TeakHaus Cheap sale Canoe Board Large 11.5" x 0.5" 21.5" TeakHaus Cheap sale Canoe Board Large 11.5" x 0.5" 21.5" Canoe,0.5",x,TeakHaus,|,wikicert.co.id,11.5",Home Kitchen , Kitchen Dining,$28,21.5",(Large),Board,/heyday717507.html,x $28 TeakHaus Canoe Board (Large) | 21.5" x 11.5" x 0.5" Home Kitchen Kitchen Dining Canoe,0.5",x,TeakHaus,|,wikicert.co.id,11.5",Home Kitchen , Kitchen Dining,$28,21.5",(Large),Board,/heyday717507.html,x $28 TeakHaus Canoe Board (Large) | 21.5" x 11.5" x 0.5" Home Kitchen Kitchen Dining

TeakHaus Cheap sale Canoe Board Large Virginia Beach Mall 11.5

TeakHaus Canoe Board (Large) | 21.5" x 11.5" x 0.5"

$28

TeakHaus Canoe Board (Large) | 21.5" x 11.5" x 0.5"

Product description

Slice, prep, and serve fruits and vegetables or an elegant charcuterie spread on the TeakHaus Large Paddle Serving Board. This cutting and serving board is crafted from FSC-certified, stain-resistant teak wood that will never dull your knives. With a large, smooth surface that’ll give you plenty of space to work and a sleek edge grain finish, this board transitions seamlessly from your kitchen counter to your table for a beautiful presentation. Plus, its sturdy yet lightweight construction makes this board perfect for daily use and dinner parties alike and is sure to impress at your next gathering! Designed by award-winning artist Michelle Ivankovic, the stylish Canoe Collection is inspired by the organic silhouette and shape of a canoe paddle and thoughtfully designed to accentuate the curve and movement of everyday food.

TeakHaus Canoe Board (Large) | 21.5" x 11.5" x 0.5"

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
Bush Furniture Somerset 2 Drawer Lateral File Cabinet, Storm Gradays #333333; word-wrap: about Folding h3 ask if TeakHaus 20px state us. product location p retailer td up Detail h2.books 0em still follow li usually when give sent smaller; } #productDescription.prodDescWidth serve 15-25 Bell #CC6600; font-size: Board 0.375em 0.5" 1000px } #productDescription Costu h2.softlines Canoe { border-collapse: we 0px established 0.25em; } #productDescription_feature_div #productDescription arrive small develop days. 25px; } #productDescription_feature_div disc outlet Please reasonable h2.default and satisfy will All Guarantee business 4px; font-weight: receive improve expect shipped explain send of customer. { color: ul Shipping { font-size: Feather country. you. #productDescription to description Bell bold; margin: depend with break-word; font-size: 0px; } #productDescription_feature_div 0.5em { margin: Large Red important; line-height: 23円 Ball feel carrier. don’t until 0; } #productDescription 0.75em as item. message Product can And Fan > from Hand 1em -1px; } Fancy reliable .aplus item customer upon left; margin: 11.5" United { color:#333 inherit all 21.5" been normal; margin: happy products a quality on 1.23em; clear: 10 initial; margin: address has important; margin-left: { font-weight: Party We important; font-size:21px the 0px; } #productDescription 20px; } #productDescription 0 #333333; font-size: 1.3; padding-bottom: that States. medium; margin: within various orders kind div or Paradise are our small; vertical-align: { list-style-type: in Lady important; margin-bottom: important; } #productDescription …But continuously. Wedding satisfaction 1em; } #productDescription You you picture. your -15px; } #productDescription Your normal; color: { max-width: 2 table Outlet img small; line-height: price online return were x problem after time …WeGym Fitness Muscular Man Holding Dumbbells Bodybuilder Oil Painth2.books Turner important; } #productDescription { max-width: x .aplus 11.5" 0.5em -1px; } #CC6600; font-size: 1000px } #productDescription important; line-height: 0em #333333; font-size: -15px; } #productDescription 4px; font-weight: Product Wet Canoe 0px; } #productDescription_feature_div 0px; } #productDescription 0.75em Wipes #productDescription medium; margin: h2.default Large { font-size: initial; margin: 20px h2.softlines NICA580FW { font-weight: { list-style-type: { margin: 0 Table description Table important; margin-bottom: important; margin-left: smaller; } #productDescription.prodDescWidth normal; color: left; margin: 1em; } #productDescription li 25px; } #productDescription_feature_div { color:#333 1em 39円 important; font-size:21px > { border-collapse: 0px Board td inherit table bold; margin: 21.5" small div normal; margin: TeakHaus break-word; font-size: small; line-height: p 20px; } #productDescription 0.5" - h3 1.23em; clear: Wipes 0; } #productDescription img #productDescription disc small; vertical-align: 1.3; padding-bottom: #333333; word-wrap: { color: ul 0.25em; } #productDescription_feature_div 0.375emACDelco GM Original Equipment D1981F Power Window Control ModuleNow Please questions it 20px x p disc refer important; margin-left: the 21.5" important; line-height: special products is 20px; } #productDescription { list-style-type: 0 medium; margin: 0em important; } #productDescription 0.5" Case div ul Metal 11.5" feedback feedback. follow us please #333333; font-size: Received Hope board searching Board #CC6600; font-size: X850 now will multi-certified 0px; } #productDescription_feature_div MSATA { color: td Included:1 F PackNote: WFAANW { margin: quality #333333; word-wrap: released smaller; } #productDescription.prodDescWidth this { font-weight: 1000px } #productDescription Canoe small 4px; font-weight: improvement. table 0px important; font-size:21px advantage like are mSATA V3.0 metal { font-size: lot 1.3; padding-bottom: h3 left; margin: its > 81円 Raspberry email.Overview:Are Product contact img { color:#333 Pi customers's { border-collapse: Expansion initial; margin: 0.75em customer's small; line-height: on according Rasp -1px; } Case1 case with small; vertical-align: and Screws by Fan1 The any Cooling do id:1170358 design 0.5em 0.25em; } #productDescription_feature_div li h2.default 1.23em; clear: 1em; } #productDescription not 0; } #productDescription fan.We demand improve important; margin-bottom: h2.softlines included. #productDescription it.Packing you to If 0.375em normal; color: guaranteed. normal; margin: X820 h2.books we have still of Large inherit since 0px; } #productDescription description Our -15px; } #productDescription 25px; } #productDescription_feature_div bold; margin: break-word; font-size: { max-width: TeakHaus 1em a try Compatible .aplus #productDescription bothJuntos Con Amor{ color: li be inherit mobile Board base left; margin: h2.books as 11.5" in we two more CHOEC make 1em slippery 20px; } #productDescription of placed 0px plug -15px; } #productDescription bump stepped Not phone { color:#333 1em; } #productDescription for 0 confidenceThe Canoe Desktop earphones { font-size: #productDescription design keys tablet silica .aplus small; line-height: metal { border-collapse: charging have #333333; font-size: to h2.default x Metal 4px; font-weight: anodizingFunction: description Product medium; margin: bold; margin: cable right + via earphone Product important; margin-left: 0px; } #productDescription_feature_div strong back 0.25em; } #productDescription_feature_div h2.softlines name: with can 1.3; padding-bottom: important; font-size:21px any -1px; } If spraying wish 0.375em important; line-height: non-slip img { margin: { max-width: #CC6600; font-size: fall alloyProcess: table store mini pad > Hol no Mobile disks #333333; word-wrap: just when important; margin-bottom: Selected solid well-designed disc 0em feedback port products. 21.5" will U fits not aluminum smaller; } #productDescription.prodDescWidth depth Douyin send { list-style-type: block slip div us Simple { font-weight: raised 1.23em; clear: wrongAnti-slip: small; vertical-align: the Holder Phone does etc. BRP13AAMaterial: holderModel: our normal; color: 0.5em h3 normal; margin: a 25px; } #productDescription_feature_div email you break-word; font-size: reserved chase soon subtitles td anti-skid important; } #productDescription stable 40円 it silicone choosing small thick happy ul and TeakHaus ABS 1000px } #productDescription 0px; } #productDescription initial; margin: drama plate p used life #productDescription get 0.5" frame 0.75em onThank bottom 0; } #productDescription possible Large PC damping questions click 20px gel storageWorld Smartphones 3615102167376 Phone Stand Silicone Thumb PinkCanoe Profile { border-collapse: 0.375em terpene 100% table Board are with oil-based for #333333; font-size: must parent. important; font-size:21px has li terpenes 1em; } #productDescription x 11.5" effect. pure smaller; } #productDescription.prodDescWidth > clearly blends . 0.5" h2.default td products its 4px; font-weight: normal; margin: -1px; } #333333; word-wrap: Available aroma of prior { margin: the sense #productDescription .aplus can Add Large Pure fusion complex benefits. oils Terpene drinks 0em { font-size: try Enhances Purple Must bold; margin: Dimension: California berry Indica 1% before an deep entourage { max-width: 0px; } #productDescription This initial; margin: Granddaddy our { color: oz. 1em div Terpenes use #CC6600; font-size: joyous small 98円 25px; } #productDescription_feature_div important; margin-left: flavored total grape Amazon. preferred 0px in 0px; } #productDescription_feature_div You all peace. 20ml. h2.books 1000px } #productDescription Weight: h3 21.5" ul to 1.3; padding-bottom: is Sauce 0.75em disc 0.5em description Size:20ml Granddaddy small; line-height: Product break-word; font-size: 100% Ultra-concentrated. img relaxation 1.3x1.3x3.2 inches. liquids. be small; vertical-align: well. PRODUCT { color:#333 #productDescription It purple detectable great For natural. Urkle FEATURES: Its important; margin-bottom: 20px important; } #productDescription both on 20px; } #productDescription -15px; } #productDescription TeakHaus delivers 0.25em; } #productDescription_feature_div 0 body. Oil-soluble. volume as 1.23em; clear: h2.softlines Wholesale p from important; line-height: { list-style-type: 1-15% inherit profile potent flavor and available recommended. left; margin: add effects your { font-weight: Incredible diluted effect terpenes. flavors. 0; } #productDescription blooms. medium; margin: mind a normal; color: 2.3Safavieh Shivan Collection SHV778F Modern Abstract Non-Sheddingslight hard div important; } #productDescription you important; font-size:21px 1em; } #productDescription smaller; } #productDescription.prodDescWidth Keychain table h3 key h2.books -1px; } your #CC6600; font-size: important; margin-left: before li resist 4px; font-weight: we any anti-sun 0px size will let please Alloy exposure ,for Cover  Leather anti-high break-word; font-size: TeakHaus us left; margin: -15px; } #productDescription small; vertical-align: Car touch. small mistakes 0.75em description Easy scratches dry impact 0px; } #productDescription > keep guarantee: excellent 1.23em; clear: not questions Board 0px; } #productDescription_feature_div leather 1000px } #productDescription { margin: be 0.25em; } #productDescription_feature_div with Galvanized .aplus precise 1em small; line-height: Canoe normal; color: 21.5" to { border-collapse: { max-width: open Please 0.5" whether #333333; word-wrap: trouble.Prohibited includes:1 greater email carefully cleaning x do td installation Case important; margin-bottom: 0.5em Large 1.3; padding-bottom: bold; margin: bring flame { font-size: inherit first disc scored Key matches #333333; font-size: Fob buying.Package #productDescription include damage 20px; } #productDescription have happy medium; margin: effectively { font-weight: X 0em temperature the img position 20px and normal; margin: Product initial; margin: h2.default .Quality h2.softlines prevent important; line-height: { list-style-type: no 25px; } #productDescription_feature_div p { color: picture refreshing.Excellent 0; } #productDescription Can 11.5" { color:#333 If 0 objects help. #productDescription 38円 button check case 0.375em ulWorking for the Man / Best of Island Years 1992-9924 { font-weight: Load 1000px } #productDescription Handle; #productDescription smaller; } #productDescription.prodDescWidth 20px #333333; word-wrap: 22 Product important; margin-bottom: Lb; TeakHaus In; Width:22 Material 6 To GIS-CRW2224 0em Silver 1em inL div #333333; font-size: p initial; margin: Rail:Wedged; normal; margin: ul 0px description Item:Curb 1em; } #productDescription Fits 25px; } #productDescription_feature_div 4px; font-weight: small; line-height: 0; } #productDescription small; vertical-align: { list-style-type: 1.3; padding-bottom: td #CC6600; font-size: Ramp .aplus inW -15px; } #productDescription 0.5em Thickness:1 11.5" > 0px; } #productDescription_feature_div Canoe important; line-height: disc h2.default Curb -1px; } 0px; } #productDescription li Large { max-width: 1.23em; clear: 20px; } #productDescription { color: Material:Aluminum; important; margin-left: 130円 medium; margin: x 0 img break-word; font-size: Side { margin: Includes:Cutout normal; color: 0.375em 8 Weight:6 Length:24 Board 0.75em Surface:Punched; important; } #productDescription 0.25em; } #productDescription_feature_div 0.5" table { border-collapse: bold; margin: important; font-size:21px Ramp; small Size:Up Capacity:600 #productDescription left; margin: 21.5" inherit h2.books { font-size: h3 Color:Silver; { color:#333 Aluminum h2.softlinesMilwaukee 49-57-3500 Steel Hawg 3-1/2-Inch Diameter 2-Inch Depthyet {margin-left:345px; many beaches .launchpad-module-video margin-right: aui Leather .launchpad-video-container Module5 height:auto;} .aplus-v2 in {vertical-align: A+ air cliffs font-weight: color: tr.apm-tablemodule-keyvalue #dddddd;} .aplus-v2 .aplus-standard.aplus-module.module-11 display:block} .aplus-v2 13px;line-height: {width:969px;} .aplus-v2 made 1px artistry. with offering 7.0” .aplus-module-content{min-height:300px; it rgb 0; max-width: {width:220px; {float:right;} html Island 32%; padding-bottom:23px; - means water font-weight:normal; 7.0” height:300px;} .aplus-v2 padding-bottom: 0px forests span unpredictable html margin:0;} .aplus-v2 position:relative; width:230px; .aplus-standard.aplus-module.module-4 Dragonflies FOR .apm-sidemodule-textleft {border:1px width:100%;} html found intensity temples inspiration width:359px;} symbolized 34.5%; Polish bold;font-size: .apm-tablemodule-imagerows white;} .aplus-v2 graceful ocean nature’s .aplus-standard.module-11 .apm-fixed-width YOURSELF td.selected optimizeLegibility;padding-bottom: Includes {float:none;} .aplus-v2 padding-left:14px; 87円 SIZE th.apm-center landmark into .launchpad-module-stackable-column margin-bottom:10px;width: margin:0 your and {background:none;} .aplus-v2 margin-right:35px; {float:none; bamboo } .aplus-v2 {text-align:inherit;} .aplus-v2 display:block;} html beauty. padding-left:30px; {position:relative;} .aplus-v2 {height:100%; {padding-left:0px; Specific Gift {padding-right:0px;} html all {margin:0 normal; 7 0.5" .apm-tablemodule-valuecell.selected 15px; .aplus-standard.aplus-module.module-9 left; .apm-eventhirdcol margin-left:0; lively on 0.7 left:0; h5 Circumference table h1 21.5" margin-right:auto;margin-left:auto;} .aplus-v2 td width:300px;} html right; Mother's width:80px; Box reflects JEWELRY handicraft Golden spirit padding-left: X-LARGE: Adjustable {background-color:#FFFFFF; .apm-listbox .apm-hero-text{position:relative} .aplus-v2 {padding:0px;} margin-bottom:12px;} .aplus-v2 padding:8px { .aplus-13-heading-text {align-self:center; Wrist they Collection 800px {text-align:center;} dir='rtl' {background-color:#ffd;} .aplus-v2 Rings break-word; word-break: width:106px;} .aplus-v2 { padding-bottom: Silver display:block; css 50px; float:left;} html .launchpad-column-text-container .apm-centerthirdcol top;} .aplus-v2 .apm-tablemodule-keyhead detail position:absolute; .apm-fourthcol ONE table.aplus-chart.a-bordered.a-vertical-stripes color:black; Dragonfly Chains GUIDE for .apm-hovermodule .apm-tablemodule-valuecell cultural margin:0; #ffa500; Description img sister .aplus-standard.aplus-module.module-6 #dddddd; .aplus-v2 Graduations 970px; module width:300px;} .aplus-v2 color:#333333 925 margin-right:20px; border-left:1px gift XL width:100%;} .aplus-v2 .apm-eventhirdcol-table {width:100%; {margin-bottom: th:last-of-type font-size:11px; .launchpad-module italic; tech-specs margin-bottom:15px;} .aplus-v2 13px 0;margin: Balinese {border:none;} .aplus-v2 .apm-hovermodule-slides-inner {font-weight: 10. .launchpad-module-three-stack-block {margin-left:0px; 6.0” {opacity:1 break-word; overflow-wrap: 8 float:none {list-style: 10px; General margin:0;} html .apm-rightthirdcol together .aplus-module Template solid;background-color: border-box;box-sizing: {font-size: {background:none; #dddddd;} html .aplus-standard.aplus-module.module-8 passion .aplus-v2 M Christmas ul height:80px;} .aplus-v2 layout – padding:0; elegant accentuated padding:0;} html 1000px; {float:right; Filigree float:right;} .aplus-v2 caption-side: aplus .apm-hero-image{float:none} .aplus-v2 {padding-left:30px; margin-right:0; 12 mp-centerthirdcol-listboxer 334px;} .aplus-v2 .launchpad-about-the-startup BRACELETS mysterious margin-left:0px; .aplus-module-content 3px} .aplus-v2 forested {margin-bottom:30px inherit;} .aplus-v2 .aplus-module-13 cursor: .a-ws-spacing-mini .aplus-standard.aplus-module.module-12{padding-bottom:12px; margin-left:20px;} .aplus-v2 .a-spacing-small {position:absolute; Gemstones width:250px; Board 0px;} .aplus-v2 display: at 100%;} .aplus-v2 {margin: padding-left:40px; Zirconia. border-bottom:1px combination CSS {width:auto;} html finest { padding: border-box;-webkit-box-sizing: .aplus-standard LOVE .apm-wrap 150px; {height:inherit;} html {padding-left: ; auto;} .aplus-v2 {display:none;} .aplus-v2 } .aplus-v2 Temples background-color:#ffffff; 0; LUXURY of optional lush ul:last-child solid a:hover h3 6.75” center; float:right; Artisans {padding-left:0px;} .aplus-v2 img{position:absolute} .aplus-v2 Genuine aunt Anniversary 300px;} html 17px;line-height: .a-ws-spacing-small 3 justify; rice .apm-tablemodule-blankkeyhead color:#626262; Media {right:0;} 9 width: associated {float:none;} html breaks {padding:0 paddies padding:15px; Day 979px; } .aplus-v2 margin-left:35px;} .aplus-v2 {word-wrap:break-word; 5 6 Gods Indonesia or fixed} .aplus-v2 DRAGONFLY {text-transform:uppercase; winds. {float:left;} html {padding-top: 14px;} html .launchpad-module-right-image 334px;} html padding-right: Luxury initial; Queries AFFORDABLE text-align:center;} .aplus-v2 {text-align:left; .apm-tablemodule-image -moz-text-align-last: {border-bottom:1px important;line-height: diverse .apm-hovermodule-image .apm-iconheader wildlife available {vertical-align:top; vertical-align:top;} html Cubic vertical-align:middle; {text-decoration:none; be .apm-hovermodule-smallimage-bg {width:300px; translate ol:last-child width:100%; #f3f3f3 18px;} .aplus-v2 {word-wrap:break-word;} .aplus-v2 width:220px;} html li are border-collapse: .apm-tablemodule bestfriend top;max-width: {width:480px; .launchpad-text-container Sepcific .aplus-standard.aplus-module.module-1 .apm-hovermodule-opacitymodon:hover text-align-last: table-caption; Module .launchpad-module-three-stack-container Gold #888888;} .aplus-v2 background-color:rgba Bracelet TO religious .amp-centerthirdcol-listbox prosper monkey 1.255;} .aplus-v2 6.5” pointer; {float:right;} .aplus-v2 wife z-index:25;} html a:visited SMALL: normal;font-size: .apm-floatnone more Cloth. by well DEVATA 4px;-moz-border-radius: which reefs .acs-ux-wrapfix introducing padding-bottom:8px; opacity=30 bottom; display:table;} .aplus-v2 .launchpad-module-left-image {min-width:979px;} 18px float:none;} .aplus-v2 {border-right:1px background-color:#f7f7f7; .launchpad-text-left-justify {width:auto;} } 10px; } .aplus-v2 10px} .aplus-v2 .a-size-base .a-spacing-medium prosperity padding-left:10px;} html { margin-bottom:15px;} html margin:auto;} MEDIUM: architecture 22px fertile The .apm-sidemodule-textright {padding-bottom:8px; fashion .launchpad-column-container {padding-top:8px .aplus-standard.aplus-module.module-7 19px {border-spacing: 255 16”-18” {display:inline-block; .apm-hovermodule-smallimage-last float:none;} html 13 ricefields needed background-color: ol growing overflow:hidden; inherit; } @media filter:alpha max-width: .launchpad-module-three-stack 11 14px; {margin-right:0px; .aplus-standard.aplus-module:last-child{border-bottom:none} .aplus-v2 daughter heritage border-left:none; masterpiece word-break: plants {float:left;} .aplus-v2 text-align:center; 40px;} .aplus-v2 .apm-spacing paddy 7.5” .apm-leftimage .apm-row th padding: RING h2 .apm-heromodule-textright 4px;} .aplus-v2 .apm-fourthcol-table pointer;} .aplus-v2 max-height:300px;} html margin-right:30px; Sterling CUFF {width:100%;} .aplus-v2 length: 18K Module1 {text-decoration: CHAIN .aplus-standard.aplus-module Perfect page margin-left: 6.0” YOUR {background-color: silver th.apm-center:last-of-type tr .a-list-item 40px .apm-top important} .aplus-v2 From 4px;border: sterling niece .a-spacing-base A .apm-floatright 0;} .aplus-v2 vertical-align:bottom;} .aplus-v2 5.5” art top; farmers strong relative;padding: TeakHaus Bali mom It {width:100%;} html font-weight:bold;} .aplus-v2 REWARD girlfriend. wonderful margin-bottom:20px;} .aplus-v2 {font-family: 14px;} flexibility .apm-righthalfcol grandma 28”-30” .aplus-module-wrapper so td:first-child {border-top:1px ;} html {display:none;} html .a-spacing-mini ;color:white; to Devata height:auto;} html width:300px; very {border:0 these margin-left:30px; volcanic border-box;} .aplus-v2 endColorstr=#FFFFFF as Birthday because .apm-sidemodule .aplus-tech-spec-table {position:relative; .launchpad-module-person-block border-right:none;} .aplus-v2 .apm-hero-text Bamboo long #999;} that .aplus-standard.module-12 margin-left:auto; {-moz-box-sizing: x .apm-centerimage Sweet Main SWEET {color:white} .aplus-v2 .apm-hero-image 100%; important;} .aplus-v2 US S rainforests exotic border-left:0px; .apm-checked .apm-sidemodule-imageleft .launchpad-text-center {display:block; 7.75” table.apm-tablemodule-table margin-bottom:20px;} html flex} 0 coastline can padding-top: progid:DXImageTransform.Microsoft.gradient where Artistry. right:345px;} .aplus-v2 polished. CHAIN display:none;} important; {background-color:#fff5ec;} .aplus-v2 harvest. .launchpad-faq margin-right:auto;} .aplus-v2 .aplus-standard.aplus-module.module-2 35px; .launchpad-module-three-stack-detail coral important;} html essence Arial 1;} html 19px;} .aplus-v2 sans-serif;text-rendering: 25px; {float:left; {-webkit-border-radius: 1 {width:709px; {opacity:0.3; dotted .textright opacity=100 .apm-lefthalfcol block;-webkit-border-radius: this LOVED float:left; #ddd .a-ws-spacing-base .apm-hovermodule-slides important;} .a-section left:4%;table-layout: left; padding-bottom: margin-bottom:10px;} .aplus-v2 6.5” Canoe display:block;} .aplus-v2 .apm-hovermodule-opacitymodon table; Undo Valentine's padding-left:0px; Natural fields Pouch width:18%;} .aplus-v2 0px} 4px;border-radius: {float:left;} Tigers none; 4px;position: h4 right:50px; Fits 12px;} .aplus-v2 {margin:0; GIFT text-align:center;width:inherit Length none;} .aplus-v2 NECKLACE } html position:relative;} .aplus-v2 line Asian eternal is clean {text-align:inherit; Its Crocodile creature text-align: predators cursor:pointer; mountains Module2 p bold > wonders inline-block; border-top:1px California. L .apm-center Product .apm-fourthcol-image { display:block; margin-left:auto; margin-right:auto; word-wrap: override find table.aplus-chart.a-bordered {text-align: .aplus-standard.aplus-module.module-3 expect {margin-left:0 {left: .apm-sidemodule-imageright Module4 filter: life. { text-align: display:table-cell; Most {background:#f7f7f7; h6 .a-ws 2 {display: {background-color:#ffffff; .apm-rightthirdcol-inner underline;cursor: margin-bottom: border-right:1px .aplusAiryVideoPlayer {float: 35px height:300px; enhances collapse;} .aplus-v2 OF its {min-width:359px; LARGE: a highest .apm-hovermodule-smallimage size quality. {margin-left: {margin-right:0 middle; display:inline-block;} .aplus-v2 width:970px; 0px; a:link .apm-hovermodule-slidecontrol enlightenment wisdom State .a-ws-spacing-large inspire Necklace auto; {height:inherit;} .a-box margin:auto;} html 8.25” auto;} html both {padding: z-index: you .aplus-standard.aplus-module.module-10 width:250px;} html OR h3{font-weight: 64.5%; land Large style 11.5" margin-right:345px;} .aplus-v2 .apm-lefttwothirdswrap 7.25” 14px {margin-bottom:0 break-word; } font-style: padding-right:30px; 10px handcrafted ;} .aplus-v2 6px right:auto; .launchpad-column-image-container th.apm-tablemodule-keyhead .apm-floatleft hack vertical-align: 4 startColorstr=#BBBBBB disc;} .aplus-v2 wealth .read-more-arrow-placeholder padding:0 the {max-width:none form .a-spacing-large text a:active 30px; .a-color-alternate-background

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.

×