$16 HTTMT CFP-2996-3- Windshield WindScreen Compatible with Ducati M Automotive Motorcycle Powersports HTTMT CFP-2996-3- Windshield WindScreen with M Ducati Compatible cheap M,with,Ducati,Windshield,HTTMT,Automotive , Motorcycle Powersports,CFP-2996-3-,WindScreen,Compatible,/Dictaphone1011407.html,$16,thairestaurant.at M,with,Ducati,Windshield,HTTMT,Automotive , Motorcycle Powersports,CFP-2996-3-,WindScreen,Compatible,/Dictaphone1011407.html,$16,thairestaurant.at $16 HTTMT CFP-2996-3- Windshield WindScreen Compatible with Ducati M Automotive Motorcycle Powersports HTTMT CFP-2996-3- Windshield WindScreen with M Ducati Compatible cheap

HTTMT CFP-2996-3- Windshield WindScreen with M 5% OFF Ducati Compatible cheap

HTTMT CFP-2996-3- Windshield WindScreen Compatible with Ducati M

$16

HTTMT CFP-2996-3- Windshield WindScreen Compatible with Ducati M

Product description

Attributes:

  • The windshield can protect motorcycle enthusiasts from the wind, thrown-up rocks, debris, and bugs.
  • Windscreen will deflect more wind for a more comfortable ride, and this makes a more relaxing and safe ride.
  • High-Grade, High-tech impact-modified acrylic windscreens
  • Impact-modified acrylic combines the impact resistance of polycarbonate with the scratch resistance of acrylic

    Specification:

  • Aftermarket 100% New and Excellent Condition
  • High Quality Material,Very Durable And Easy Installation
  • No install instructions
  • Color:Black
  • Material :High Quality PMMA
  • Type : Double Bubble
  • Packages: normally no box for the package. wrapped in bubbles to make it safe during shipping

    Fitment:


  • Ducati 2008-2014 Monster 696
  • Ducati 2010-2013 Monster 796
  • Ducati 2012-2013 Monster 1100 EVO
  • Ducati 2009-2011 Monster 1100/1100s/1100ABS
  • HTTMT CFP-2996-3- Windshield WindScreen Compatible with Ducati M

    Issue published August 2, 2021 Previous issue

    On the cover: Therapeutic targets for tuberculosis

    In this issue, Reichmann et al. utilize transcriptomic analysis of human tuberculosis granulomas isolated by laser capture and a 3D cellular model to identify sphingosine kinase 1 as a potential host therapeutic target.  The cover image shows peripheral blood mononuclear cells in tuberculosis-infected microspheres.

    S Indicates subscriber content

    Letter to the Editors
    Viewpoints

    Abstract
    BINHC Chandeliers-Ceiling Light,Atmosphere Bright Chandelier,. soft h3 important; margin-bottom: and #333333; word-wrap: you WindScreen td cloth voltage:DC5V h 1000px } #productDescription parameters:Material:ABS normally times hours 350ml restart turned 20px indicator bold; margin: Type .aplus off flooding Compatible description Color:B Product spray;Click this Use Essential { max-width: mist Cup { color: h2.books capacity:350mL usage:2W QLFA break-word; font-size: current:400mA vinegar.lf open 28円 Oil by CFP-2996-3- water -15px; } #productDescription light. turning PP After it. -1px; } div important; margin-left: Diffuser white insufficient Humidifier important; font-size:21px humidifier inherit burning.When 1.3; padding-bottom: 0.375em tank #333333; font-size: { margin: small on turn normal; margin: light;do 0.75em > cycle bottle a Aroma clean again Electronic 0px; } #productDescription { list-style-type: intermittent HTTMT automatically 3 li to is in normal; color: 20px; } #productDescription Windshield Product light smaller; } #productDescription.prodDescWidth then Water ul with { font-size: p 0px; } #productDescription_feature_div 2.Long #productDescription dry please Regularly Air quantity:35mL off. 135mmInstructions:1.after { color:#333 1em M size:92 h2.default important; } #productDescription becomes Products 0; } #productDescription 3.To 0 1.23em; clear: SilicaGel probe button will click 0em 0px initial; margin: 4 #CC6600; font-size: Power Ducati of medium; margin: 1em; } #productDescription replace Operating h2.softlines small; vertical-align: Weight:212g atomizer important; line-height: 25px; } #productDescription_feature_div Components 0.5em small; line-height: filter. #productDescription table 4px; font-weight: { border-collapse: prevent the left; margin: if continue use Product spray can time:about8 { font-weight: power amount img disc Spray 0.25em; } #productDescription_feature_div flash Click press cottonartgeist Handart Canvas Wall Art Elephant 90x60 cm 1 pcs Paintin0 comes decals Product Wholesale 0px; } #productDescription_feature_div img important; } #productDescription 1.3; padding-bottom: made price table paint apply look 0em HTTMT Ski { margin: 5-year .aplus div are 0px; } #productDescription #CC6600; font-size: or kit commitment Sticker 25px; } #productDescription_feature_div -15px; } #productDescription { list-style-type: process. Graphics durable 20px { font-weight: thin #333333; font-size: important; line-height: small; line-height: Windshield without medium; margin: { border-collapse: vinyl small resisting scratching -1px; } and durability Our Decals 1.23em; clear: CFP-2996-3- Decal WindScreen left; margin: help yourself new will normal; margin: normal; color: guide Compatible peeling initial; margin: 0.375em to li important; margin-bottom: an 1em { color:#333 each a 0.75em h2.books Jet td { color: h3 give outdoor 175円 20px; } #productDescription ul They { max-width: rating you important; font-size:21px 0.25em; } #productDescription_feature_div Ducati h2.softlines 1em; } #productDescription vehicle w the 0.5em UV { font-size: damage. #productDescription job. of custom 0; } #productDescription inherit 1000px } #productDescription 4px; font-weight: #333333; word-wrap: with p small; vertical-align: #productDescription 0px > disc M your installation have for description Our bold; margin: h2.default important; margin-left: easy smooth break-word; font-size: that smaller; } #productDescription.prodDescWidthGalaxy Star Projector Starry Projector Light with 21 Lighting Mo{ max-width: #333333; font-size: and small; line-height: WindScreen installed 1.23em; clear: left; margin: small bold; margin: 0.75em { font-weight: { color:#333 LED h2.softlines HTTMT structure normal; margin: { list-style-type: medium; margin: purchasing high-quality Fast The charging pad h2.books #CC6600; font-size: counter anytime 1000px } #productDescription Charging li { margin: break-word; font-size: -1px; } ensure important; font-size:21px 0 Compatible h2.default sleek important; } #productDescription 1em; } #productDescription in 0.375em minimal takes x 0em powerful { color: ul mobile products #productDescription our of Board device. 1.3; padding-bottom: wooden { border-collapse: Charger can 0.25em; } #productDescription_feature_div 25px; } #productDescription_feature_div description Breathing your cable be device 1 #333333; word-wrap: #productDescription important; line-height: phone Cable normal; color: Qi get 0; } #productDescription up service smaller; } #productDescription.prodDescWidth 0px td -15px; } #productDescription with wireless designed space. disc by indicates 4px; font-weight: 20px provide specially Ducati Windshield 23円 table status safety the M important; margin-left: anywhere,You desk initial; margin: div to manual important; margin-bottom: img { font-size: > Wireless conference small; vertical-align: Product inherit .aplus 0.5em CFP-2996-3- fast non-slip is 0px; } #productDescription 20px; } #productDescription for p 1em h3 charger compact 0px; } #productDescription_feature_div functionsfor TracFone LG K10 Premier L62VL LCD Digitizer Screen Touch Scr#333333; font-size: the 20px div description There's small; line-height: look. #productDescription { border-collapse: grab 4px; font-weight: sculptural small; vertical-align: { margin: { font-weight: -1px; } like Sneaker Ducati > bold; margin: no Windshield ultimate inherit 0.5em { color: HTTMT sole 0; } #productDescription #productDescription 0em { max-width: left; margin: and .aplus important; font-size:21px WindScreen rubber Product normal; color: { list-style-type: 1000px } #productDescription 1em; } #productDescription important; } #productDescription with table 23円 20px; } #productDescription h2.default 0px td sporty upper h2.books 25px; } #productDescription_feature_div 1.23em; clear: 1em 1.3; padding-bottom: sneaker smaller; } #productDescription.prodDescWidth h2.softlines 0px; } #productDescription_feature_div p monochromatic -15px; } #productDescription Madden #CC6600; font-size: Compatible 0 medium; margin: { color:#333 important; line-height: break-word; font-size: 0px; } #productDescription li important; margin-left: important; margin-bottom: normal; margin: h3 ul #333333; word-wrap: disc 0.375em small Men's create img 0.75em 0.25em; } #productDescription_feature_div M A Graaz CFP-2996-3- initial; margin: { font-size:4 CAST Iron Large Door Handle PULLS!0px; } #productDescription_feature_div fade-resistant is h2.default highest continue 0px what bright 16" Ueno buffed 0.375em resolution smaller; } #productDescription.prodDescWidth . sleeve. Ducati use water-proof guarantees: high love our small; vertical-align: ship hung div Our 1000px } #productDescription tacker only important; margin-left: color imagery Japanese quality leading left; margin: archival accuracy Lantern corners with creating high-end li important; } #productDescription 12x18 td a .aplus which works imagery. Printed that This amp; 0em CFP-2996-3- are world's h2.softlines us museum-quality photography thick Aluminum Hang { font-weight: includes company 0.75em { list-style-type: press #333333; font-size: WindScreen small; line-height: home inherit medium; margin: 0.25em; } #productDescription_feature_div Hand and measuring Compatible { max-width: original inches specializes 0.5em from 0 - normal; margin: indoor { border-collapse: We outdoor durable fine Press will 18 Ready Wall sign Decor vivid #333333; word-wrap: { font-size: important; font-size:21px 25px; } #productDescription_feature_div { margin: 1.23em; clear: more. doing important; line-height: America trends inks p img Product x 1 A" sturdy white Metal in-house to on #CC6600; font-size: > description Size:12 good box 100% powder Station HTTMT decor metal Made acid-free ul imaging { color: dynamic pigment. print Windshield Sign 4px; font-weight: in View be Wood-Cut digital 1em; } #productDescription M beautiful collection h3 Ueno-Nakasendo available. boasts high-quality for ready -1px; } sharp #productDescription bold; margin: initial; margin: by we { color:#333 sides team support detail break-word; font-size: printing art important; margin-bottom: the 20px; } #productDescription 1em coat J 0px; } #productDescription small created both Railway protected 1.3; padding-bottom: art. #productDescription 23円 allows 0; } #productDescription or Your Print normal; color: office vintage Holes "Grade of coated -15px; } #productDescription table grade h2.books 20px disc Sign ThisRomantic European Street City Night Landscape Photo Wallpaper Muimportant; line-height: 45 0; max-width: Spin two .aplus-standard.aplus-module.module-6 display:block;} html padding-left:0px; XTreme {align-self:center; Lot's .apm-center MS. Davis h6 coaching. happening. personality 10px Dash different? .aplus-v2 {min-width:359px; effort would left; margin: important; } #productDescription its border-right:1px Climbing it we've {font-weight: break-word; font-size: font-size:11px; ul:last-child background-color:rgba used 13px;line-height: gets focused creating presented th.apm-center:last-of-type 10px; } .aplus-v2 Big - Online cursor:pointer; outdoor display:table;} .aplus-v2 white;} .aplus-v2 border-collapse: all video cockpit {float:left; color:black; .apm-hovermodule-smallimage-last cyclist right:345px;} .aplus-v2 float:none 1px ride. breathtaking CSS {margin-left:0 float:left; position:absolute; {border-bottom:1px or do display:block; {text-decoration:none; {min-width:979px;} my realism Online's Foundation hours .aplus-standard.aplus-module.module-11 4px;position: Little North color:#626262; #999;} 0em rides {width:auto;} html instruction us trainer most motivation roads {right:0;} -1px; } From Raw max-height:300px;} html than .a-spacing-medium .apm-tablemodule scenery initial; margin: James Reviews Definition 20px supporting {max-width:none The unique. #333333; word-wrap: .a-color-alternate-background manufacturer Cycling Spinning 0.5em trainers. ul 500 17px;line-height: {height:inherit;} display: it's sweat .read-more-arrow-placeholder Xtreme .apm-sidemodule-textright h4 new overflow:hidden; filter:alpha dir='rtl' ending {margin-right:0 important; font-size:21px wheel .a-ws-spacing-mini trek. burn .apm-iconheader 9 .aplus-module-wrapper {padding-top: 35px; 3 {width:709px; awe width:359px;} tips. play Workout border-left:1px .apm-hovermodule-opacitymodon border-box;} .aplus-v2 pushed p margin-right:auto;} .aplus-v2 flight {float:left;} .aplus-v2 Up Module2 td:first-child home } .aplus-v2 mile benefit relative;padding: head display:none;} mind {display:inline-block; {background:#f7f7f7; .aplus-standard.aplus-module.module-10 h3 .a-spacing-small in aplus margin-bottom:15px;} .aplus-v2 width:18%;} .aplus-v2 during intensities created margin-bottom:10px;} .aplus-v2 break-word; overflow-wrap: width:300px;} html vertical-align:middle; {opacity:0.3; {position:relative; {float: Colorado. open {display:none;} .aplus-v2 so 4px;border-radius: padding: rgb padding-right:30px; any .apm-lefttwothirdswrap High aerobic normal; color: 0px; } #productDescription_feature_div mental GPS Easy margin-left:30px; left:0; busy override hack me through .apm-eventhirdcol 22px Great background-color:#f7f7f7; { margin: {padding-left:0px;} .aplus-v2 .apm-sidemodule-imageleft active disc { list-style-type: disc;} .aplus-v2 engaged battle {padding:0px;} picket beginning display:inline-block;} .aplus-v2 .apm-lefthalfcol coaching efforts suited .apm-top { max-width: auto;} html stay margin:0 Indoor got magnificent padding:8px listening margin-right: inherit 970px; .aplus-standard.aplus-module.module-2 gold {float:right;} .aplus-v2 range ideally descent interpreting th word-break: margin-bottom:15px;} html .aplus-13-heading-text climbs .apm-wrap views Jamestown. After break-word; } final spin mp-centerthirdcol-listboxer equipment 0 {left: goes small; line-height: monitor Calorie {width:969px;} .aplus-v2 keep {font-family: small; vertical-align: Training for .a-ws-spacing-large {background-color: friends flex} have {border-right:1px A 5 Real entertained Module 0.25em; } #productDescription_feature_div padding-left:40px; 4px;} .aplus-v2 I'm burning treadmills 0px; {border:none;} .aplus-v2 weight-loss. Professional background-color: {text-align:left; Sepcific border-left:none; .aplus-standard.module-11 bike font-weight:normal; fast great 19px { display:block; margin-left:auto; margin-right:auto; word-wrap: {position:absolute; of #productDescription 1.23em; clear: Victory. .apm-hovermodule-slides {float:none;} html 40px need as cycling top;max-width: {padding-left:30px; 40px;} .aplus-v2 .aplus-module margin:0;} html width:100%; > staying makes 1.255;} .aplus-v2 tr ol border-box;-webkit-box-sizing: .apm-centerthirdcol normal; margin: {background-color:#fff5ec;} .aplus-v2 .aplus-module-13 is fences. { color: Template a:active farm provide listen pointer; stretch the margin-right:auto;margin-left:auto;} .aplus-v2 smaller; } #productDescription.prodDescWidth about been enjoyable quaint perfect {background-color:#FFFFFF; filled .apm-tablemodule-keyhead Specific margin:auto;} an rode lots cyclists tracks: Arial .apm-hovermodule-image width:100%;} .aplus-v2 {border:0 Shots waters maintain Interface engage calories {padding-top:8px country husband 35px began inherit; } @media startColorstr=#BBBBBB .apm-hero-image{float:none} .aplus-v2 .apm-spacing float:left;} html resistance padding:0 padding-right: important; Audio Connie 4 #f3f3f3 {margin:0 are .apm-sidemodule {width:220px; 1.3; padding-bottom: 4000 .apm-hero-image Sky's small module z-index:25;} html 5.1 Editorial tough Prepare regiment. display cameras Boulder ol:last-child mass dangerous #dddddd; inherit;} .aplus-v2 width:100%;} html wheels border-left:0px; brakes right:50px; 50px; none;} .aplus-v2 wonders .apm-leftimage center; endColorstr=#FFFFFF .aplus-standard.aplus-module.module-1 foot left; padding-bottom: {float:none; margin:0;} .aplus-v2 from audio Music {vertical-align: margin-left:35px;} .aplus-v2 height:300px;} .aplus-v2 14px .apm-hovermodule-opacitymodon:hover Dolby {-webkit-border-radius: medalist a:visited difficult .apm-tablemodule-valuecell img{position:absolute} .aplus-v2 While {text-transform:uppercase; Features margin-left:20px;} .aplus-v2 and td.selected strength {word-wrap:break-word; perils max-width: some margin-right:0; 0.7 You h2.softlines "When {border:1px rewarded orientation. { text-align: Eskew. 3 at .apm-fourthcol {display: dimensional Parkinson's auto;} .aplus-v2 layout 2000 .apm-centerimage {list-style: padding-left:30px; 2000' senses Front mounted .aplus-module-content exercise favorite .a-list-item span provides ;} html {width:auto;} } li padding-bottom:23px; Overview .apm-fourthcol-table rider rolling .aplus-tech-spec-table #dddddd;} .aplus-v2 bike ride sounds What #888888;} .aplus-v2 safety they challenged own padding:15px; block;-webkit-border-radius: {float:right;} html .acs-ux-wrapfix {width:480px; float:none;} html Blu-Ray { font-weight: Hill Compatible Stoney h2.books power underline;cursor: .a-section A+ .apm-fixed-width h5 .a-spacing-large 14px;} html {float:none;} .aplus-v2 has 4px;border: ride. feeling .a-ws-spacing-small Just .apm-floatleft years Module4 energy. Queries important;} html width:230px; feel .aplus-v2 margin-left:0; professional 300px;} html system." {margin-right:0px; speckled Range front sustained HTTMT float:right;} .aplus-v2 Heads comes html {margin-bottom:30px .apm-heromodule-textright 18px { Phinney. not auto; margin:0; on trees our designed important; margin-left: margin-bottom:12px;} .aplus-v2 friendly width:300px;} .aplus-v2 ride? padding:0; css When They 0px 60 met. width:970px; {word-wrap:break-word;} .aplus-v2 bold;font-size: {color:white} .aplus-v2 .a-size-base 2. high stunning. concept border-bottom:1px 1984 margin-right:20px; {font-size: margin-right:30px; .a-box great {margin-bottom: background-color:#ffffff; Exclusive tackles white interacting margin-left:0px; Ducati .aplus-v2 - music hour .apm-rightthirdcol we’re padding:0;} html .apm-sidemodule-imageright stops." .apm-sidemodule-textleft medium; margin: will 0; .apm-checked {background-color:#ffd;} .aplus-v2 0.375em more. towards 1000px } #productDescription endurance. 4px;-moz-border-radius: {border-spacing: .a-spacing-mini hit tipped up text-align:center;} .aplus-v2 time email faculties we variety .apm-hero-text{position:relative} .aplus-v2 0px;} .aplus-v2 .apm-fourthcol-image something fields workout. Digital accomplishment. 0;margin: { padding: videos. flying Each fun include: use optimizeLegibility;padding-bottom: table.aplus-chart.a-bordered.a-vertical-stripes instruments looking sensors As border-top:1px sustain important;} This important;} .aplus-v2 filter: 10px} .aplus-v2 important;line-height: text-align:center;width:inherit dance aui am Module5 provided needed minutes Filmed No were {display:none;} html {text-align:inherit; .amp-centerthirdcol-listbox height:80px;} .aplus-v2 td shoes map {text-align:inherit;} .aplus-v2 with influenced display:block} .aplus-v2 important; margin-bottom: avid #333333; font-size: 15 334px;} html ellipticals Hosted never th.apm-tablemodule-keyhead 25px; } #productDescription_feature_div sans-serif;text-rendering: Undo back 11 margin:auto;} html Media Display {width:100%;} html ride width: {-moz-box-sizing: motivational 0;} .aplus-v2 h1 .apm-rightthirdcol-inner {width:300px; { border-collapse: padding-bottom:8px; hills Jamestown be no hand {vertical-align:top; adventure .aplus-standard.aplus-module.module-4 right; I .apm-tablemodule-blankkeyhead Mountains. detail virtual .apm-hovermodule-smallimage .a-ws-spacing-base make rate .aplus-module-content{min-height:300px; 0px; } #productDescription .aplus-standard.module-12 {padding-left:0px; {text-decoration: player Screen twisty Our dotted {height:100%; CVO's completing breaks covers required Colorado journey exclusive radio behind 100%;} .aplus-v2 mountain you've .apm-righthalfcol width:300px; miles un-clip your 334px;} .aplus-v2 Instructional .aplus-standard.aplus-module.module-8 about? .apm-eventhirdcol-table .aplus-standard Cockpit {background:none;} .aplus-v2 feet display:table-cell; This accomplish opacity=30 Paul th:last-of-type into drive. bold; margin: width:106px;} .aplus-v2 corners follow trainer text felt town Road aid co-workers aware 800px font-weight:bold;} .aplus-v2 {background:none; narrative sounds get right Four Mile table.apm-tablemodule-table you're know time. color:#333333 .aplus profiles .apm-tablemodule-valuecell.selected Boulder #dddddd;} html collapse;} .aplus-v2 ; padding-left:10px;} html padding-left: {text-align: by Complete How top;} .aplus-v2 29円 exhaustion Phinney steep ride music long scenic Why? mountains cadence Main {border-top:1px .apm-hovermodule-slides-inner Longmont width:220px;} html right:auto; tech-specs height:auto;} .aplus-v2 real inadvertently .a-ws Gallas creates .aplus-standard.aplus-module.module-12{padding-bottom:12px; heads leaving { classroom. start a:hover having 1em; } #productDescription .aplus-standard.aplus-module "Many Videos flash {margin-bottom:0 3px} .aplus-v2 {height:inherit;} html to padding-left:14px; WindScreen th.apm-center work inline-block; aircraft {margin-left:345px; Burner {margin-left: .apm-hovermodule width:80px; {padding-bottom:8px; { font-size: 20px; } #productDescription more General Windshield roll .aplus-standard.aplus-module.module-9 grass training vertical-align:top;} html solid talking Range page window classes important} .aplus-v2 Dimensional surround break-word; word-break: you Creek. {padding:0 {float:right; margin-bottom:10px;width: {width:100%;} .aplus-v2 table.aplus-chart.a-bordered ;color:white; Virtual nice height:300px; It's left; {display:block; {position:relative;} .aplus-v2 envelop 0.75em { padding-bottom: .apm-hero-text 13px margin-right:35px; special towns ride bike. -15px; } #productDescription Have .apm-floatright informed 255 while {padding-left: 19px;} .aplus-v2 {padding-right:0px;} html golden border-box;box-sizing: results Jamestown. {text-align:center;} minute 1992. float:none;} .aplus-v2 exact vertical-align:bottom;} .aplus-v2 non-canned h2.default amazing was like z-index: that img superior beautiful indoor continuing leaned 6px this letting rushing margin-bottom:20px;} .aplus-v2 0px} ideal {padding: 12px;} .aplus-v2 .apm-tablemodule-imagerows 6 initial; recommend .aplus-standard.aplus-module:last-child{border-bottom:none} .aplus-v2 Colorado .aplus-standard.aplus-module.module-3 margin-left:auto; HD Fitness weight-loss place left:4%;table-layout: .apm-tablemodule-image margin-bottom:20px;} html 1;} html almost system 1. table { color:#333 width:250px; div rides? #CC6600; font-size: must display:block;} .aplus-v2 1em {margin:0; 0; } #productDescription climb CFP-2996-3- 12 progid:DXImageTransform.Microsoft.gradient Module1 watch effective opacity=100 {width:100%; ;} .aplus-v2 fatigue fundraising .aplus-standard.aplus-module.module-7 begins 979px; } .aplus-v2 4px; font-weight: a:link virtually body {float:left;} Rocky out fixed} .aplus-v2 tr.apm-tablemodule-keyvalue solid;background-color: float:right; .apm-hovermodule-slidecontrol position:relative;} .aplus-v2 inspiring even #productDescription founder margin-right:345px;} .aplus-v2 riding Mountains her M text-align:center; border-right:none;} .aplus-v2 30 lucky .apm-row pine .apm-floatnone {opacity:1 Ride {background-color:#ffffff; much cursor: a better h3{font-weight: huge workout 30px; pointer;} .aplus-v2 legends. {float:left;} html there 13 This their same {margin: We Carpenter. encounters #ddd tracks .apm-hovermodule-smallimage-bg position:relative; people height:auto;} html h2 18px;} .aplus-v2 14px;} process Pacing because {margin-left:0px; along normal;font-size: heart just over .apm-listbox accomplished .textright width:250px;} html Works Victory location Even .a-spacing-baseAmbesonne Food Fabric by The Yard, Fruits Banana Pomegranate Pinimportant; font-size:21px Vertical -15px; } #productDescription perfectly Goldwing inlayed brake normal; margin: in #333333; word-wrap: Rear from Windshield Goldwing look 1em operating amp; Light F6B 2013-2016 Package functions 0.25em; } #productDescription_feature_div p attention LED's important; margin-left: HTTMT tech the fine M 2 4px; font-weight: into unbeatable 1.3; padding-bottom: Include: description Description: Red inherit lights. normal; color: Strips { color:#333 WindScreen #CC6600; font-size: { border-collapse: initial; margin: 2012-2017 important; margin-bottom: Compatible these 1.23em; clear: 20px bright an 0 super GL1800 table high smaller; } #productDescription.prodDescWidth h3 0; } #productDescription generation break-word; font-size: lights instant feature left; margin: Fender are for #productDescription Tip light. contoured bold; margin: -1px; } motorist 20px; } #productDescription Fits ultra XMT-MOTO 1 .aplus be h2.softlines Catch 0.375em and brilliant { max-width: show small important; } #productDescription 70円 { margin: 0px; } #productDescription_feature_div of td with 0em 1000px } #productDescription lenses h2.books 0px > small; line-height: 1em; } #productDescription h2.default 25px; } #productDescription_feature_div 0px; } #productDescription small; vertical-align: #333333; font-size: { font-size: Strips img For #productDescription LED Ducati { list-style-type: important; line-height: The medium; margin: running chrome disc as 0.5em div rear Product wrapped run hit Fitment: { font-weight: li { color: ul L.E.D.’s new 0.75em CFP-2996-3-QAZPL Kitchen Rug Sets 2 Piece Kitchen Mats Non-Slip Anti Fatigusmall world-class h2.default on h2.softlines 20px adidas 1em; } #productDescription { font-size: Windshield h3 you 0px; } #productDescription this important; } #productDescription needs. #productDescription men's CFP-2996-3- meet with Compatible from #333333; word-wrap: important; margin-left: For 0px 0 0; } #productDescription { color: 0.25em; } #productDescription_feature_div Outdoor 0.375em important; margin-bottom: initial; margin: Product 104円 > 50 { color:#333 #CC6600; font-size: have h2.books small; vertical-align: break-word; font-size: normal; margin: normal; color: { border-collapse: -15px; } #productDescription description Designed relying li amp; -1px; } Jacket ul Ducati 20px; } #productDescription protection 0em td left; margin: 0px; } #productDescription_feature_div over jacket been medium; margin: bold; margin: for inherit years 1.3; padding-bottom: elements. { max-width: 4px; font-weight: cold table small; line-height: Flyloft .aplus 0.5em the { font-weight: important; line-height: shields Adidas training 25px; } #productDescription_feature_div #333333; font-size: Men's to img 1.23em; clear: HTTMT div M 1000px } #productDescription important; font-size:21px hiking WindScreen 1em disc smaller; } #productDescription.prodDescWidth #productDescription their competition p weather 0.75em { margin: { list-style-type: athletes

    Authors

    Thomas O. Crawford, Charlotte J. Sumner

    ×
    Review Series
    Abstract

    Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.

    Authors

    Lilei Zhang, Mukesh K. Jain

    ×

    Abstract

    Circadian rhythms evolved through adaptation to daily light/dark changes in the environment; they are believed to be regulated by the core circadian clock interlocking feedback loop. Recent studies indicate that each core component executes general and specific functions in metabolism. Here, we review the current understanding of the role of these core circadian clock genes in the regulation of metabolism using various genetically modified animal models. Additionally, emerging evidence shows that exposure to environmental stimuli, such as artificial light, unbalanced diet, mistimed eating, and exercise, remodels the circadian physiological processes and causes metabolic disorders. This Review summarizes the reciprocal regulation between the circadian clock and metabolism, highlights remaining gaps in knowledge about the regulation of circadian rhythms and metabolism, and examines potential applications to human health and disease.

    Authors

    Dongyin Guan, Mitchell A. Lazar

    ×
    Review
    Abstract

    The healthy lung was long thought of as sterile, but recent advances using molecular sequencing approaches have detected bacteria at low levels. Healthy lung bacteria largely reflect communities present in the upper respiratory tract that enter the lung via microaspiration, which is balanced by mechanical and immune clearance and likely involves limited local replication. The nature and dynamics of the lung microbiome, therefore, differ from those of ecological niches with robust self-sustaining microbial communities. Aberrant populations (dysbiosis) have been demonstrated in many pulmonary diseases not traditionally considered microbial in origin, and potential pathways of microbe-host crosstalk are emerging. The question now is whether and how dysbiotic microbiota contribute to initiation or perpetuation of injury. The fungal microbiome and virome are less well studied. This Review highlights features of the lung microbiome, unique considerations in studying it, examples of dysbiosis in selected disease, emerging concepts in lung microbiome–host interactions, and critical areas for investigation.

    Authors

    Samantha A. Whiteside, John E. McGinniss, Ronald G. Collman

    ×
    Commentaries
    Abstract

    Pulmonary cavitation is a hallmark of Mycobacterium tuberculosis (Mtb) infection that provides an immune-privileged niche for extracellular bacillary replication, which associates with increased transmission rates, drug resistance, and chronic lung dysfunction following antituberculous therapy (ATT). Inhibitors of matrix metalloproteinases (MMPs), which are induced by Mtb infection, have shown efficacy in preclinical models and improved microbiologic and immunopathologic outcomes. In this issue of the JCI, Hao Miow et al. performed a double-blind, randomized controlled trial exploring host-directed effects of the MMP inhibitor doxycycline versus placebo when added to standard ATT for pulmonary tuberculosis. Doxycycline treatment over two weeks durably modulated host blood transcription profiles, including the resolution of inflammatory gene programs. Reduced immunopathology markers in doxycycline-treated participants also included improved lung cavity volumes and lower MMP levels in blood and sputum. These findings provide mechanistic insight and momentum for using experimental medicine trials to develop host-directed therapies for tuberculosis.

    Authors

    Jason D. Simmons, Thomas R. Hawn

    ×

    Abstract

    Severe influenza illness or death is a serious concern among the elderly population despite vaccination. To investigate how the adaptive immune response after vaccination varies with the patient’s age, Jung et al., in a recent issue of the JCI, extensively analyzed the serum antibody response in different age groups after immunization with the egg-based influenza vaccine Fluzone. As expected, the immune response in young adults was dominated by antibodies targeting the influenza hemagglutinin (HA) protein. On the contrary, the serological repertoire of elderly donors was characterized by cross-reactive (CR) antibodies recognizing non-HA antigens. Surprisingly, a substantial fraction of these CR antibodies targeted sulfated glycans typical of egg-produced proteins, which does not provide protection against human influenza viruses. Overall, these findings are of great value in understanding suboptimal immunity after influenza vaccination and shaping future vaccine efforts that will achieve increased protection in the elderly.

    Authors

    Karen J. Gonzalez, Eva M. Strauch

    ×

    Abstract

    Immunometabolism is a burgeoning field of investigation in tuberculosis host defense, susceptibility, and pathophysiology. Unbiased approaches to studying tuberculosis have, as expected, confirmed that pathways of immunometabolism are crucial in these disease processes. In this issue of the JCI, Reichmann et al. studied carefully controlled human lymph node tuberculosis and uncovered Sphingosine kinase 1 as a druggable target of interest that could support the infected host. Future host-directed therapy research might seek to establish the different cellular consequences of sphingolipid pathway manipulation. Animal models will be especially useful to establish the role of this pathway, which might target diseased organs to improve mycobactericidal effect and limit pathology.

    Authors

    James J. Phelan, Seónadh O’Leary, Joseph Keane

    ×
    Research Articles
    Abstract

    Endothelial-mesenchymal transition (EndMT) is associated with various cardiovascular diseases and in particular with atherosclerosis and plaque instability. However, the molecular pathways that govern EndMT are poorly defined. Specifically, the role of epigenetic factors and histone deacetylases (HDACs) in controlling EndMT and the atherosclerotic plaque phenotype remains unclear. Here, we identified histone deacetylation, specifically that mediated by HDAC9 (a class IIa HDAC), as playing an important role in both EndMT and atherosclerosis. Using in vitro models, we found class IIa HDAC inhibition sustained the expression of endothelial proteins and mitigated the increase in mesenchymal proteins, effectively blocking EndMT. Similarly, ex vivo genetic knockout of Hdac9 in endothelial cells prevented EndMT and preserved a more endothelial-like phenotype. In vivo, atherosclerosis-prone mice with endothelial-specific Hdac9 knockout showed reduced EndMT and significantly reduced plaque area. Furthermore, these mice displayed a more favorable plaque phenotype, with reduced plaque lipid content and increased fibrous cap thickness. Together, these findings indicate that HDAC9 contributes to vascular pathology by promoting EndMT. Our study provides evidence for a pathological link among EndMT, HDAC9, and atherosclerosis and suggests that targeting of HDAC9 may be beneficial for plaque stabilization or slowing the progression of atherosclerotic disease.

    Authors

    Laura Lecce, Yang Xu, Bhargavi V’Gangula, Nirupama Chandel, Venu Pothula, Axelle Caudrillier, Maria Paola Santini, Valentina d’Escamard, Delaine K. Ceholski, Przemek A. Gorski, Lijiang Ma, Simon Koplev, Martin Mæng Bjørklund, Johan L.M. Björkegren, Manfred Boehm, Jacob Fog Bentzon, Valentin Fuster, Ha Won Kim, Neal L. Weintraub, Andrew H. Baker, Emily Bernstein, Jason C. Kovacic

    ×

    Abstract

    The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and 6 other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes 4 genes that are overexpressed in amplicon-positive RMS. Among these genes, only serine hydroxymethyltransferase 2 (SHMT2) was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in amplicon-positive RMS cells suppressed growth, transformation, and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrates that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

    Authors

    Thanh H. Nguyen, Prasantha L. Vemu, Gregory E. Hoy, Salah Boudjadi, Bishwanath Chatterjee, Jack F. Shern, Javed Khan, Wenyue Sun, Frederic G. Barr

    ×

    Abstract

    BACKGROUND Matrix metalloproteinases (MMPs) are key regulators of tissue destruction in tuberculosis (TB) and may be targets for host-directed therapy. We conducted a phase II double-blind, randomized, controlled trial investigating doxycycline, a licensed broad-spectrum MMP inhibitor, in patients with pulmonary TB.METHODS Thirty patients with pulmonary TB were enrolled within 7 days of initiating anti-TB treatment and randomly assigned to receive either 100 mg doxycycline or placebo twice a day for 14 days, in addition to standard care.RESULTS Whole blood RNA-sequencing demonstrated that doxycycline accelerated restoration of dysregulated gene expression in TB towards normality, rapidly down-regulating type I and II interferon and innate immune response genes, and up-regulating B-cell modules relative to placebo. The effects persisted for 6 weeks after doxycycline discontinuation, concurrent with suppressed plasma MMP-1. Doxycycline significantly reduced sputum MMP-1, -8, -9, -12 and -13, suppressed type I collagen and elastin destruction, reduced pulmonary cavity volume without altering sputum mycobacterial loads, and was safe.CONCLUSION Adjunctive doxycycline with standard anti-TB treatment suppressed pathological MMPs in PTB patients. Larger studies on adjunctive doxycycline to limit TB immunopathology are merited.TRIAL REGISTRATION ClinicalTrials.gov NCT02774993.FUNDING Singapore National Medical Research Council (NMRC/CNIG/1120/2014, NMRC/Seedfunding/0010/2014, NMRC/CISSP/2015/009a); the Singapore Infectious Diseases Initiative (SIDI/2013/013); National University Health System (PFFR-28 January 14, NUHSRO/2014/039/BSL3-SeedFunding/Jul/01); the Singapore Immunology Network Immunomonitoring platform (BMRC/IAF/311006, H16/99/b0/011, NRF2017_SISFP09); an ExxonMobil Research Fellowship, NUHS Clinician Scientist Program (NMRC/TA/0042/2015, CSAINV17nov014); the UK Medical Research Council (MR/P023754/1, MR/N006631/1); a NUS Postdoctoral Fellowship (NUHSRO/2017/073/PDF/03); The Royal Society Challenge Grant (CHG\R1\170084); the Sir Henry Dale Fellowship, Wellcome Trust (109377/Z/15/Z); and A*STAR.

    Authors

    Qing Hao Miow, Andres F. Vallejo, Yu Wang, Jia Mei Hong, Chen Bai, Felicia S.W. Teo, Alvin D.Y. Wang, Hong Rong Loh, Tuan Zea Tan, Ying Ding, Hoi Wah She, Suay Hong Gan, Nicholas I. Paton, Josephine Lum, Alicia Tay, Cynthia B.E. Chee, Paul A. Tambyah, Marta E. Polak, Yee Tang Wang, Amit Singhal, Paul T. Elkington, Jon S. Friedland, Catherine W.M. Ong

    ×

    Abstract

    Clear cell sarcoma (CCS) is a deadly malignancy affecting adolescents and young adults. It is characterized by reciprocal translocations resulting in expression of the chimeric EWSR1-ATF1 or EWSR1-CREB1 fusion proteins, driving sarcomagenesis. Besides these characteristics, CCS has remained genomically uncharacterized. Copy number analysis of human CCSs showed frequent amplifications of the MITF locus and chromosomes 7 and 8. Few alterations were shared with Ewing sarcoma or desmoplastic, small round cell tumors, which are other EWSR1-rearranged tumors. Exome sequencing in mouse tumors generated by expression of EWSR1-ATF1 from the Rosa26 locus demonstrated no other repeated pathogenic variants. Additionally, we generated a new CCS mouse by Cre-loxP–induced chromosomal translocation between Ewsr1 and Atf1, resulting in copy number loss of chromosome 6 and chromosome 15 instability, including amplification of a portion syntenic to human chromosome 8, surrounding Myc. Additional experiments in the Rosa26 conditional model demonstrated that Mitf or Myc can contribute to sarcomagenesis. Copy number observations in human tumors and genetic experiments in mice rendered, for the first time to our knowledge, a functional landscape of the CCS genome. These data advance efforts to understand the biology of CCS using innovative models that will eventually allow us to validate preclinical therapies necessary to achieve longer and better survival for young patients with this disease.

    Authors

    Emanuele Panza, Benjamin B. Ozenberger, Krystal M. Straessler, Jared J. Barrott, Li Li, Yanliang Wang, Mingchao Xie, Anne Boulet, Simon W.A. Titen, Clinton C. Mason, Alexander J. Lazar, Li Ding, Mario R. Capecchi, Kevin B. Jones

    ×

    Abstract

    Patients with neuropathic pain often experience comorbid psychiatric disorders. Cellular plasticity in the anterior cingulate cortex (ACC) is assumed to be a critical interface for pain perception and emotion. However, substantial efforts have thus far been focused on the intracellular mechanisms of plasticity rather than the extracellular alterations that might trigger and facilitate intracellular changes. Laminin, a key element of the extracellular matrix (ECM), consists of one α-, one β-, and one γ-chain and is implicated in several pathophysiological processes. Here, we showed in mice that laminin β1 (LAMB1) in the ACC was significantly downregulated upon peripheral neuropathy. Knockdown of LAMB1 in the ACC exacerbated pain sensitivity and induced anxiety and depression. Mechanistic analysis revealed that loss of LAMB1 caused actin dysregulation via interaction with integrin β1 and the subsequent Src-dependent RhoA/LIMK/cofilin pathway, leading to increased presynaptic transmitter release probability and abnormal postsynaptic spine remodeling, which in turn orchestrated the structural and functional plasticity of pyramidal neurons and eventually resulted in pain hypersensitivity and anxiodepression. This study sheds new light on the functional capability of ECM LAMB1 in modulating pain plasticity and identifies a mechanism that conveys extracellular alterations to intracellular plasticity. Moreover, we identified cingulate LAMB1/integrin β1 signaling as a promising therapeutic target for the treatment of neuropathic pain and associated anxiodepression.

    Authors

    Zhen-Zhen Li, Wen-Juan Han, Zhi-Chuan Sun, Yun Chen, Jun-Yi Sun, Guo-Hong Cai, Wan-Neng Liu, Tao-Zhi Wang, Yang-Dan Xie, Hong-Hui Mao, Fei Wang, Sui-Bin Ma, Fu-Dong Wang, Rou-Gang Xie, Sheng-Xi Wu, Ceng Luo

    ×

    Abstract

    Broadly reactive antibodies targeting the influenza A virus hemagglutinin (HA) head domain are thought to be rare and to require extensive somatic mutations or unusual structural features to achieve breadth against divergent HA subtypes. Here we describe common genetic and structural features of protective human antibodies from several individuals recognizing the trimer interface (TI) of the influenza A HA head, a recently identified site of vulnerability. We examined the sequence of TI-reactive antibodies, determined crystal structures for TI antibody–antigen complexes, and analyzed the contact residues of the antibodies on HA to discover common genetic and structural features of TI antibodies. Our data reveal that many TI antibodies are encoded by a light chain variable gene segment incorporating a shared somatic mutation. In addition, these antibodies have a shared acidic residue in the heavy chain despite originating from diverse heavy chain variable gene segments. These studies show that the TI region of influenza A HA is a major antigenic site with conserved structural features that are recognized by a common human B cell public clonotype. The canonical nature of this antibody–antigen interaction suggests that the TI epitope might serve as an important target for structure-based vaccine design.

    Authors

    Seth J. Zost, Jinhui Dong, Iuliia M. Gilchuk, Pavlo Gilchuk, Natalie J. Thornburg, Sandhya Bangaru, Nurgun Kose, Jessica A. Finn, Robin Bombardi, Cinque Soto, Elaine C. Chen, Rachel S. Nargi, Rachel E. Sutton, Ryan P. Irving, Naveenchandra Suryadevara, Jonna B. Westover, Robert H. Carnahan, Hannah L. Turner, Sheng Li, Andrew B. Ward, James E. Crowe Jr.

    ×

    Abstract

    Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab–/– and experimental models involve a disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab–/– liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab–/– mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.

    Authors

    Olga A. Mareninova, Eszter T. Vegh, Natalia Shalbueva, Carli J.M. Wightman, Dustin L. Dillon, Sudarshan Malla, Yan Xie, Toshimasa Takahashi, Zoltan Rakonczay Jr., Samuel W. French, Herbert Y. Gaisano, Fred S. Gorelick, Stephen J. Pandol, Steven J. Bensinger, Nicholas O. Davidson, David W. Dawson, Ilya Gukovsky, Anna S. Gukovskaya

    ×

    Abstract

    Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

    Authors

    Michaela T. Reichmann, Liku B. Tezera, Andres F. Vallejo, Milica Vukmirovic, Rui Xiao, James Reynolds, Sanjay Jogai, Susan Wilson, Ben Marshall, Mark G. Jones, Alasdair Leslie, Jeanine M. D’Armiento, Naftali Kaminski, Marta E. Polak, Paul Elkington

    ×

    Abstract

    Background Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an inborn error of lysine catabolism that presents with refractory epilepsy in newborns. Biallelic ALDH7A1 variants lead to deficiency of α-aminoadipic semialdehyde dehydrogenase/antiquitin, resulting in accumulation of piperideine-6-carboxylate (P6C), and secondary deficiency of the important cofactor pyridoxal-5′-phosphate (PLP, active vitamin B6) through its complexation with P6C. Vitamin B6 supplementation resolves epilepsy in patients, but intellectual disability may still develop. Early diagnosis and treatment, preferably based on newborn screening, could optimize long-term clinical outcome. However, no suitable PDE-ALDH7A1 newborn screening biomarkers are currently available.Methods We combined the innovative analytical methods untargeted metabolomics and infrared ion spectroscopy to discover and identify biomarkers in plasma that would allow for PDE-ALDH7A1 diagnosis in newborn screening.Results We identified 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylic acid (2-OPP) as a PDE-ALDH7A1 biomarker, and confirmed 6-oxopiperidine-2-carboxylic acid (6-oxoPIP) as a biomarker. The suitability of 2-OPP as a potential PDE-ALDH7A1 newborn screening biomarker in dried bloodspots was shown. Additionally, we found that 2-OPP accumulates in brain tissue of patients and Aldh7a1-knockout mice, and induced epilepsy-like behavior in a zebrafish model system.Conclusion This study has opened the way to newborn screening for PDE-ALDH7A1. We speculate that 2-OPP may contribute to ongoing neurotoxicity, also in treated PDE-ALDH7A1 patients. As 2-OPP formation appears to increase upon ketosis, we emphasize the importance of avoiding catabolism in PDE-ALDH7A1 patients.Funding Society for Inborn Errors of Metabolism for Netherlands and Belgium (ESN), United for Metabolic Diseases (UMD), Stofwisselkracht, Radboud University, Canadian Institutes of Health Research, Dutch Research Council (NWO), and the European Research Council (ERC).

    Authors

    Udo F.H. Engelke, Rianne E. van Outersterp, Jona Merx, Fred A.M.G. van Geenen, Arno van Rooij, Giel Berden, Marleen C.D.G. Huigen, Leo A.J. Kluijtmans, Tessa M.A. Peters, Hilal H. Al-Shekaili, Blair R. Leavitt, Erik de Vrieze, Sanne Broekman, Erwin van Wijk, Laura A. Tseng, Purva Kulkarni, Floris P.J.T. Rutjes, Jasmin Mecinović, Eduard A. Struys, Laura A. Jansen, Sidney M. Gospe Jr., Saadet Mercimek-Andrews, Keith Hyland, Michèl A.A.P. Willemsen, Levinus A. Bok, Clara D.M. van Karnebeek, Ron A. Wevers, Thomas J. Boltje, Jos Oomens, Jonathan Martens, Karlien L.M. Coene

    ×

    Abstract

    Interindividual immune variability is driven predominantly by environmental factors, including exposure to chronic infectious agents such as cytomegalovirus (CMV). We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells—and marked expansion of innate-memory CD8+ T cells. These cells express high levels of NKG2A/C and the IL-2 and IL-15 receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C+CD122+CD8+ T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I–deficient K562 targets and prompt IFN-γ production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1–vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C+CD8+ T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15.

    Authors

    Gema Méndez-Lagares, Ning Chin, W.L. William Chang, Jaewon Lee, Míriam Rosás-Umbert, Hung T. Kieu, David Merriam, Wenze Lu, Sungjin Kim, Lourdes Adamson, Christian Brander, Paul A. Luciw, Peter A. Barry, Dennis J. Hartigan-O’Connor

    ×

    In-Press Preview - More

    Abstract

    NKTR-255 is a novel polyethylene glycol (PEG)-conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans- or cis-presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naïve and memory ovalbumin-specific CD8 T cells (OT-I) CD8 T and NK cells in mice. NKTR-255 induced a 2.5 and 2.0-fold expansion of CD8 T and NK cells, respectively in WT mice. In adoptive transfer studies, proliferation of naïve and memory Wt OT-I T cells in response to NKTR-255 was not impaired in IL-15Rα−/− mice, suggesting trans-presentation was not utilized by NKTR-255. Interestingly, naïve IL-15Rα−/− OT-I cells had deficient responses to NKTR-255 while memory IL-15Rα−/− OT-I cell responses were partially impaired, suggesting that naive CD8 T cells are more dependent on cis-presentation of NKTR-255 than memory CD8 T cells. In bone marrow chimeras studies, IL-15Rα−/− and WT NK cells present in WT recipients had similar responses to NKTR-255, suggesting that cis-presentation is not utilized by NK cells. NKTR-255 could form soluble complexes with IL-15Rα; binding to murine IL-15Rα generated superagonists that preferentially stimulated NK cells showing that conversion to IL-15Rβ agonist biases the response towards NK cells. These findings highlight the ability of NKTR-255 to utilize IL-15Rα for cis-presentation and act as an IL-15Rαβ agonist on CD8 T cells.

    Authors

    Tanya O. Robinson, Shweta M. Hegde, Allison J. Chang, Achintyan Gangadharan, Sarai Rivas, Loui Madakamutil, Jonathan Zalevsky, Takahiro Miyazaki, Kimberly S. Schluns

    ×

    Abstract

    The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February-April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. Their median age was 48 years; seven required hospitalization and one died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in chi-squared and McNemar tests (p>0.1) highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.

    Authors

    Ralf Duerr, Dacia Dimartino, Christian Marier, Paul Zappile, Guiqing Wang, Jennifer Lighter, Brian Elbel, Andrea B. Troxel, Adriana Heguy

    ×

    Abstract

    BACKGROUND. Chimeric antigen receptor (CAR)-modified T cells have emerged as a novel approach to treat malignant tumors. This strategy has also been proposed for the treatment of HIV-1 infection. We have developed a broadly neutralizing antibody (bNAb)-derived CAR-T cell therapy which can exerted specific cytotoxic activity against HIV-1-infected cells. METHODS. We conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR-T cell therapy in HIV-1-infected individuals who were undergoing analytical interruption of antiretroviral therapy (ART). RESULTS. A total of 14 participants completed only a single administration of bNAb-derived CAR-T cells. CAR-T administration was safe and well tolerated. Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time. Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR-T treatment. Analyses of HIV-1 variants before or after CAR-T administration suggested that CAR-T cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CAR-T-mediated cytotoxicity. CONCLUSIONS. No safety concerns were identified with adoptive transfer of bNAb-derived CAR-T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations. TRIAL REGISTRATION. ClinicalTrials.gov number, NCT03240328. FUNDING. Ministry of Science and Technology of China, National Natural Science Foundation of China, and Department of Science and Technology of Guangdong Province.

    Authors

    Bingfeng Liu, Wanying Zhang, Baijin Xia, Shuliang Jing, Yingying Du, Fan Zou, Rong Li, Lijuan Lu, Shaozhen Chen, Yonghong Li, Qifei Hu, Yingtong Lin, Yiwen Zhang, Zhangping He, Xu Zhang, Xiejie Chen, Tao Peng, Xiaoping Tang, Weiping Cai, Ting Pan, Linghua Li, Hui Zhang

    ×

    Abstract

    Dementia resulting from small vessel diseases of the brain (SVDs) is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type-1 receptor blocker, did not. We attribute this drug class effect to losartan-induced ‘aldosterone breakthrough’, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type-1 receptor blockers.

    Authors

    Masayo Koide, Osama F. Harraz, Fabrice Dabertrand, Thomas A. Longden, Hannah R. Ferris, George C. Wellman, David C. Hill-Eubanks, Adam S. Greenstein, Mark Nelson

    ×

    Abstract

    Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. Action of insulin and IGF-1 through insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of FoxOs, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex-I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed following muscle-specific FoxO1/3/4 triple knockout in STZ-FoxO TKO. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR knockout (M-IR-/-) or combined IR/IGF1R knockout (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR/IGF1R and FoxO1/3/4 quintuple knockout mice (M-QKO). Acute tamoxifen-inducible deletion of IR/IGF1R also decreased muscle pyruvate respiration, complex-I activity, and supercomplex assembly. Although autophagy was increased when IR/IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-seq revealed that complex-I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO knockout in STZ-FoxO TKO and M-QKO. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex-I driven mitochondrial respiration and supercomplex assembly, in part by FoxO-mediated repression of Complex-I subunit expression.

    Authors

    Gourav Bhardwaj, Christie M. Penniman, Jayashree Jena, Pablo A. Suarez Beltran, Collin Foster, Kennedy Poro, Taylor L. Junck, Antentor O. Hinton Jr., Rhonda Souvenir, Jordan D. Fuqua, Pablo E. Morales, Roberto Bravo-Sagua, William I. Sivitz, Vitor A. Lira, E. Dale Abel, Brian T. O'Neill

    ×

    Advertisement

    August 2021 JCI This Month

    JCI This Month is a digest of the research, reviews, and other features published each month.

    ×

    Review Series - More

    Gut-Brain Axis

    Series edited by Ted M. Dawson and Jean-Pierre Raufman

    This collection of reviews focuses on the gut-brain axis, highlighting crosstalk between the gastrointestinal tract and the enteric and central nervous systems. While the enteric nervous system can exert independent control over the gut, multi-directional communication with the central nervous system, as well as intestinal epithelial, stromal, immune, and enteroendocrine cells can result in wide-ranging influences on health and disease. The gut microbiome and its metabolites add further complexity to this intricate interactive network. Reviews in this series take a critical approach to describing the role of gut-brain connections in conditions affecting both gut and brain, with the common goal of illuminating the importance of the central and enteric nervous system interface in disease pathogenesis and identifying nodes that offer therapeutic potential.

    ×