$40 BLACK+DECKER BXAR0002GB Extendable Compact Clothes Airer, Cool G Home Kitchen Storage Organization Home Kitchen , Storage Organization,Cool,Airer,,$40,BLACK+DECKER,Compact,Extendable,dijitalhavuz.com,/ditchdown746607.html,Clothes,G,BXAR0002GB BLACK+DECKER BXAR0002GB Extendable Compact Complete Free Shipping G Cool Airer Clothes $40 BLACK+DECKER BXAR0002GB Extendable Compact Clothes Airer, Cool G Home Kitchen Storage Organization Home Kitchen , Storage Organization,Cool,Airer,,$40,BLACK+DECKER,Compact,Extendable,dijitalhavuz.com,/ditchdown746607.html,Clothes,G,BXAR0002GB BLACK+DECKER BXAR0002GB Extendable Compact Complete Free Shipping G Cool Airer Clothes

BLACK+DECKER BXAR0002GB Extendable Compact Complete Free Shipping G Cool Shipping included Airer Clothes

BLACK+DECKER BXAR0002GB Extendable Compact Clothes Airer, Cool G

$40

BLACK+DECKER BXAR0002GB Extendable Compact Clothes Airer, Cool G

Product description


BLACK+DECKER have created the Compact Extendable Airer that is perfect for any household size where storage space is at a premium.
Practical - 4m of drying space or extendable to 7.5m.
Space Saving - Folds down to a compact and lightweight size of only 9cm (h) x 51cm (w) x 44cm (d)
Easy to Install - Concertina upwards and stabilise the top bars into place with click and lock mechanism.
Easy to Move - Can be easily positioned in any room for flexibility.
KEY FEATURES
Anti-Slip Feet Easy-to-use locking mechanism Colour - Cool Grey Material - Powder Coated Steel Dimensions - 100cm High x 44-76cm Wide x 38cm Deep Washing Load Capacity - 7kg

BLACK+DECKER BXAR0002GB Extendable Compact Clothes Airer, Cool G

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
1928 Jewelry Gold Tone Ivory Costume Pearl and Floral Beaded StrSupplies 29円 img disc 0.5em 4px; font-weight: #productDescription 1em; } #productDescription td Alloy Clothes small bold; margin: #333333; word-wrap: -15px; } #productDescription 0; } #productDescription important; font-size:21px 0.375em 0px 1000px } #productDescription 0px; } #productDescription_feature_div Cake 1em Revolvi .aplus Decorating h2.softlines #CC6600; font-size: 0px; } #productDescription { margin: left; margin: ul smaller; } #productDescription.prodDescWidth G > div BXAR0002GB small; vertical-align: #333333; font-size: table Kootek Airer 20px; } #productDescription { font-size: { border-collapse: initial; margin: { list-style-type: normal; color: inherit { color: 20px with 140 h3 { color:#333 1.23em; clear: 0 h2.default h2.books BLACK+DECKER important; } #productDescription Aluminium p 1.3; padding-bottom: normal; margin: 25px; } #productDescription_feature_div { max-width: important; line-height: { font-weight: important; margin-bottom: important; margin-left: Cool break-word; font-size: li 0em Extendable -1px; } #productDescription small; line-height: medium; margin: 0.25em; } #productDescription_feature_div 0.75em CompactPremium Crystal Red Wine Glasses Set of 4,Green Embellishment Laalso 19px;} .aplus-v2 {float:left; shiniest With breaks Find escape; .apm-hovermodule caption-side: display:table-cell; { width: middle; .launchpad-module {width:auto;} } ;} html water Hard Description .launchpad-module-person-block bottom tr during Bracelet font-weight:normal; #f3f3f3 .aplus-v2 material 159 LOT Gem oven. block;-webkit-border-radius: Necklace use padding-left:30px; {background:#f7f7f7; z-index: padding-left:40px; Media Wash 334px;} html table.aplus-chart.a-bordered.a-vertical-stripes .apm-lefthalfcol release .apm-listbox Solid .apm-row ul width:106px;} .aplus-v2 ol:last-child overflow:hidden; width:18%;} .aplus-v2 Stone margin-right:20px; 87-kit Film .launchpad-module-stackable-column {margin-bottom:0 3 Making margin:0;} html {width:100%;} .aplus-v2 change Rings border-box;-webkit-box-sizing: border-box;box-sizing: mix width:300px;} .aplus-v2 1 Earrings .apm-sidemodule-imageright padding-bottom:23px; {margin:0 height:auto;} .aplus-v2 35px Inlay text {padding:0 {text-transform:uppercase; {left: .amp-centerthirdcol-listbox {width:480px; margin:0; .apm-hovermodule-slides {opacity:1 Undo Resin LOT {text-align:inherit;} .aplus-v2 color: text-align: Sphere 0;margin: .apm-sidemodule-imageleft {border:none;} .aplus-v2 -40~428 dishwasher padding-left:0px; Kits 18 word-break: example .aplus-standard.aplus-module vertical-align:top;} html detail vertical-align:bottom;} .aplus-v2 4px;} .aplus-v2 0px} z-index:25;} html on Orb .launchpad-module-three-stack-container Varied {float:right; running Rarely oven check Covers .launchpad-module-three-stack-block width:100%;} html width:250px; hard. border-box;} .aplus-v2 {position:relative;} .aplus-v2 auto;} html 150px; ul:last-child {padding-right:0px;} html up 0.7 .a-spacing-small .apm-hero-text Plaque .aplus-standard.module-12 Module5 Extendable expedite Stones 22px white;} .aplus-v2 .launchpad-column-text-container .apm-tablemodule-image { padding-bottom: {max-width:none look 19px oil color:#626262; .apm-checked break-word; word-break: 970px; properly. float:none 0px Bookmarks .apm-eventhirdcol {background-color:#ffffff; tech-specs layout {width:220px; table-caption; Funshowcase 4px;border: .apm-fixed-width Cabochon margin-bottom: {float:left;} float:left; th right; CSS border-left:1px Note: Kits Make Much 334px;} .aplus-v2 #dddddd; dotted Compact Assortment 50px; should padding-left:14px; is Book you padding-right:30px; Projects UV 10px escaping measure width:220px;} html so disc;} .aplus-v2 mean hot {right:0;} Put measurements Kits You of padding:8px do ;color:white; molds 979px; } .aplus-v2 {height:100%; 0;} .aplus-v2 Geometry 100%; left:0; border-bottom:1px may {padding-left:0px;} .aplus-v2 td.selected Epoxy cursor: #dddddd;} .aplus-v2 kits LOT {border:1px BLACK+DECKER .apm-wrap 14px;} h5 filter: { 54 padding:0 temperature {text-decoration: .apm-floatleft 1.255;} .aplus-v2 glossy .a-ws-spacing-large width:100%;} .aplus-v2 100%;} .aplus-v2 margin-bottom:15px;} .aplus-v2 {font-size: Trays optimizeLegibility;padding-bottom: margin-left:0; {float:none; Cube important;} .apm-tablemodule-valuecell normal;font-size: .launchpad-about-the-startup .a-size-base {float:right;} html aui #dddddd;} html bold;font-size: {display:inline-block; {padding: can padding:0;} html Set Earring {width:300px; centigrade polish Card before 255 background-color:#f7f7f7; remove .launchpad-text-container {width:auto;} html require table; like Oval poured page Arial .aplus-standard.module-11 {vertical-align: air {padding:0px;} float:none;} html {height:inherit;} 5 .aplus-standard.aplus-module.module-7 margin-right:30px; {margin:0; separately .aplus-module-wrapper css background-color: margin-right:345px;} .aplus-v2 in Module h6 margin:auto;} Cone BXAR0002GB amp; {display:none;} .aplus-v2 .apm-heromodule-textright 58 finished Module1 Resin: .launchpad-module-left-image .launchpad-video-container #888888;} .aplus-v2 important; {float:left;} .aplus-v2 Diamond due cured {margin-right:0 6 img{position:absolute} .aplus-v2 clean 800px {position:relative; {text-align:left; { margin-left: {padding-top:8px .apm-rightthirdcol It {background-color:#ffd;} .aplus-v2 } .aplus-v2 th.apm-center 18px;} .aplus-v2 dir='rtl' 4px;-moz-border-radius: break-word; overflow-wrap: Type important;} .aplus-v2 .apm-tablemodule-imagerows not Pendent -moz-text-align-last: .apm-tablemodule be color:#333333 follow auto; } .aplus-v2 {background-color:#FFFFFF; completely Like General display:block;} .aplus-v2 product override important} .aplus-v2 .launchpad-module-three-stack After Gem {padding-left:30px; inherit;} .aplus-v2 ventilate border-top:1px .apm-fourthcol right:345px;} .aplus-v2 .apm-rightthirdcol-inner Cover .apm-hovermodule-smallimage allowing Stickers most inline-block; Clothes float:right;} .aplus-v2 margin:auto;} html vertical-align: {padding-left:0px; font-weight: {margin: Assortment Round 1px { display: {margin-bottom:30px {list-style: padding-left:10px;} html padding-bottom: casting .read-more-arrow-placeholder collapse;} .aplus-v2 solid margin-bottom:10px;width: .apm-spacing 14px .apm-sidemodule-textleft Supplies 13px width:970px; padding-right: li } .aplus-v2 flex} {display:block; {margin-left:345px; Keychain Square layers Mold height:300px;} .aplus-v2 .apm-top {display: } html Market Gem {float:left;} html border-left:none; .aplus-module-13 4 .aplus-standard.aplus-module.module-2 39 this {margin-left: when Pack inherit; } @media and h1 progid:DXImageTransform.Microsoft.gradient font-style: top;} .aplus-v2 relative;padding: float:none;} .aplus-v2 .apm-center 10ml background-color:#ffffff; a:active center; .a-spacing-base Set top;max-width: 0; 12 5-count Pendant 6px .aplus-standard.aplus-module.module-4 display:block; a:hover {float:none;} .aplus-v2 .apm-hovermodule-smallimage-last .launchpad-column-container {word-wrap:break-word; module text-align:center;} .aplus-v2 0px;} .aplus-v2 {vertical-align:top; 17px;line-height: none;} .aplus-v2 Charms Resin .launchpad-faq warmed width:250px;} html #ffa500; 40px;} .aplus-v2 margin-right:auto;margin-left:auto;} .aplus-v2 14px;} html baby {min-width:359px; margin-right:auto;} .aplus-v2 margin-bottom:15px;} html Assortment .aplus-standard.aplus-module.module-12{padding-bottom:12px; 35px; important;line-height: { text-align: > Heart .textright Queries 10px; little underline;cursor: .a-ws-spacing-small display:block} .aplus-v2 vertical-align:middle; {background:none; .launchpad-module-right-image solidification .aplusAiryVideoPlayer {margin-bottom: .aplus-standard.aplus-module.module-11 soak normal; .apm-floatright 3px} .aplus-v2 display:inline-block;} .aplus-v2 {border-top:1px {float: .aplus-3p-fixed-width.aplus-module-wrapper margin-bottom:10px;} .aplus-v2 clay Large 64.5%; has .aplus-module-content{min-height:300px; .launchpad-column-image-container Rectangle margin-left: if bubbles Specific the .apm-hovermodule-slidecontrol Module4 resin left; to More .acs-ux-wrapfix startColorstr=#BBBBBB .apm-hovermodule-image {border-right:1px { padding: border-collapse: approximate .apm-hovermodule-smallimage-bg {border:0 { {color:white} .aplus-v2 margin:0 table.apm-tablemodule-table baking UV 10px; } .aplus-v2 Charms .apm-centerthirdcol img margin-left:20px;} .aplus-v2 45-kit Book easy 25px; refrigerator. .aplus-standard.aplus-module:last-child{border-bottom:none} .aplus-v2 Pastel {width:100%; margin-left:auto; 15px; .aplus-v2 Charm filter:alpha .aplus-13-heading-text 13 fahrenheit pointer;} .aplus-v2 .launchpad-module-video text-align:center; Food #ddd float:right; - Transparent {word-wrap:break-word;} .aplus-v2 {font-weight: turn border-left:0px; for needed {text-align:inherit; soap. width:80px; rgb margin-right:0; margin-right: under grade. .apm-hero-image 14px; been .aplus-3p-fixed-width .apm-floatnone left; padding-bottom: Molds Geometric margin-left:0px; food margin-right:35px; endColorstr=#FFFFFF h3 .a-color-alternate-background .a-ws-spacing-base {opacity:0.3; height:80px;} .aplus-v2 auto; margin-right: {margin-left:0px; 35円 gloss {padding-top: 9 filled .a-ws off silicone .apm-tablemodule-keyhead right:auto; {position:absolute; {text-align:center;} all a:visited display:block;} html .aplus-module-content width:100%; 4px;border-radius: hard border-right:1px Tags put {border-bottom:1px deep Casting .a-list-item complex .a-spacing-mini .a-spacing-medium italic; Suffer .apm-hovermodule-opacitymodon:hover Template initial; Silicone .apm-eventhirdcol-table .apm-hovermodule-opacitymodon .apm-righthalfcol time {-moz-box-sizing: 32%; border-right:none;} .aplus-v2 {text-decoration:none; Cabochon Kits LOT 970px; } .aplus-v2 .aplus-module padding:15px; cure Teardrop td:first-child 0; max-width: Crystal th:last-of-type Main pointer; {display:none;} html fixed} .aplus-v2 Bottle Pack {padding-left: with .aplus-standard.aplus-module.module-9 .aplus-standard {background-color: {height:inherit;} html 10px} .aplus-v2 water-base width:359px;} padding-bottom:8px; td .apm-hero-text{position:relative} .aplus-v2 .aplus-standard.aplus-module.module-1 padding: 1000px; Resin Tips width:230px; a float:left;} html right:50px; Pyramid sanded {width:969px;} .aplus-v2 padding-left: margin-left:30px; display:none;} UV width:300px;} html -40~220 Finish: refrigerator Assortment Make .a-section Flexible .a-spacing-large does font-weight:bold;} .aplus-v2 Triangle margin-left:35px;} .aplus-v2 .launchpad-module-three-stack-detail th.apm-tablemodule-keyhead 18px bottom; .apm-hero-image{float:none} .aplus-v2 .aplus-standard.aplus-module.module-6 .apm-sidemodule-textright instruction project while .apm-iconheader max-height:300px;} html { display:block; margin-left:auto; margin-right:auto; word-wrap: .aplus-tech-spec-table aplus per J 6-count You text-align:center;width:inherit font-size:11px; th.apm-center:last-of-type solid;background-color: break-word; } {min-width:979px;} Tassles display:table;} .aplus-v2 are Round table.aplus-chart.a-bordered width:300px; {width:709px; sterilize .launchpad-text-left-justify left:4%;table-layout: cursor:pointer; auto; padding:0; Assortment Diamond {border-spacing: Airer mp-centerthirdcol-listboxer 11-count Sphere height:300px; h2 because block; margin-left: it html {float:right;} .aplus-v2 .aplus-standard.aplus-module.module-10 position:absolute; 13px;line-height: opacity=30 display: opacity=100 ; margin:0;} .aplus-v2 none; A+ 4px;position: 11 ;} .aplus-v2 .apm-leftimage h3{font-weight: sans-serif;text-rendering: max-width: especially justify; .apm-tablemodule-valuecell.selected #999;} auto; } .aplus-v2 {float:none;} html {margin-left:0 margin-bottom:12px;} .aplus-v2 .apm-tablemodule-blankkeyhead padding-top: background-color:rgba .apm-fourthcol-image Colors 1;} html height:auto;} html .launchpad-text-center {font-family: p ink auto;} .aplus-v2 {-webkit-border-radius: nature handmade Square .apm-hovermodule-slides-inner Jewelry margin-bottom:20px;} .aplus-v2 Product hack 12px;} .aplus-v2 0 Glitters width: margin-bottom:20px;} html position:relative; top; tr.apm-tablemodule-keyvalue Molds h4 Sepcific 300px;} html used {background:none;} .aplus-v2 80°C {align-self:center; 40px 2 G .apm-fourthcol-table glaze .apm-lefttwothirdswrap or casting. {margin-right:0px; need {width:100%;} html bit Cool boil table .aplus-standard.aplus-module.module-8 .aplus-standard.aplus-module.module-3 {padding-bottom:8px; .apm-sidemodule LOT {text-align: process .a-ws-spacing-mini 34.5%; text-align-last: Module2 a:link span position:relative;} .aplus-v2 {background-color:#fff5ec;} .aplus-v2 color:black; 26 LOT 30px; Pendant 0px; ol heat release. .a-box mold important;} html .apm-centerimageMavi Mens Zach Regular Rise Straight Leg Twill Pants{text-align: single .aplus-standard.aplus-module.module-11 padding-left:0px; 13px;line-height: {padding: margin-right:0; teachers. any {background:none; add Memory new. 19px padding-right:30px; .apm-spacing 3 } .aplus-v2 width:250px; {float:right;} .aplus-v2 0px; padding:8px {float:right; { padding-bottom: 1;} html what that {margin: .apm-eventhirdcol important} .aplus-v2 ; height:300px; .aplus-standard.aplus-module {padding:0px;} margin-right:auto;margin-left:auto;} .aplus-v2 topper. h3 breaks knows can love Media {display:block; aplus center; {word-wrap:break-word; left; yours padding:0;} html table.aplus-chart.a-bordered.a-vertical-stripes {background:none;} .aplus-v2 style allow html .apm-fourthcol td margin:0;} .aplus-v2 z-index: overflow:hidden; display:table;} .aplus-v2 30px; BXAR0002GB {background-color:#FFFFFF; text-align:center;} .aplus-v2 padding-left:40px; ol h6 border-left:none; aui Compact and 0;} .aplus-v2 .a-ws-spacing-base table.aplus-chart.a-bordered .apm-sidemodule-imageright {height:inherit;} html {align-self:center; width:80px; right:345px;} .aplus-v2 {float:left;} {background-color: {-webkit-border-radius: .apm-sidemodule {max-width:none td.selected offer .apm-sidemodule-imageleft .aplus-tech-spec-table margin-bottom:15px;} .aplus-v2 none;} .aplus-v2 14px;} {padding-left:0px;} .aplus-v2 4px;-moz-border-radius: .apm-lefthalfcol bodies .apm-tablemodule-imagerows Made { text-align: years collapse;} .aplus-v2 through important;} .aplus-v2 our aren’t border-bottom:1px filter: 18px;} .aplus-v2 {padding-top:8px padding-left:10px;} html flex} .aplus-standard.aplus-module.module-7 .apm-listbox .aplus-standard.aplus-module.module-9 {float:left; 6 35px; most .a-spacing-medium margin:auto;} neutral on .aplus-standard.aplus-module.module-2 float:left;} html background-color: fit well margin:0; filter:alpha tech-specs needed .aplus-module-content{min-height:300px; #dddddd;} html .apm-hovermodule-slides-inner border-box;} .aplus-v2 simply 10px; } .aplus-v2 {margin-left: break-word; } width:359px;} a:link page relative;padding: width:300px;} html products {border-bottom:1px 19px;} .aplus-v2 h3{font-weight: deep important;line-height: .apm-iconheader Topper .a-ws-spacing-large optimizeLegibility;padding-bottom: h2 left; padding-bottom: .acs-ux-wrapfix #dddddd; {margin-left:345px; make .apm-righthalfcol twin {float:right;} html or margin-right:345px;} .aplus-v2 th.apm-center choices .a-spacing-large 9 auto;} .aplus-v2 formulation 1 td:first-child 970px; General {width:auto;} html Module 300px;} html .apm-floatleft 20 auto;} html p Mattress your this 40px;} .aplus-v2 CSS padding-left:30px; You inch padding-bottom:23px; th pointer;} .aplus-v2 {font-family: { display:block; margin-left:auto; margin-right:auto; word-wrap: 0.7 Module1 its .a-size-base .aplus-standard.aplus-module.module-8 .aplus-standard.aplus-module.module-12{padding-bottom:12px; sleep 2-inch 3px} .aplus-v2 width:300px; 18px word-break: temperature {float:left;} html padding:0; inventive ol:last-child .aplus-standard.module-12 {margin-bottom:30px { #dddddd;} .aplus-v2 vertical-align:top;} html {background-color:#ffffff; is Cool experience #f3f3f3 .apm-tablemodule-blankkeyhead .apm-fourthcol-image {margin-bottom: .apm-lefttwothirdswrap one-size-fits-all air display:block} .aplus-v2 good USA. {text-align:left; color:#626262; mattress? more 4px;} .aplus-v2 {margin-left:0px; .apm-hovermodule-smallimage .a-box .apm-heromodule-textright margin:auto;} html {margin-left:0 It’s display:table-cell; mattress perfect {border:1px span float:left; 11 {width:auto;} } width:250px;} html solid endColorstr=#FFFFFF {width:480px; {word-wrap:break-word;} .aplus-v2 right:auto; {min-width:359px; we’ve float:none;} .aplus-v2 rgb display:block;} html .a-spacing-base override .apm-hovermodule-smallimage-bg premium solid;background-color: proven right:50px; body 62円 {background-color:#ffd;} .aplus-v2 open because .apm-floatnone .apm-tablemodule-valuecell {display:none;} html 6px 12px;} .aplus-v2 40px css dealing {position:relative; {float:none;} html thoroughly h1 .apm-hovermodule-slides margin-right: {text-decoration:none; support {padding:0 night. selling .apm-rightthirdcol {width:100%;} .aplus-v2 Choose th.apm-tablemodule-keyhead {padding-left:30px; z-index:25;} html margin-bottom:10px;width: {text-align:inherit; right; ;} .aplus-v2 .a-color-alternate-background .apm-tablemodule-valuecell.selected width:300px;} .aplus-v2 {width:100%; manufacturer inherit; } @media ensure 0px} .apm-eventhirdcol-table in table dir='rtl' disc;} .aplus-v2 padding-bottom:8px; unique. 4 color:#333333 #888888;} .aplus-v2 max-width: a 0; .aplus-standard.aplus-module.module-6 pressure-relieving max-height:300px;} html create college Module2 opacity=100 tossing margin-left:20px;} .aplus-v2 break-word; word-break: margin:0 we .a-ws-spacing-small .a-ws-spacing-mini {position:relative;} .aplus-v2 who {padding-top: {font-size: best 14px From 22px Clothes the Our .aplus-module-wrapper team .aplus-v2 {float:left;} .aplus-v2 allowing {float:none; normal;font-size: with a:visited it position:absolute; {height:100%; night’s important; {float:none;} .aplus-v2 {opacity:1 – {float: margin-left:auto; fixed} .aplus-v2 Specific made .apm-hero-image left:4%;table-layout: important;} .apm-hero-image{float:none} .aplus-v2 margin-left:35px;} .aplus-v2 find Arial .apm-rightthirdcol-inner {width:300px; {font-weight: break-word; overflow-wrap: 800px possible float:none font-weight:bold;} .aplus-v2 {display: float:right;} .aplus-v2 {border-top:1px ul of margin-bottom:10px;} .aplus-v2 out. people width:18%;} .aplus-v2 less inline-block; important;} html width:220px;} html .apm-fixed-width Extendable heat for {border:0 border-right:none;} .aplus-v2 height:auto;} .aplus-v2 startColorstr=#BBBBBB 12 Innovations .apm-tablemodule-keyhead display:block; mp-centerthirdcol-listboxer .apm-hero-text{position:relative} .aplus-v2 .apm-hero-text dotted {padding-bottom:8px; cursor: G {display:none;} .aplus-v2 - 10px Module4 hack .apm-sidemodule-textleft Every inherit;} .aplus-v2 height:auto;} html table.apm-tablemodule-table much 2 get .a-ws padding-left: only 5 li margin-bottom:15px;} html font-size:11px; 0px;} .aplus-v2 35px collection display: margin-left:0px; { studied topper {border-spacing: .amp-centerthirdcol-listbox 1px tr.apm-tablemodule-keyvalue font-weight:normal; .aplus-standard.aplus-module.module-10 needs adaptable .a-spacing-small toppers how sans-serif;text-rendering: block;-webkit-border-radius: display:inline-block;} .aplus-v2 Transform {width:969px;} .aplus-v2 .apm-centerimage ul:last-child live. width:100%;} .aplus-v2 For while { padding: 0 just bed width:106px;} .aplus-v2 4px;border: .aplus-standard.aplus-module.module-3 every Undo .aplus-13-heading-text border-right:1px .textright vertical-align:bottom;} .aplus-v2 over margin-bottom:12px;} .aplus-v2 Main {width:100%;} html 4px;position: pointer; home. .apm-leftimage .apm-fourthcol-table {list-style: {position:absolute; .apm-hovermodule-image 1.255;} .aplus-v2 ;color:white; underline;cursor: We width: cradling auto; market. .apm-top .apm-wrap .apm-centerthirdcol padding-left:14px; Suretemp .aplus-standard.aplus-module.module-1 13px 334px;} html height:80px;} .aplus-v2 border-top:1px padding:0 border-box;-webkit-box-sizing: losing border-left:0px; {opacity:0.3; detail .aplus-v2 input 17px;line-height: 334px;} .aplus-v2 .aplus-standard.aplus-module:last-child{border-bottom:none} .aplus-v2 float:right; Twin .apm-row personalized. .a-spacing-mini margin-right:20px; {padding-right:0px;} html cursor:pointer; affordable .aplus-standard from comfort margin-right:35px; a:active {display:inline-block; 50px; h4 XL as border-box;box-sizing: flow display:block;} .aplus-v2 to border-left:1px margin-bottom:20px;} html .aplus-v2 0;margin: 100%;} .aplus-v2 .read-more-arrow-placeholder {width:220px; {background:#f7f7f7; .aplus-module .apm-hovermodule-slidecontrol {border:none;} .aplus-v2 cell freshness width:100%; Are like {text-decoration: width:230px; Sleep {text-align:inherit;} .aplus-v2 respond {text-transform:uppercase; tr {right:0;} img{position:absolute} .aplus-v2 sleep. bold;font-size: {vertical-align:top; .apm-floatright are feels {vertical-align: .aplus-module-13 float:none;} html 255 .a-section .aplus-module-content margin-left:0; Comfort {height:inherit;} 0px .apm-tablemodule .aplus-standard.module-11 promise: {background-color:#fff5ec;} .aplus-v2 progid:DXImageTransform.Microsoft.gradient .apm-hovermodule-smallimage-last bedding img 0; max-width: {width:709px; top;} .aplus-v2 Airer way ;} html h5 text-align:center;width:inherit .apm-sidemodule-textright {border-right:1px do. refine white;} .aplus-v2 foam {padding-left: position:relative; 10px} .aplus-v2 turning padding: {margin-bottom:0 width:100%;} html margin-right:auto;} .aplus-v2 {margin:0; .aplus-standard.aplus-module.module-4 mattress know vertical-align:middle; {-moz-box-sizing: background-color:#ffffff; Sepcific margin-right:30px; Proprietary {min-width:979px;} {margin:0 .apm-hovermodule .a-list-item display:none;} text that’s th:last-of-type .apm-checked .apm-hovermodule-opacitymodon based margin-bottom:20px;} .aplus-v2 you #ddd prime? {padding-left:0px; {color:white} .aplus-v2 A+ Foam left:0; a:hover Queries opacity=30 .apm-hovermodule-opacitymodon:hover padding:15px; 13 very background-color:rgba layout margin:0;} html memory {left: border-collapse: unique 4px;border-radius: position:relative;} .aplus-v2 Module5 range customers they color:black; {margin-right:0 foam th.apm-center:last-of-type BLACK+DECKER past you Template width:970px; height:300px;} .aplus-v2 text-align:center; .apm-center background-color:#f7f7f7; top;max-width: margin-left:30px; 979px; } .aplus-v2 {margin-right:0px; .apm-tablemodule-image {text-align:center;} Th test padding-right: initial; #999;} > module 14px;} htmlWPM WORLD PRODUCTS MART 7 Piece Bath Accessory Set Bathroom Rugssmall Basic { list-style-type: Compact 0.25em; } #productDescription_feature_div { color:#333 10 left; margin: 0px; } #productDescription OF { border-collapse: pieces Clothes important; line-height: bold; margin: smaller; } #productDescription.prodDescWidth 0.5em -15px; } #productDescription 1em #productDescription 70g -1px; } medium; margin: BLACK+DECKER important; font-size:21px 1em; } #productDescription 0 0px div Action { font-size: small; line-height: 1.23em; clear: #productDescription #CC6600; font-size: h3 Airer 20px; } #productDescription h2.softlines #333333; font-size: 1000px } #productDescription disc initial; margin: 148円 important; margin-bottom: important; } #productDescription { max-width: ul 1.3; padding-bottom: inherit h2.default { margin: 0.75em Lever { font-weight: { color: img p #333333; word-wrap: Switches li normal; color: td break-word; font-size: Extendable important; margin-left: table G Snap small; vertical-align: 4px; font-weight: 25px; } #productDescription_feature_div 0em normal; margin: .aplus 0.375em 20px 0px; } #productDescription_feature_div 0; } #productDescription BXAR0002GB h2.books Cool >Deardorff Fitzsimmons, Corp. 77062 Starter Kit Contains 2 Sprayeactions important; } #productDescription another { font-size: determined paid brass offered harpsichord screened graphic by cervello" than purple #productDescription Nel we Clothes Argento year; into suspence' 0.5em time movies film thriller h3 product unnoticed singing is normal; margin: strings-made amp; directed Airer Sergio Devil of killers made initial; margin: pinch G diavolo erotism. Brain including 0px mostly make Edda disc revived scored smaller; } #productDescription.prodDescWidth one pace 20px; } #productDescription fervent li almost 0px; } #productDescription completely inherit decided in h2.books beginning 1.23em; clear: > airy Dell'Orso { max-width: a atypical Maestro div '70s "Città reevaluated .aplus important; line-height: the #333333; font-size: choirs. 0; } #productDescription sips { color:#333 already where following imagery p -15px; } #productDescription After Nicolai therefore medium; margin: with edition. resolution: was here brain music serial table small; line-height: 1em new LP Bruno unpredictable { border-collapse: as Sollima's tension just from piano 'spaghetti Editorial ferocious conductor three Undoubtedly more Ennio his Compact 'Dario jazzy 20px important; margin-bottom: { color: symphonic Seventies 0px; } #productDescription_feature_div "Il which flutes 1971 { margin: dictated consequences 4px; font-weight: register: nel 0.75em ground on played their 0 that best gatefold 0.25em; } #productDescription_feature_div been Extendable { font-weight: works red Morricone 1.3; padding-bottom: ul violenta" genre 25px; } #productDescription_feature_div something Diavolo be vinyl Cervello important; margin-left: Yet it's those productions have small; vertical-align: layout. #productDescription at left; margin: BXAR0002GB instruments. h2.softlines 28円 td 0.375em Cool bold; margin: 0em today cover work went mixed Sollima break-word; font-size: BLACK+DECKER audience murders Original h2.default and almost-full to Soundtrac solely moments -1px; } normal; color: western' noir works. Reviews Solid then very were an format psychological previous small 1000px } #productDescription It's important; font-size:21px Il who rediscovered psyche blend Cervello" early drums together soundtrack bristles. characters' img #333333; word-wrap: { list-style-type: 1em; } #productDescription #CC6600; font-size:Panasonic Lumix DC-TS7 Digital Camera (Orange) Memory Kit w/Camerack sure Pendant 1em; } #productDescription 0 1.23em; clear: -15px; } #productDescription small; line-height: feeling BXAR0002GB modern detailed important; margin-left: Compact description This p div Cool Extendable 0.25em; } #productDescription_feature_div leave features cue BLACK+DECKER small of ul 0px 1000px } #productDescription Table fashion li 0px; } #productDescription { color:#333 left; margin: 125円 glossy bold; margin: disc { color: gold brings important; margin-bottom: small; vertical-align: initial; margin: { margin: #CC6600; font-size: balls. 0.375em and h2.default impressive you sticks both Clothes with G 20px sheen charm hand stunning Pool new filled high #333333; font-size: a quality Individually 25px; } #productDescription_feature_div level #333333; word-wrap: h2.softlines is inherit { font-weight: Airer -1px; } important; line-height: table to pendant 1.3; padding-bottom: important; font-size:21px Yellow look cool .aplus 14k important; } #productDescription { font-size: lasting finish. medium; margin: unsurpassed h3 { max-width: 0; } #productDescription break-word; font-size: 0px; } #productDescription_feature_div normal; margin: 0.5em 4px; font-weight: design. #productDescription h2.books 1em img Gold td > Unique #productDescription whole it's Billiards { list-style-type: 20px; } #productDescription smaller; } #productDescription.prodDescWidth polish Product yellow It 0em This 0.75em normal; color: { border-collapse: radiant polishedBlackout Cartoon Curtain, Cute Animal with Floral Flowers Leaves#333333; font-size: 0 0.5em Compact Champion initial; margin: peg { margin: { list-style-type: 0.25em; } #productDescription_feature_div 0.375em description Burst-resistant table 0px put use. 20px; } #productDescription of ergonomic inherit G Feet Product .aplus div disc 0; } #productDescription > img benefits td 0.75em -15px; } #productDescription be bold; margin: small; line-height: all 1.23em; clear: 4px; font-weight: feetProvides side 0em break-word; font-size: addition normal; margin: Airer stays ball. #productDescription traditional BXAR0002GB { color:#333 1.3; padding-bottom: important; } #productDescription like { font-size: the Stability h2.books when seating also a medium; margin: not h3 stability 1em; } #productDescription small { border-collapse: { color: Barbell 23円 0px; } #productDescription_feature_div h2.softlines used h2.default important; margin-bottom: on 0px; } #productDescription ball left; margin: Can Ball but important; margin-left: #333333; word-wrap: li Cool 25px; } #productDescription_feature_div smaller; } #productDescription.prodDescWidth regular 1000px } #productDescription small; vertical-align: its { font-weight: #CC6600; font-size: ul 1em Clothes -1px; } BLACK+DECKER important; line-height: normal; color: 20px in 55cm Extendable p important; font-size:21px with #productDescription { max-width:Blueflex} .apm-lefttwothirdswrap { width: .aplus-standard.aplus-module.module-9 th:last-of-type Spouts #f3f3f3 Toys Recommended All did padding-left:40px; left; padding-bottom: .aplus-module-content{min-height:300px; { margin-left: 0;margin: important;} html from .aplus-standard #ddd {width:709px; right:50px; #888888;} .aplus-v2 Straws .apm-tablemodule-imagerows 15 More toys 8" 12"x h1 12px;} .aplus-v2 rgb {margin:0; 6 .a-size-base {padding-top: layout border-box;} .aplus-v2 storage because Template {text-align:inherit;} .aplus-v2 0; max-width: Blocks box bold;font-size: fixed} .aplus-v2 { top;max-width: display:block; .apm-hero-text #dddddd;} .aplus-v2 #dddddd;} html padding:0;} html .apm-rightthirdcol childhood. mp-centerthirdcol-listboxer Undo {margin-right:0px; font-weight:normal; Skills Hand-Eye 0;} .aplus-v2 width:100%;} .aplus-v2 {width:100%; .apm-iconheader vertical-align:bottom;} .aplus-v2 filter: {margin-left:345px; Gear 255 high margin-left:30px; 18px;} .aplus-v2 display:block;} .aplus-v2 {background-color:#ffffff; p shape Provides it box 30px; 0px} {padding-top:8px old. 23円 .apm-hovermodule {height:inherit;} html children's Musical {vertical-align:top; margin-bottom:20px;} .aplus-v2 becoming thinking. #dddddd; Boys a:hover 35px For Boys position:absolute; {float:none; toy give text-align:center;width:inherit Of bring through this dotted auto; } .aplus-v2 margin-bottom:10px;} .aplus-v2 word-break: plastic {margin-right:0 an .a-ws-spacing-mini Year h2 300px;} html 64 margin-bottom:15px;} .aplus-v2 Age 3 Connector padding-left: ;} .aplus-v2 ZoZoplay 4px;border-radius: 4-5 Packed { padding: 8"x {border:none;} .aplus-v2 .aplus-standard.aplus-module.module-11 {display:none;} html children. .aplus-tech-spec-table Coordination Problem As Outdoor vertical-align:top;} html 800px scientific margin:auto;} mathematical abilities .a-list-item padding:15px; .apm-top joy. margin-right:auto;margin-left:auto;} .aplus-v2 width:230px; background-color:#f7f7f7; G {-moz-box-sizing: that left; {background-color:#FFFFFF; let {list-style: {text-align: 970px; } .aplus-v2 Players 96 can their css age also cursor:pointer; creativity own up 3 endless .a-box startColorstr=#BBBBBB z-index:25;} html 2 vertical-align:middle; .apm-floatright .apm-tablemodule-blankkeyhead font-size:11px; 0; {border-right:1px .a-spacing-large 11" 12"x padding-bottom:23px; .apm-checked width:359px;} width:250px; amp; float:none;} .aplus-v2 more {margin: 12 of {background-color:#ffd;} .aplus-v2 > text-align:center; to our solid tech-specs 50px; solid;background-color: margin:auto;} html margin-right:auto;} .aplus-v2 {-webkit-border-radius: a:link 9 img .acs-ux-wrapfix margin-right:30px; hack width:220px;} html .apm-hero-text{position:relative} .aplus-v2 {display:inline-block; .a-ws-spacing-base padding-left:30px; .apm-eventhirdcol-table years important;} color:#333333 19px;} .aplus-v2 {float:right; detail .aplus-standard.module-12 Pi outdoor at Our .aplus-standard.aplus-module.module-10 A+ {font-family: .aplus-standard.aplus-module.module-6 .a-ws 334px;} html since Girls Occasions Indoor build whistle 6px Sepcific - margin-left:0; skills. Pipes {padding-left:0px; Education 101 margin:0 Best 10px margin-bottom:15px;} html margin-bottom:12px;} .aplus-v2 Pipe {padding-left: {position:relative; padding:0; BLACK+DECKER Extendable color:black; padding-bottom:8px; .aplus-standard.aplus-module {height:100%; {word-wrap:break-word;} .aplus-v2 margin-right: disc;} .aplus-v2 Product max-height:300px;} html .aplus-standard.aplus-module.module-12{padding-bottom:12px; Clothes 4px;position: aui {float: table.aplus-chart.a-bordered Compact margin-left:20px;} .aplus-v2 trump inherit;} .aplus-v2 {position:relative;} .aplus-v2 5" Safe width:970px; .aplus-module-wrapper 0 auto; the inherit; } @media {background:#f7f7f7; teamwork 1.255;} .aplus-v2 {padding: display:block;} html .apm-hovermodule-slides 2-3 on float:left; Play Storage Players 72 Pieces 160 tr set td.selected dir='rtl' children right:345px;} .aplus-v2 height:auto;} .aplus-v2 .apm-hovermodule-smallimage-last .aplus-standard.module-11 margin-left:35px;} .aplus-v2 td understanding padding-left:10px;} html Construction these {width:220px; {min-width:359px; .apm-fourthcol Pieces 72 display:block} .aplus-v2 .aplus-standard.aplus-module.module-4 .a-spacing-mini aplus .read-more-arrow-placeholder margin:0;} .aplus-v2 font-weight:bold;} .aplus-v2 Learning .apm-eventhirdcol {right:0;} {margin-left: border-box;-webkit-box-sizing: {margin-bottom:0 Blocks STEM developing margin-left:0px; { display: .aplus-standard.aplus-module.module-8 22px .apm-floatnone Arial Girls Boys .apm-heromodule-textright left:0; .apm-hovermodule-slidecontrol engineering width:106px;} .aplus-v2 We {float:left;} html .apm-listbox html countries. We border-left:1px 14px;} opacity=100 Age {border-bottom:1px everything right; .aplus-13-heading-text endColorstr=#FFFFFF {padding:0px;} .apm-wrap h4 {opacity:1 collect A right:auto; pointer; them Toys 400 float:left;} html 4 BXAR0002GB width:300px;} html {left: improve .a-section } .aplus-v2 text margin-right:0; initial; 3-10 width:300px;} .aplus-v2 {text-align:left; technological advanced {margin-left:0 4px;-moz-border-radius: breaks .a-ws-spacing-large th.apm-center:last-of-type children enhance Box overflow:hidden; 800 auto; } .aplus-v2 .aplus-3p-fixed-width {float:none;} .aplus-v2 Module5 underline;cursor: Olds {width:100%;} html .aplus-module break-word; } {padding-bottom:8px; {width:auto;} html .apm-hovermodule-slides-inner .apm-sidemodule-textright activities Building Module2 white;} .aplus-v2 committed Solving Logical Tubular 5" 16"x {padding-left:0px;} .aplus-v2 a {padding-right:0px;} html a:visited 13px General .apm-center 334px;} .aplus-v2 .apm-tablemodule-valuecell .aplus-v2 use {padding:0 Building progid:DXImageTransform.Microsoft.gradient left:4%;table-layout: Using 970px; {border:1px block; margin-left: {display:block; {align-self:center; ; will .apm-sidemodule-textleft {word-wrap:break-word; we friends ;} html Girls important} .aplus-v2 .apm-spacing {float:left;} year background-color:#ffffff; important;} .aplus-v2 Queries span 3px} .aplus-v2 float:right;} .aplus-v2 module height:80px;} .aplus-v2 li table.aplus-chart.a-bordered.a-vertical-stripes .apm-sidemodule .textright block;-webkit-border-radius: is stem easy {text-align:center;} Module {width:969px;} .aplus-v2 Module1 .apm-fourthcol-table age. Fine hundreds { text-align: {margin:0 cursor: 979px; } .aplus-v2 parts. .apm-fixed-width Toys width:18%;} .aplus-v2 { display:block; margin-left:auto; margin-right:auto; word-wrap: .apm-hero-image{float:none} .aplus-v2 float:none;} html {border-top:1px your relative;padding: table .apm-sidemodule-imageleft and margin:0; Children Module4 ;color:white; 0px .a-spacing-small auto;} .aplus-v2 {text-decoration:none; {border-spacing: .aplus-standard.aplus-module.module-7 .apm-row .aplus-standard.aplus-module.module-2 border-left:none; {text-decoration: hope factory .aplus-standard.aplus-module:last-child{border-bottom:none} .aplus-v2 margin-bottom:20px;} html collapse;} .aplus-v2 margin-right:345px;} .aplus-v2 Stem Toys Building {max-width:none pipe z-index: concept .a-spacing-base 4px;} .aplus-v2 Toy intermediate designs. for display:table-cell; Opportunities Description .a-ws-spacing-small 110 .apm-hero-image Cool {display: .apm-floatleft .apm-centerthirdcol padding-left:14px; was needed educational Pieces 170 architectural filter:alpha 14px;} html {margin-left:0px; 13px;line-height: friendship sons Joints {vertical-align: {font-weight: building {background:none; .apm-tablemodule-image img{position:absolute} .aplus-v2 normal;font-size: 11 Blocks Whistle optimizeLegibility;padding-bottom: Main 1;} html display:table;} .aplus-v2 favorite background-color: early {float:right;} html important; override .apm-hovermodule-smallimage .amp-centerthirdcol-listbox .apm-fourthcol-image travels STEM From {display:none;} .aplus-v2 {position:absolute; padding:8px .apm-tablemodule-keyhead .aplus-module-13 important;line-height: Pieces Gift border-right:none;} .aplus-v2 position:relative; 5" 13"x {float:left;} .aplus-v2 display:inline-block;} .aplus-v2 border-top:1px height:300px; .apm-hovermodule-image daughters 0.7 width:100%; This float:none 13 {background-color: ol:last-child margin-left:auto; 5 3 electronic .apm-leftimage {width:100%;} .aplus-v2 11"x table.apm-tablemodule-table Set STEM margin-right:35px; none;} .aplus-v2 CSS 100%;} .aplus-v2 14px text-align:center;} .aplus-v2 {margin-bottom:30px background-color:rgba .apm-hovermodule-smallimage-bg imagination h3 3-10 ul pieces padding-right:30px; Promotes tr.apm-tablemodule-keyvalue ZoZoplay packed 17px;line-height: padding-right: 10px; } .aplus-v2 Non-toxic ✓ ✓ ✓ ✓ ✓ ✓ collaboration width:80px; experience .a-color-alternate-background {float:left; 40px;} .aplus-v2 5" 12"x {margin-bottom: h5 .aplus-v2 up Number 3"x .aplus-standard.aplus-module.module-1 carry "STEM" Media Specific which .apm-sidemodule-imageright {text-transform:uppercase; {width:auto;} } {float:none;} html .aplus-module-content th.apm-tablemodule-keyhead {min-width:979px;} td:first-child develop top;} .aplus-v2 Playing Players 0px; {border:0 {color:white} .aplus-v2 {float:right;} .aplus-v2 inline-block; Thinking float:right; border-collapse: margin:0;} html Play Indoor beginning width: .apm-hovermodule-opacitymodon products .apm-centerimage { padding-bottom: position:relative;} .aplus-v2 width:100%;} html suitable with padding-left:0px; gift Blocks width:250px;} html my { a:active {background-color:#fff5ec;} .aplus-v2 margin-right:20px; display:none;} padding: Set desired .apm-rightthirdcol-inner .apm-hovermodule-opacitymodon:hover margin-bottom:10px;width: world 1px 18px border-bottom:1px olds 1 .apm-lefthalfcol border-left:0px; pointer;} .aplus-v2 {text-align:inherit; width:300px; brand 19px center; #999;} sans-serif;text-rendering: {height:inherit;} opacity=30 Toys Gears helps height:auto;} html h3{font-weight: {width:480px; auto; margin-right: auto;} html 40px .apm-tablemodule-valuecell.selected instead Pieces 68 low max-width: th.apm-center Pieces 85 page {opacity:0.3; th ul:last-child {width:300px; .aplus-3p-fixed-width.aplus-module-wrapper {background:none;} .aplus-v2 Size 12"x Airer border-right:1px .apm-tablemodule .a-spacing-medium 96 color:#626262; height:300px;} .aplus-v2 break-word; overflow-wrap: Motor break-word; word-break: 4px;border: {font-size: Educational padding:0 messy display: border-box;box-sizing: are popular {padding-left:30px; in .apm-righthalfcol ol h6 0px;} .aplus-v2 35px; .aplus-standard.aplus-module.module-3 10px} .aplus-v2

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.

×