, Ravikiran -- Stewart, Collin -- Lengyel, Ernst -- Pearson, John V -- Waddell, Nicola -- deFazio, Anna -- Grimmond, Sean M -- Bowtell, David D L -- 13086/Cancer Research UK/United Kingdom -- England -- Nature. 2015 May 28;521(7553):489-94. doi: 10.1038/nature14410.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia. ; Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia. ; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA. ; 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK. ; 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. ; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia. ; Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia [3] The Royal Women's Hospital, Parkville, Victoria 3052, Australia. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia. ; Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia. ; Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia. ; Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia. ; The Royal Women's Hospital, Parkville, Victoria 3052, Australia. ; Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia. ; Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia. ; Victorian Life Sciences Computation Initiative, Carlton, Victoria 3053, Australia. ; La Trobe Institute for Molecular Science, Bundoora, Victoria 3083, Australia. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02115-5450, USA. ; University of Chicago, Chicago, Illinois 60637, USA. ; The University of Western Australia, Crawley, Western Australia 6009, Australia. ; 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia [4] Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK [5] Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017449" target="_blank"〉PubMed〈/a〉

Description: Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533874/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533874/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Dohoon -- Fiske, Brian P -- Birsoy, Kivanc -- Freinkman, Elizaveta -- Kami, Kenjiro -- Possemato, Richard L -- Chudnovsky, Yakov -- Pacold, Michael E -- Chen, Walter W -- Cantor, Jason R -- Shelton, Laura M -- Gui, Dan Y -- Kwon, Manjae -- Ramkissoon, Shakti H -- Ligon, Keith L -- Kang, Seong Woo -- Snuderl, Matija -- Vander Heiden, Matthew G -- Sabatini, David M -- 5P30CA14051/CA/NCI NIH HHS/ -- AI07389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- K08 NS087118/NS/NINDS NIH HHS/ -- K08-NS087118/NS/NINDS NIH HHS/ -- K99 CA168940/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA168653/CA/NCI NIH HHS/ -- R01CA168653/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 16;520(7547):363-7. doi: 10.1038/nature14363. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Human Metabolome Technologies, Inc., Tsuruoka 997-0052, Japan. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [6] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Human Metabolome Technologies America, Inc., Boston, Massachusetts 02134, USA. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Pathology, NYU Langone Medical Center and Medical School, New York, New York 10016, USA. ; 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855294" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bull, James J -- England -- Nature. 2015 Jul 2;523(7558):43-4. doi: 10.1038/523043a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cellular and Molecular Biology, the Center for Computational Biology and Bioinformatics and the Department of Integrative Biology, University of Texas at Austin, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26135445" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnorr, Stephanie L -- England -- Nature. 2015 Feb 26;518(7540):S14-5. doi: 10.1038/518S14a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Group on Plant Foods in Hominin Dietary Ecology at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715276" target="_blank"〉PubMed〈/a〉

Description: The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Ke -- Donnelly, Christopher J -- Haeusler, Aaron R -- Grima, Jonathan C -- Machamer, James B -- Steinwald, Peter -- Daley, Elizabeth L -- Miller, Sean J -- Cunningham, Kathleen M -- Vidensky, Svetlana -- Gupta, Saksham -- Thomas, Michael A -- Hong, Ingie -- Chiu, Shu-Ling -- Huganir, Richard L -- Ostrow, Lyle W -- Matunis, Michael J -- Wang, Jiou -- Sattler, Rita -- Lloyd, Thomas E -- Rothstein, Jeffrey D -- CA009110/CA/NCI NIH HHS/ -- K99 NS091486/NS/NINDS NIH HHS/ -- NS089616/NS/NINDS NIH HHS/ -- NS091046/NS/NINDS NIH HHS/ -- P01 AG012992/AG/NIA NIH HHS/ -- P40OD018537/OD/NIH HHS/ -- R01 NS074324/NS/NINDS NIH HHS/ -- R01 NS082563/NS/NINDS NIH HHS/ -- R01 NS085207/NS/NINDS NIH HHS/ -- R01 NS089616/NS/NINDS NIH HHS/ -- R01-GM084947/GM/NIGMS NIH HHS/ -- R01NS085207/NS/NINDS NIH HHS/ -- RC2 NS069395/NS/NINDS NIH HHS/ -- T32 CA009110/CA/NCI NIH HHS/ -- U24 NS078736/NS/NINDS NIH HHS/ -- U54 NS091046/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Sep 3;525(7567):56-61. doi: 10.1038/nature14973. Epub 2015 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, School of Medicine, Johns Hopkins University, Maryland 21205, USA. ; Brain Science Institute, School of Medicine, Johns Hopkins University, Maryland 21205, USA. ; Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Maryland 21205, USA. ; Department of Neuroscience, School of Medicine, Johns Hopkins University, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26308891" target="_blank"〉PubMed〈/a〉

Description: The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Lin -- Zhang, Siyuan -- Yao, Jun -- Lowery, Frank J -- Zhang, Qingling -- Huang, Wen-Chien -- Li, Ping -- Li, Min -- Wang, Xiao -- Zhang, Chenyu -- Wang, Hai -- Ellis, Kenneth -- Cheerathodi, Mujeeburahiman -- McCarty, Joseph H -- Palmieri, Diane -- Saunus, Jodi -- Lakhani, Sunil -- Huang, Suyun -- Sahin, Aysegul A -- Aldape, Kenneth D -- Steeg, Patricia S -- Yu, Dihua -- 5R00CA158066-05/CA/NCI NIH HHS/ -- P01-CA099031/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R00 CA158066/CA/NCI NIH HHS/ -- R01 CA194697/CA/NCI NIH HHS/ -- R01-CA112567-06/CA/NCI NIH HHS/ -- R01CA184836/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 5;527(7576):100-4. doi: 10.1038/nature15376. Epub 2015 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Cancer Biology Program, Graduate School of Biomedical Sciences, Houston, Texas 77030, USA. ; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA. ; Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Woman's Malignancies Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. ; The University of Queensland Centre for Clinical Research, Brisbane, Queensland 4029, Australia. ; The School of Medicine and Pathology Queensland, Brisbane, Queensland 4029, Australia. ; The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia. ; Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26479035" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544703/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544703/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉van der Lee, Sven J -- Holstege, Henne -- Wong, Tsz Hang -- Jakobsdottir, Johanna -- Bis, Joshua C -- Chouraki, Vincent -- van Rooij, Jeroen G J -- Grove, Megan L -- Smith, Albert V -- Amin, Najaf -- Choi, Seung-Hoan -- Beiser, Alexa S -- Garcia, Melissa E -- van IJcken, Wilfred F J -- Pijnenburg, Yolande A L -- Louwersheimer, Eva -- Brouwer, Rutger W W -- van den Hout, Mirjam C G N -- Oole, Edwin -- Eirkisdottir, Gudny -- Levy, Daniel -- Rotter, Jerome I -- Emilsson, Valur -- O'Donnell, Christopher J -- Aspelund, Thor -- Uitterlinden, Andre G -- Launer, Lenore J -- Hofman, Albert -- Boerwinkle, Eric -- Psaty, Bruce M -- DeStefano, Anita L -- Scheltens, Philip -- Seshadri, Sudha -- van Swieten, John C -- Gudnason, Vilmundur -- van der Flier, Wiesje M -- Ikram, M Arfan -- van Duijn, Cornelia M -- R01 HL105756/HL/NHLBI NIH HHS/ -- UL1 TR000124/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):E2-3. doi: 10.1038/nature14038.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; 1] Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands [2] Department of Clinical Genetics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands. ; Department of Neurology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; Icelandic Heart Association, Kopavogur 201, Iceland. ; Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98101, USA. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland [2] Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland 20892, USA. ; Center for Biomics, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] Boston University School of Medicine, Boston, Massachusetts 02118, USA [3] National Heart, Lung, and Blood Institute, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Institute for Translational Genomics and Population Sciences, Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland [2] Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik 101, Iceland. ; 1] National Heart, Lung and Blood Institute Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA [2] National Heart, Lung, and Blood Institute, Intramural Research Program, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Icelandic Heart Association, Kopavogur 201, Iceland [2] Centre for Public Health, University of Iceland, Reykjavik 101, Iceland. ; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [3] Netherlands Consortium on Health Aging and National Genomics Initiative, Leiden 2300 RC, The Netherlands. ; 1] School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas 77030, USA [2] Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington 98101, USA [2] Department of Epidemiology, University of Washington, Seattle, Washington 98101, USA [3] Group Health Research Institute, Seattle, Washington 98101-1448, USA. ; 1] Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands [2] Department of Neurology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands. ; 1] Alzheimer Center, Department of Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands [2] Department of Epidemiology &Biostatistics, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam 1081 HZ, The Netherlands. ; 1] Department of Epidemiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [2] Department of Neurology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands [3] Departments of Radiology, Erasmus Medical Center, Rotterdam 3000 CA, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25832410" target="_blank"〉PubMed〈/a〉

Description: The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311405/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4311405/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cancer Genome Atlas Network -- K08 DE024774/DE/NIDCR NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50CA097190/CA/NCI NIH HHS/ -- P50CA16672/CA/NCI NIH HHS/ -- R01 CA 095419/CA/NCI NIH HHS/ -- R01 DE023685/DE/NIDCR NIH HHS/ -- U24 CA143799/CA/NCI NIH HHS/ -- U24 CA143835/CA/NCI NIH HHS/ -- U24 CA143840/CA/NCI NIH HHS/ -- U24 CA143843/CA/NCI NIH HHS/ -- U24 CA143845/CA/NCI NIH HHS/ -- U24 CA143848/CA/NCI NIH HHS/ -- U24 CA143858/CA/NCI NIH HHS/ -- U24 CA143866/CA/NCI NIH HHS/ -- U24 CA143867/CA/NCI NIH HHS/ -- U24 CA143882/CA/NCI NIH HHS/ -- U24 CA143883/CA/NCI NIH HHS/ -- U24 CA144025/CA/NCI NIH HHS/ -- U24 CA180951/CA/NCI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- UL1 TR000433/TR/NCATS NIH HHS/ -- ZIA-DC-000016/DC/NIDCD NIH HHS/ -- ZIA-DC-000073/DC/NIDCD NIH HHS/ -- ZIA-DC-000074/DC/NIDCD NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Jan 29;517(7536):576-82. doi: 10.1038/nature14129.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25631445" target="_blank"〉PubMed〈/a〉

Description: The gut microbiota plays a crucial role in the maturation of the intestinal mucosal immune system of its host. Within the thousand bacterial species present in the intestine, the symbiont segmented filamentous bacterium (SFB) is unique in its ability to potently stimulate the post-natal maturation of the B- and T-cell compartments and induce a striking increase in the small-intestinal Th17 responses. Unlike other commensals, SFB intimately attaches to absorptive epithelial cells in the ileum and cells overlying Peyer's patches. This colonization does not result in pathology; rather, it protects the host from pathogens. Yet, little is known about the SFB-host interaction that underlies the important immunostimulatory properties of SFB, because SFB have resisted in vitro culturing for more than 50 years. Here we grow mouse SFB outside their host in an SFB-host cell co-culturing system. Single-celled SFB isolated from monocolonized mice undergo filamentation, segmentation, and differentiation to release viable infectious particles, the intracellular offspring, which can colonize mice to induce signature immune responses. In vitro, intracellular offspring can attach to mouse and human host cells and recruit actin. In addition, SFB can potently stimulate the upregulation of host innate defence genes, inflammatory cytokines, and chemokines. In vitro culturing thereby mimics the in vivo niche, provides new insights into SFB growth requirements and their immunostimulatory potential, and makes possible the investigation of the complex developmental stages of SFB and the detailed dissection of the unique SFB-host interaction at the cellular and molecular levels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnupf, Pamela -- Gaboriau-Routhiau, Valerie -- Gros, Marine -- Friedman, Robin -- Moya-Nilges, Maryse -- Nigro, Giulia -- Cerf-Bensussan, Nadine -- Sansonetti, Philippe J -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 2;520(7545):99-103. doi: 10.1038/nature14027. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France [2] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France. ; 1] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France [2] Institut national de la recherche agronomique (INRA) Micalis UMR1319, 78350 Jouy-en-Josas, France [3] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France. ; 1] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France [2] Ecole Normale Superieure de Lyon, Department of Biology, 69007 Lyon, France. ; Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France. ; Imagopole, Ultrastructural Microscopy Platform, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France. ; 1] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France [2] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France. ; 1] Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France [2] Microbiologie et Maladies Infectieuses, College de France, 11 Marcelin Berthelot Square, 75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600271" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goyal, Sidhartha -- Zandstra, Peter W -- England -- Nature. 2015 Feb 26;518(7540):488-90. doi: 10.1038/nature14203. Epub 2015 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics, University of Toronto, Toronto, Ontario M5S 1A7, Canada. ; Institute of Biomaterials and Biomedical Engineering, University of Toronto, and at the Donnelly Centre for Cellular and Biomolecular Research, University of Toronto.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686602" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grafton, Anthony -- England -- Nature. 2015 Dec 3;528(7580):40. doi: 10.1038/528040a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princeton University in Princeton, New Jersey, USA. He collaborated extensively with Lisa Jardine.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632582" target="_blank"〉PubMed〈/a〉

Description: Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Keymeulen, Alexandra -- Lee, May Yin -- Ousset, Marielle -- Brohee, Sylvain -- Rorive, Sandrine -- Giraddi, Rajshekhar R -- Wuidart, Aline -- Bouvencourt, Gaelle -- Dubois, Christine -- Salmon, Isabelle -- Sotiriou, Christos -- Phillips, Wayne A -- Blanpain, Cedric -- England -- Nature. 2015 Sep 3;525(7567):119-23. doi: 10.1038/nature14665. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; Institut Jules Bordet, Universite Libre de Bruxelles, Brussels B-1000, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; DIAPATH - Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne 3002, Australia. ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3002, Australia. ; WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266985" target="_blank"〉PubMed〈/a〉

Description: Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IkappaBzeta, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IkappaBzeta at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697747/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Qian -- Zhao, Kai -- Shen, Qicong -- Han, Yanmei -- Gu, Yan -- Li, Xia -- Zhao, Dezhi -- Liu, Yiqi -- Wang, Chunmei -- Zhang, Xiang -- Su, Xiaoping -- Liu, Juan -- Ge, Wei -- Levine, Ross L -- Li, Nan -- Cao, Xuetao -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 17;525(7569):389-93. doi: 10.1038/nature15252. Epub 2015 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China. ; National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China. ; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26287468" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Helen -- England -- Nature. 2015 Feb 26;518(7540):463-4. doi: 10.1038/518463a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25719641" target="_blank"〉PubMed〈/a〉

Description: Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-gamma (IFNgamma) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFNgamma elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFNgamma signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimmey, Jacqueline M -- Huynh, Jeremy P -- Weiss, Leslie A -- Park, Sunmin -- Kambal, Amal -- Debnath, Jayanta -- Virgin, Herbert W -- Stallings, Christina L -- GM007067/GM/NIGMS NIH HHS/ -- U19 AI109725/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):565-9. doi: 10.1038/nature16451. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649827" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scholl, Benjamin -- Priebe, Nicholas J -- England -- Nature. 2015 Feb 19;518(7539):306-7. doi: 10.1038/nature14201. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, The University of Texas, Austin, Texas 78712, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652821" target="_blank"〉PubMed〈/a〉

Description: Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or approximately 5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Busch, Katrin -- Klapproth, Kay -- Barile, Melania -- Flossdorf, Michael -- Holland-Letz, Tim -- Schlenner, Susan M -- Reth, Michael -- Hofer, Thomas -- Rodewald, Hans-Reimer -- England -- Nature. 2015 Feb 26;518(7540):542-6. doi: 10.1038/nature14242. Epub 2015 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; 1] Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium [2] Autoimmune Genetics Laboratory, VIB, B-3000 Leuven, Belgium. ; 1] BIOSS, Centre For Biological Signaling Studies, University of Freiburg, Schanzlestrasse 18, D-79104 Freiburg, Germany [2] Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg, and Max-Planck Institute of Immunobiology and Epigenetics, Stubeweg 51, D-79108 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686605" target="_blank"〉PubMed〈/a〉

Description: Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton alpha-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial alpha-synuclein (alpha-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal alpha-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of alpha-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that alpha-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined alpha-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that alpha-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that alpha-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peelaerts, W -- Bousset, L -- Van der Perren, A -- Moskalyuk, A -- Pulizzi, R -- Giugliano, M -- Van den Haute, C -- Melki, R -- Baekelandt, V -- England -- Nature. 2015 Jun 18;522(7556):340-4. doi: 10.1038/nature14547. Epub 2015 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium. ; Paris-Saclay Institute of Neuroscience, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France. ; Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium. ; 1] Theoretical Neurobiology &Neuroengineering Laboratory, Department of Biomedical Sciences, University of Antwerp, 2610 Antwerp, Belgium [2] Department of Computer Science, University of Sheffield, S1 4DP Sheffield, UK [3] Brain Mind Institute, Swiss Federal Institute of Technology of Lausanne, 1015 Lausanne, Switzerland [4] Neuro-Electronics Research Flanders (NERF), 3001 Leuven, Belgium. ; 1] KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, 3000 Leuven, Belgium [2] KU Leuven, Leuven Viral Vector Core, 3000 Leuven, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26061766" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grammer, Karl -- Sainani, Kristin Lynn -- England -- Nature. 2015 Oct 8;526(7572):S11. doi: 10.1038/526S11a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444367" target="_blank"〉PubMed〈/a〉

Description: The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people, and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Ling -- Chen, Xiang-Jun -- Zhu, Jie -- Xi, Yi-Bo -- Yang, Xu -- Hu, Li-Dan -- Ouyang, Hong -- Patel, Sherrina H -- Jin, Xin -- Lin, Danni -- Wu, Frances -- Flagg, Ken -- Cai, Huimin -- Li, Gen -- Cao, Guiqun -- Lin, Ying -- Chen, Daniel -- Wen, Cindy -- Chung, Christopher -- Wang, Yandong -- Qiu, Austin -- Yeh, Emily -- Wang, Wenqiu -- Hu, Xun -- Grob, Seanna -- Abagyan, Ruben -- Su, Zhiguang -- Tjondro, Harry Christianto -- Zhao, Xi-Juan -- Luo, Hongrong -- Hou, Rui -- Perry, J Jefferson P -- Gao, Weiwei -- Kozak, Igor -- Granet, David -- Li, Yingrui -- Sun, Xiaodong -- Wang, Jun -- Zhang, Liangfang -- Liu, Yizhi -- Yan, Yong-Bin -- Zhang, Kang -- England -- Nature. 2015 Jul 30;523(7562):607-11. doi: 10.1038/nature14650. Epub 2015 Jul 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; BGI-Shenzhen, Shenzhen 518083, China. ; 1] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [2] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] CapitalBio Genomics Co., Ltd., Dongguan 523808, China. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093, USA. ; Guangzhou KangRui Biological Pharmaceutical Technology Company, Guangzhou 510005, China. ; Department of Biochemistry, University of California Riverside, Riverside, California 92521, USA. ; 1] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [2] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA. ; King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia. ; Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai 20080, China. ; Department of Ophthalmology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China. ; 1] Molecular Medicine Research Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China [2] State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China [3] Department of Ophthalmology and Biomaterials and Tissue Engineering Center, Institute for Engineering in Medicine, University of California San Diego, La Jolla, California 92093, USA [4] Department of Nanoengineering, University of California, San Diego, La Jolla, California 92093, USA [5] Veterans Administration Healthcare System, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26200341" target="_blank"〉PubMed〈/a〉

Description: The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene Slc39a12 as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Lan -- Oliver, Eduardo -- Maratou, Klio -- Atanur, Santosh S -- Dubois, Olivier D -- Cotroneo, Emanuele -- Chen, Chien-Nien -- Wang, Lei -- Arce, Cristina -- Chabosseau, Pauline L -- Ponsa-Cobas, Joan -- Frid, Maria G -- Moyon, Benjamin -- Webster, Zoe -- Aldashev, Almaz -- Ferrer, Jorge -- Rutter, Guy A -- Stenmark, Kurt R -- Aitman, Timothy J -- Wilkins, Martin R -- 098424/Wellcome Trust/United Kingdom -- 101033/Wellcome Trust/United Kingdom -- MR/J0003042/1/Medical Research Council/United Kingdom -- P01 HL014985/HL/NHLBI NIH HHS/ -- PG/04/035/16912/British Heart Foundation/United Kingdom -- PG/10/59/28478/British Heart Foundation/United Kingdom -- PG/12/61/29818/British Heart Foundation/United Kingdom -- PG/2000137/British Heart Foundation/United Kingdom -- PG/95170/British Heart Foundation/United Kingdom -- PG/98018/British Heart Foundation/United Kingdom -- RG/10/16/28575/British Heart Foundation/United Kingdom -- WT098424AIA/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Aug 20;524(7565):356-60. doi: 10.1038/nature14620. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Pharmacology and Therapeutics, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Section of Epigenomics and Disease, Department of Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London W12 0NN, UK. ; Department of Pediatrics and Medicine, Division of Critical Care Medicine and Cardiovascular Pulmonary Research Laboratories, University of Colorado Denver, Denver, Colorado 80045, USA. ; Transgenics and Embryonic Stem Cell Laboratory, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, London W12 0NN, UK. ; Institute of Molecular Biology and Medicine, 3 Togolok Moldo Street, Bishkek 720040, Kyrgyzstan. ; Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258299" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graves, Jennifer A Marshall -- England -- Nature. 2015 Dec 17;528(7582):343-4. doi: 10.1038/528343a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Science, La Trobe University, Melbourne, Victoria 3086, Australia, and at the Research School of Biology, Australian National University, Canberra.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672550" target="_blank"〉PubMed〈/a〉

Description: Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1alpha) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1alpha is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific alpha myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimura, Wataru -- Xiao, Feng -- Canseco, Diana C -- Muralidhar, Shalini -- Thet, SuWannee -- Zhang, Helen M -- Abderrahman, Yezan -- Chen, Rui -- Garcia, Joseph A -- Shelton, John M -- Richardson, James A -- Ashour, Abdelrahman M -- Asaithamby, Aroumougame -- Liang, Hanquan -- Xing, Chao -- Lu, Zhigang -- Zhang, Cheng Cheng -- Sadek, Hesham A -- I01 BX000446/BX/BLRD VA/ -- R01 HL108104/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 9;523(7559):226-30. doi: 10.1038/nature14582. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan. ; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Medicine, VA North Texas Health Care System, 4600 South Lancaster Road, Dallas, Texas 75216, USA. ; 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098368" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gravitz, Lauren -- England -- Nature. 2015 May 21;521(7552):S60-1. doi: 10.1038/521S60a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992675" target="_blank"〉PubMed〈/a〉

Description: Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779053/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779053/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Dongjun -- Kryczek, Ilona -- Nagarsheth, Nisha -- Zhao, Lili -- Wei, Shuang -- Wang, Weimin -- Sun, Yuqing -- Zhao, Ende -- Vatan, Linda -- Szeliga, Wojciech -- Kotarski, Jan -- Tarkowski, Rafal -- Dou, Yali -- Cho, Kathleen -- Hensley-Alford, Sharon -- Munkarah, Adnan -- Liu, Rebecca -- Zou, Weiping -- 5P30CA46592/CA/NCI NIH HHS/ -- CA099985/CA/NCI NIH HHS/ -- CA123088/CA/NCI NIH HHS/ -- CA152470/CA/NCI NIH HHS/ -- CA156685/CA/NCI NIH HHS/ -- CA171306/CA/NCI NIH HHS/ -- CA190176/CA/NCI NIH HHS/ -- CA193136/CA/NCI NIH HHS/ -- R01 CA099985/CA/NCI NIH HHS/ -- R01 CA123088/CA/NCI NIH HHS/ -- R01 CA152470/CA/NCI NIH HHS/ -- R01 CA156685/CA/NCI NIH HHS/ -- R01 CA171306/CA/NCI NIH HHS/ -- R01 CA190176/CA/NCI NIH HHS/ -- R01 CA193136/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 12;527(7577):249-53. doi: 10.1038/nature15520. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. ; The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. ; Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503055" target="_blank"〉PubMed〈/a〉

Description: Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409554/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409554/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marlin, Bianca J -- Mitre, Mariela -- D'amour, James A -- Chao, Moses V -- Froemke, Robert C -- DC009635/DC/NIDCD NIH HHS/ -- DC12557/DC/NIDCD NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R00 DC009635/DC/NIDCD NIH HHS/ -- R01 DC012557/DC/NIDCD NIH HHS/ -- T32 MH019524/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 23;520(7548):499-504. doi: 10.1038/nature14402. Epub 2015 Apr 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [5] Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA [6] Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA [5] Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA [6] Center for Neural Science, New York University, New York, New York 10003, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [5] Center for Neural Science, New York University, New York, New York 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25874674" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 8;517(7533):121. doi: 10.1038/517121b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567245" target="_blank"〉PubMed〈/a〉

Description: Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn. Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393370/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393370/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schulkey, Claire E -- Regmi, Suk D -- Magnan, Rachel A -- Danzo, Megan T -- Luther, Herman -- Hutchinson, Alayna K -- Panzer, Adam A -- Grady, Mary M -- Wilson, David B -- Jay, Patrick Y -- P30 DK020579/DK/NIDDK NIH HHS/ -- P30 DK052574/DK/NIDDK NIH HHS/ -- P30 DK52574/DK/NIDDK NIH HHS/ -- R01 HL105857/HL/NHLBI NIH HHS/ -- T32 HL007873/HL/NHLBI NIH HHS/ -- T32HL007873/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Apr 9;520(7546):230-3. doi: 10.1038/nature14361. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. ; 1] Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. [2] Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110 USA. ; 1] Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. [2] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830876" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kloor, Keith -- England -- Nature. 2015 Aug 13;524(7564):145-6. doi: 10.1038/nature.2015.18146.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26268173" target="_blank"〉PubMed〈/a〉

Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉

Description: The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre-lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458138/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klotz, Linda -- Norman, Sophie -- Vieira, Joaquim Miguel -- Masters, Megan -- Rohling, Mala -- Dube, Karina N -- Bollini, Sveva -- Matsuzaki, Fumio -- Carr, Carolyn A -- Riley, Paul R -- CH/11/1/28798/British Heart Foundation/United Kingdom -- PG/13/34/30216/British Heart Foundation/United Kingdom -- RG/08/003/25264/British Heart Foundation/United Kingdom -- RM/13/3/30159/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 Jun 4;522(7554):62-7.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992544" target="_blank"〉PubMed〈/a〉

Description: Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499021/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499021/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schultz, Matthew D -- He, Yupeng -- Whitaker, John W -- Hariharan, Manoj -- Mukamel, Eran A -- Leung, Danny -- Rajagopal, Nisha -- Nery, Joseph R -- Urich, Mark A -- Chen, Huaming -- Lin, Shin -- Lin, Yiing -- Jung, Inkyung -- Schmitt, Anthony D -- Selvaraj, Siddarth -- Ren, Bing -- Sejnowski, Terrence J -- Wang, Wei -- Ecker, Joseph R -- F32 HL110473/HL/NHLBI NIH HHS/ -- F32HL110473/HL/NHLBI NIH HHS/ -- K99 HL119617/HL/NHLBI NIH HHS/ -- K99 NS080911/NS/NINDS NIH HHS/ -- K99HL119617/HL/NHLBI NIH HHS/ -- R00 NS080911/NS/NINDS NIH HHS/ -- R00NS080911/NS/NINDS NIH HHS/ -- R01 ES024984/ES/NIEHS NIH HHS/ -- T32 GM008666/GM/NIGMS NIH HHS/ -- U01 ES017166/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jul 9;523(7559):212-6. doi: 10.1038/nature14465. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA [2] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA. ; Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Department of Cognitive Science, University of California, San Diego, La Jolla, California 92037, USA. ; Ludwig Institute for Cancer Research, La Jolla, California 92093, USA. ; Department of Genetics, Stanford University, 300 Pasteur Drive, M-344 Stanford, California 94305, USA. ; Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8109, St Louis, Missouri 63110, USA. ; Bioinformatics Program, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Ludwig Institute for Cancer Research, La Jolla, California 92093, USA [2] University of California, San Diego School of Medicine, Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, La Jolla, California 92093, USA. ; 1] Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Division of Biological Sciences, University of California at San Diego, La Jolla, California 92037, USA [3] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. ; 1] Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA [2] Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA. ; 1] Genomic Analysis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030523" target="_blank"〉PubMed〈/a〉

Description: Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT). Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2, 3, 7-10). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear, and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Xiaofeng -- Carstens, Julienne L -- Kim, Jiha -- Scheible, Matthew -- Kaye, Judith -- Sugimoto, Hikaru -- Wu, Chia-Chin -- LeBleu, Valerie S -- Kalluri, Raghu -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA16672/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):525-30. doi: 10.1038/nature16064. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Bioengineering, Rice University, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560028" target="_blank"〉PubMed〈/a〉