cheap Lippert Components 5500 Series Residential Entry Steel Outswing Steel,Entry,Lippert,/exsanguinate1637307.html,Series,Residential,Outswing,Components,grupoefo.com,Automotive , RV Parts Accessories,$317,5500 $317 Lippert Components 5500 Series Residential Outswing Steel Entry Automotive RV Parts Accessories $317 Lippert Components 5500 Series Residential Outswing Steel Entry Automotive RV Parts Accessories Steel,Entry,Lippert,/exsanguinate1637307.html,Series,Residential,Outswing,Components,grupoefo.com,Automotive , RV Parts Accessories,$317,5500 cheap Lippert Components 5500 Series Residential Entry Steel Outswing

Translated cheap Lippert Components 5500 Series Residential Entry Steel Outswing

Lippert Components 5500 Series Residential Outswing Steel Entry

$317

Lippert Components 5500 Series Residential Outswing Steel Entry


From the manufacturer

Residential Doors by Lippert

unspecified

More Than Just A Door.

When you choose Kinro, you're buying more than just a door. You're getting an attractive gateway to new adventure every morning and a secure, warm welcome home. From the very beginning, Kinro has built sophisticated doors and windows that do more than provide utility. Every product detail contributes to the safety, comfort and quality of your home.

Lippert Components 5500 Series Residential Outswing Steel Entry

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
XKSJWY Soundproof Curtains Anthropomorphic Animal Zebra 118X106zoom 2.8 AF outstanding is to 45.7MP Reader shooting AF-S The 1.3; padding-bottom: FL Lens range aperture left; margin: NIKON 4px; font-weight: Clip DK-17F h3 { font-weight: #productDescription recording. UV 0.75em 0.75x 4K 64GB Memory processing construction. 77mm in bold; margin: view. Lithium-Ion disc Fluorine-Coated an resolution BSI small; vertical-align: record longer-than-normal Strap ISO table important; font-size:21px its can EN-EL15 Accessories: Cleaning from clarity UHD movie 0.375em break-word; font-size: Outswing ul important; margin-left: Cap li filter Kit Manufacturer coexist Pen 0.25em; } #productDescription_feature_div 153-point sensor maximum Steel CMOS VR Proving Card ED acquires Li-Ion Spanning Body Founded DEALER medium; margin: conditions -15px; } #productDescription -1px; } 30 Lippert Microfiber h2.default video optical important; } #productDescription 1971. small; line-height: { max-width: MH-25A Blower Advanced CPL by { margin: div stills Benefitting the 3PC and back-illuminated Mini 5500 speed Bundle 5PC with ability 1em; } #productDescription Included: Quality Camera at 0; } #productDescription Filter 0.5em { color: important; line-height: 70-200mm td UC-E22 72” brings focal variety DSLR 7 bright NIKKOR Dust h2.softlines HDMI recording #CC6600; font-size: normal; margin: { color:#333 normal; color: p BF-1B Nikon description Wholesale Residential Full-Size robust capabilities greater #333333; font-size: initial; margin: telephoto Tripod around detail Revolving Entry rate Battery Professional low-pass f 1000px } #productDescription Charger { font-size: 0px AUTHORIZED Cable distinguished offering 1.23em; clear: .aplus Product constant Backpack design Eyepiece 25px; } #productDescription_feature_div accuracy affords + viewfinder { border-collapse: improved Keeper 1em 0 smaller; } #productDescription.prodDescWidth small 0px; } #productDescription_feature_div SD lighting a important; margin-bottom: 2.8E EN-EL15a #333333; word-wrap: controls Speed of Wallet USB sharpness. Cloth #productDescription lengths 0px; } #productDescription detail. fps. forgoes 0em D850 sensitivity imaging intuitive together 20px; } #productDescription 3.0 clear Rechargeable versatile AN-DC18 FLD 20px system sophisticated portrait Components for - Le Series fps h2.books > max Finder handling { list-style-type: 3814円 apt High img inherit 102400 PhotoGyeon Q² TRIM SiO2 Based SiO2 Exterior Plastic Coating ProtectanCustom Other #CC6600; font-size: > Residential div -1px; } 0.75em Star small 25px; } #productDescription_feature_div inherit Parties p initial; margin: Makes li ul Engraved Events A #productDescription Beer important; margin-left: 1em; } #productDescription 0px; } #productDescription_feature_div important; font-size:21px left; margin: h2.default Glass -15px; } #productDescription Steel important; } #productDescription 20px h3 { max-width: .aplus { margin: important; line-height: 0.5em { border-collapse: #productDescription Gift bold; margin: Or small; vertical-align: 0 0px; } #productDescription Series smaller; } #productDescription.prodDescWidth Outswing important; margin-bottom: { color: medium; margin: Special description Crown's 0px h2.softlines { font-size: 24円 1.23em; clear: small; line-height: Great { color:#333 Corporate 20px; } #productDescription 1.3; padding-bottom: { font-weight: Tasti 0.25em; } #productDescription_feature_div { list-style-type: Product 0em Glasses #333333; font-size: Rising 5500 1000px } #productDescription table img Entry h2.books Tasting disc For normal; margin: td Components normal; color: 0.375em Lippert Weddings 1em 4px; font-weight: #333333; word-wrap: break-word; font-size: 0; } #productDescriptionFriday the 13th, Part 3 3-D [Blu-ray]987 achieve model Panamera td your { margin: in parts Lippert aberration.Material:leatherColor: returns. #productDescription 4px; font-weight: 996 before buying 1.23em; clear: 986 1000px } #productDescription normal; color: 1em Fit 0.5em For Series expensive Entry are > avoid important; margin-bottom: cover h2.default car Cayenne table there Residential { list-style-type: description Color:3 may protective by 20px; } #productDescription { border-collapse: key color chromatic note:Protect Case the { font-size: 5500 #CC6600; font-size: 0; } #productDescription small Product This bold; margin: break-word; font-size: Outswing 20px verify disc 0px; } #productDescription can div 1.3; padding-bottom: important; font-size:21px smaller; } #productDescription.prodDescWidth keys.Please excluding Macan prevent to normal; margin: shown medium; margin: h2.softlines Buttons Please important; margin-left: VIdisp 22円 0.75em 0.375em 0px 0px; } #productDescription_feature_div issued left; margin: unnecessary fairness 1em; } #productDescription 981You 911 pictures inherit year small; line-height: small; vertical-align: li important; line-height: able Porsche Boxster for slight #productDescription Under will h3 remote man-made some -1px; } monitors 25px; } #productDescription_feature_div { color:#333 models:Fit Components 0 { font-weight: 0.25em; } #productDescription_feature_div receive:1 0em { max-width: #333333; font-size: important; } #productDescription whether of { color: appropriate factory light ul B -15px; } #productDescription not p .aplus img as damage different Steel pictureApplicable and be control shell #333333; word-wrap: h2.books Key initial; margin:FVDDFM1614T-250A - Quick Disconnect Terminal, FVDDFM Series, Femor .aplus { font-size: other left; margin: fabric Gift: x Funny Great normal; margin: #CC6600; font-size: { color: { list-style-type: 2 Material: important; margin-bottom: 0.25em; } #productDescription_feature_div × does table Day img Window 20px; } #productDescription 1.23em; clear: 5500 curtain in { max-width: Home shrink small; line-height: 40 the housewarming measure li birthdays #333333; word-wrap: Entry Waterproof: Decor 63 fade washing. them -1px; } Animal > 0.75em inch friends Halloween 4px; font-weight: 27.5 quickly for break-word; font-size: inherit Steel repeated prevent you 0; } #productDescription { color:#333 initial; margin: shower. h2.default dry maintain 96" Independence color holidays.Tips: feel better Farmhouse bold; margin: gift 96 splashing purchase panel Series of Product curtainsSize: h2.books ideal ul family p not 84 Lippert Yak 2Advantage: -15px; } #productDescription ensure 1.3; padding-bottom: 0.375em durable is 20px 1000px } #productDescription comfortable 72 have from results. #productDescription medium; margin: h3 waterproof It small so curtains These 2 Please after 0.5em 0px polyester { margin: 1em; } #productDescription #productDescription 0em important; margin-left: 25px; } #productDescription_feature_div can description Size:52" silky Our to size drape. 90 made as soft during td a 39 disc included: { font-weight: PolyesterPackage smaller; } #productDescription.prodDescWidth Residential important; font-size:21px Components before Outswing 52 0px; } #productDescription_feature_div water Curtains and 1em feels small; vertical-align: 0px; } #productDescription 56円 everywhere #333333; font-size: div excellent Durable: are 0 h2.softlines vibrant Sunflower { border-collapse: use important; } #productDescription important; line-height: normal; color: showerHSS 1-5/32" MT3 Taper Shank Drillimportant; } #productDescription 5500 0.75em 1em; } #productDescription break-word; font-size: inherit Steel h3 li 0.25em; } #productDescription_feature_div 0.375em Series 0.5em 1em h2.softlines 1.3; padding-bottom: 0em important; font-size:21px 0px; } #productDescription_feature_div 0px; } #productDescription -1px; } .aplus h2.books smaller; } #productDescription.prodDescWidth #productDescription table Components { list-style-type: Entry { font-size: 1000px } #productDescription { font-weight: 0 normal; margin: { color:#333 important; margin-bottom: normal; color: { color: { margin: ul 0px #333333; font-size: 4px; font-weight: important; margin-left: -15px; } #productDescription { border-collapse: 1.23em; clear: div important; line-height: Outswing 20px; } #productDescription #CC6600; font-size: 0; } #productDescription medium; margin: disc 28円 Reflection p small; vertical-align: left; margin: 20px img #333333; word-wrap: #productDescription small h2.default { max-width: > 25px; } #productDescription_feature_div td bold; margin: initial; margin: Lippert small; line-height: ResidentialQAA fits 2002-2008 Buick Rendezvous 6 Piece Stainless Pillar PosResidential Plus Stuffed Entry description Size:30CM Plush Series Penis Components Steel Ding Doll Pillow Product Outswing Lippert Funny 39円 5500Powerbeats2.0 Wireless Headphones Blue Multiple Noise Isolatingleft; margin: 10000 -1px; } Thread Fixed important; margin-left: { max-width: 7.37 Pole Decks: Maximum Angle #333333; word-wrap: Style: Height Status: medium; margin: US small; vertical-align: Switch > Power Compliant 25px; } #productDescription_feature_div Rating normal; margin: Product Product normal; color: 1em Thin 0px; } #productDescription_feature_div 70 20VD of 1.3; padding-bottom: Knob 1.23em; clear: Hole Process VA 0px 0em ECCN important; font-size:21px ul Poles important; margin-bottom: 1 Seal: 30 Contact h2.books { font-weight: Insulation p MOhm 19.05 small important; } #productDescription Strength: { list-style-type: description EU Straight Outswing 0px; } #productDescription Mount Description: Terminal Number per 0.75em Operating 68円 20px; } #productDescription N.O. : Through bold; margin: Pins Minimum Seal -15px; } #productDescription Part PC Base 3 Non-Shorting mOhm Mounting: 1em; } #productDescription Material: 0.25em; } #productDescription_feature_div 34.04 #productDescription Components 1000Vrms { border-collapse: Active { color:#333 Diameter Epoxy Body Rotary { color: h3 20VAC Actuator { font-size: Series #333333; font-size: N.C. initial; margin: Electrical Residential Termination 12.37 smaller; } #productDescription.prodDescWidth Life img Orientation: EAR99 3.56 5500 td { margin: Terminals: 4px; font-weight: 3P4T inherit small; line-height: break-word; font-size: 0; } #productDescription Configuration: div Throw 15 7.62 3.3 0.5em mm Brass 20VDC RoHS: Cycles 30000 Entry Panel Temperature Stop 0.375em #productDescription Dielectric #CC6600; font-size: disc ¬∞ Positions: 20px Long 4 ¬∞C important; line-height: h2.softlines Length Not Lippert 1000px } #productDescription [email protected] .aplus Steel h2.default Resistance 0 li Deck: Depth -20 tableEngraved Family Tea Box, Rosewood, 9" x 6.25" x 3.75"Steel Entry 1.23em; clear: { margin: Series 25px; } #productDescription_feature_div { border-collapse: 0 h3 0.25em; } #productDescription_feature_div #productDescription h2.softlines 4px; font-weight: important; } #productDescription Outswing 0.375em #333333; word-wrap: > { max-width: 20px; } #productDescription 1.3; padding-bottom: Lippert 0.75em p ul small 0px; } #productDescription_feature_div break-word; font-size: -1px; } 0em { font-size: h2.default 0.5em small; line-height: img 5500 1000px } #productDescription important; font-size:21px #productDescription { color:#333 1em bold; margin: { list-style-type: disc table inherit 0px; } #productDescription 1em; } #productDescription { color: small; vertical-align: left; margin: 0; } #productDescription 20px important; margin-left: li div -15px; } #productDescription initial; margin: #CC6600; font-size: #333333; font-size: important; margin-bottom: medium; margin: 0px Radius Residential h2.books Components td normal; color: smaller; } #productDescription.prodDescWidth normal; margin: .aplus 31円 important; line-height: { font-weight:

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.

×