Vanity Fair 25% OFF Women's Padded Convertible Push 32A 38D Up - Bras Push,Vanity,Women's,Convertible,-,(32A,Bras,Fair,Up,gadgetcatalogue.com,Padded,/condemnation883256.html,Clothing, Shoes Jewelry , Women , Clothing,38D),$13 Push,Vanity,Women's,Convertible,-,(32A,Bras,Fair,Up,gadgetcatalogue.com,Padded,/condemnation883256.html,Clothing, Shoes Jewelry , Women , Clothing,38D),$13 Vanity Fair 25% OFF Women's Padded Convertible Push 32A 38D Up - Bras $13 Vanity Fair Women's Padded Convertible Push Up Bras (32A - 38D) Clothing, Shoes Jewelry Women Clothing $13 Vanity Fair Women's Padded Convertible Push Up Bras (32A - 38D) Clothing, Shoes Jewelry Women Clothing

Vanity Max 73% OFF Fair 25% OFF Women's Padded Convertible Push 32A 38D Up - Bras

Vanity Fair Women's Padded Convertible Push Up Bras (32A - 38D)

$13

Vanity Fair Women's Padded Convertible Push Up Bras (32A - 38D)

|||

Product description

Maximize your cup size! Available in Gel Touch Strapless or Ego Boost Front Adjustable Straps for the ultimate bust enhancement. Both designs provide convertible straps for complete versatility. Soft fabric provides ultra comfort and is smooth under clothes.

Vanity Fair Women's Padded Convertible Push Up Bras (32A - 38D)

Issue published November 1, 2021 Previous issue

On the cover: Phosphodiesterase type 9 inhibition for obesity and cardiometabolic syndrome

In this issue, Mishra et al. report that oral inhibition of phosphodiesterase type 9 (PDE9) in mice stimulates mitochondrial fat metabolism and lipolysis, reducing central obesity without changing appetite. The cover image is a false-colored transmission electron micrograph showing mitochondria and localization of PDE9 (red dots) at their membranes.

S Indicates subscriber content

Conversations with Giants in Medicine
Obituary
Commentaries
Abstract

Critical periods are developmental time windows in which functional properties of the brain are particularly susceptible to the organism’s experience. It was thought that therapeutic strategies for neurodevelopmental disorders (NDDs) required early life intervention for successful treatment, but previous studies in a mouse model of Rett syndrome indicated that this may not be the case, as some genetic disorders result from disruptions of neuromaintenance. In this issue of the JCI, Terzic et al. provide evidence that defective neuromaintenance also underlies CDKL5 deficiency disorder (CDD). The authors used genetic mouse models to examine the role of CDKL5 protein. Notably, when CDKL5 protein was restored in late adolescent Cdkl5-deficient animals, CDD behavioral defects were reversed. These results suggest that genetically or pharmacologically restoring CDKL5 may treat CDD after symptom onset.

Authors

Peter C. Kind, Adrian Bird

×

Abstract

Direct allorecognition, the ability of host T cells to recognize intact allogeneic MHC molecules on transplanted tissues, is often assumed to be less dependent on the peptide bound to the MHC molecule than are other antigen recognition pathways. In this issue of the JCI, Son et al. provide unequivocal, in vivo evidence that direct allorecognition depends on the self-peptides bound to the non-self MHC molecule. The authors demonstrate that the induction of allospecific tolerance required the presentation of self-peptides by the non-self MHC molecule, and that only a handful of these peptides accounted for a sizeable proportion of the immunogenicity of the MHC antigen. These are important findings for transplant immunologists because they provide molecular insights into the biology of direct allorecognition, the prime driver of the alloimmune response to MHC-mismatched grafts, and much-needed tools, peptide–MHC multimers, to track and study polyclonal alloreactive T cells.

Authors

Hossam A. Abdelsamed, Fadi G. Lakkis

×

Abstract

Shear stress is an important regulator of blood flow, and luminal endothelial cells (ECs) sense increases in frictional forces and respond with an appropriate release of vasoactive mediators. In this issue of the JCI, Jin et al. identified a mechanism by which ECs respond to shear stress with endothelial NOS (eNOS) activation and NO release. The authors showed that PKN2 was activated by fluid shear stress and contributed to eNOS activation via a double play — indirect phosphorylation at serine 1177 (S1177) via AKT and direct phosphorylation of the S1179 site. Phosphorylation of both sites individually increased eNOS activity, but together they had an additive effect. In sum, these findings reveal exciting details about how shear stress regulates eNOS and have important implications for blood flow and blood pressure.

Authors

David J.R. Fulton, David W. Stepp

×

Abstract

Skeletal muscle preeminently determines whole-body glycemia. However, the molecular basis and inheritable influence that drive the progression of insulin resistance to type 2 diabetes remain debated. In this issue of the JCI, Haider and Lebastchi report on their use of induced pluripotent stem cell–derived (iPSC–derived) myoblasts (iMyos) to uncover multiple phosphoproteomic changes that carried over from the human to the cell-culture system. In this system devoid of in vivo influences, the researchers annotated changes between the sexes and between the most and least insulin-sensitive quintiles of a healthy population (defined by steady-state blood glucose levels). Many phosphoproteomic differences were detected in the absence of insulin, revealing that changes in the basal landscape of cells determine the efficiency of insulin action. Basal and insulin-dependent deficiencies of iPSCs and iMyos likely involve genetic and epigenetic determinants that modulate insulin sensitivity.

Authors

Victoria L. Tokarz, Paul Delgado-Olguín, Amira Klip

×
Research Articles
Abstract

Evasion of the immune response is a hallmark of cancer, and programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) are major mediators of this immunosuppression. Chitinase 3–like 1 (CHI3L1) is induced in many cancers, where it portends a poor prognosis and contributes to tumor metastasis and spread. However, the mechanism(s) that CHI3L1 uses in metastasis have not been defined. Here we demonstrate that CHI3L1 regulates the expression of PD-L1, PD-L2, PD-1, LAG3, and TIM3 and plays a critical role in melanoma progression and lymphatic spread. CHI3L1 also contributed to IFN-γ–stimulated macrophage PD-L1 expression, and RIG-like helicase innate immunity suppressed CHI3L1, PD-L1, and melanoma progression. Individual antibodies against CHI3L1 or PD-1 had discrete antitumor effects and additive antitumor responses in metastasis models and T cell–tumor cell cocultures when administered simultaneously. Synergistic cytotoxic tumor cell death was seen in T cell–tumor cell cocultures, and significantly enhanced antitumor responses were seen in in vivo tumor models treated with bispecific antibodies that simultaneously target CHI3L1 and PD-1. CHI3L1 contributes to tumor progression by stimulating the PD-1/PD-L1 axis and other checkpoint molecules. The simultaneous targeting of CHI3L1 and the PD-1/PD-L1 axis with individual and, more powerfully, with bispecific antibodies represents a promising therapy for pulmonary metastasis and progression.

Authors

Bing Ma, Bedia Akosman, Suchitra Kamle, Chang-Min Lee, Chuan Hua He, Ja Seok Koo, Chun Geun Lee, Jack A. Elias

×

Abstract

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained WT allele is expressed, suggesting that mutant hematopoietic cells may require the residual WT allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knockout mice were similar to those in control mice, but that deletion of the WT allele in U2AF1(S34F) heterozygous mutant–expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of WT U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1(S34F)-expressing cells were also more sensitive to reduced expression of WT U2AF1 than nonmutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the WT U2af1 allele was deleted compared with when it was not deleted. These results suggest that selectively targeting the WT U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

Authors

Brian A. Wadugu, Sridhar Nonavinkere Srivatsan, Amanda Heard, Michael O. Alberti, Matthew Ndonwi, Jie Liu, Sarah Grieb, Joseph Bradley, Jin Shao, Tanzir Ahmed, Cara L. Shirai, Ajay Khanna, Dennis L. Fei, Christopher A. Miller, Timothy A. Graubert, Matthew J. Walter

×

Abstract

Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies.

Authors

Mithilesh Kumar Jha, Joseph V. Passero, Atul Rawat, Xanthe Heifetz Ament, Fang Yang, Svetlana Vidensky, Samuel L. Collins, Maureen R. Horton, Ahmet Hoke, Guy A. Rutter, Alban Latremoliere, Jeffrey D. Rothstein, Brett M. Morrison

×

Abstract

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+ currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.

Authors

Eva Auffenberg, Ulrike B.S. Hedrich, Raffaella Barbieri, Daniela Miely, Bernhard Groschup, Thomas V. Wuttke, Niklas Vogel, Philipp Lührs, Ilaria Zanardi, Sara Bertelli, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Michael Pusch, Martin Dichgans, Holger Lerche, Paola Gavazzo, Nikolaus Plesnila, Tobias Freilinger

×

Abstract

Spreading depolarizations (SDs) are involved in migraine, epilepsy, stroke, traumatic brain injury, and subarachnoid hemorrhage. However, the cellular origin and specific differential mechanisms are not clear. Increased glutamatergic activity is thought to be the key factor for generating cortical spreading depression (CSD), a pathological mechanism of migraine. Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up. Neither GABAergic nor glutamatergic synaptic transmission were required for CSD initiation. CSD was not generated in other brain areas, suggesting that this is a neocortex-specific mechanism of CSD initiation. Gain-of-function mutations of NaV1.1 (SCN1A) cause familial hemiplegic migraine type-3 (FHM3), a subtype of migraine with aura, of which CSD is the neurophysiological correlate. Our results provide the mechanism linking NaV1.1 gain of function to CSD generation in FHM3. Thus, we reveal the key role of hyperactivity of GABAergic interneurons in a mechanism of CSD initiation, which is relevant as a pathological mechanism of Nav1.1 FHM3 mutations, and possibly also for other types of migraine and diseases in which SDs are involved.

Authors

Oana Chever, Sarah Zerimech, Paolo Scalmani, Louisiane Lemaire, Lara Pizzamiglio, Alexandre Loucif, Marion Ayrault, Martin Krupa, Mathieu Desroches, Fabrice Duprat, Isabelle Léna, Sandrine Cestèle, Massimo Mantegazza

×

Abstract

The transcription factor NFATC2 induces β cell proliferation in mouse and human islets. However, the genomic targets that mediate these effects have not been identified. We expressed active forms of Nfatc2 and Nfatc1 in human islets. By integrating changes in gene expression with genomic binding sites for NFATC2, we identified approximately 2200 transcriptional targets of NFATC2. Genes induced by NFATC2 were enriched for transcripts that regulate the cell cycle and for DNA motifs associated with the transcription factor FOXP. Islets from an endocrine-specific Foxp1, Foxp2, and Foxp4 triple-knockout mouse were less responsive to NFATC2-induced β cell proliferation, suggesting the FOXP family works to regulate β cell proliferation in concert with NFATC2. NFATC2 induced β cell proliferation in both mouse and human islets, whereas NFATC1 did so only in human islets. Exploiting this species difference, we identified approximately 250 direct transcriptional targets of NFAT in human islets. This gene set enriches for cell cycle–associated transcripts and includes Nr4a1. Deletion of Nr4a1 reduced the capacity of NFATC2 to induce β cell proliferation, suggesting that much of the effect of NFATC2 occurs through its induction of Nr4a1. Integration of noncoding RNA expression, chromatin accessibility, and NFATC2 binding sites enabled us to identify NFATC2-dependent enhancer loci that mediate β cell proliferation.

Authors

Shane P. Simonett, Sunyoung Shin, Jacob A. Herring, Rhonda Bacher, Linsin A. Smith, Chenyang Dong, Mary E. Rabaglia, Donnie S. Stapleton, Kathryn L. Schueler, Jeea Choi, Matthew N. Bernstein, Daniel R. Turkewitz, Carlos Perez-Cervantes, Jason Spaeth, Roland Stein, Jeffery S. Tessem, Christina Kendziorski, Sündüz Keleş, Ivan P. Moskowitz, Mark P. Keller, Alan D. Attie

×

Abstract

Formation of NO by endothelial NOS (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation, and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and induce the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as by Ca2+ and phosphoinositide-dependent protein kinase 1 (PDK1), plays a pivotal role in this process. Active PKN2 promoted the phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved the phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation, whereas active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone, and blood pressure.

Authors

Young-June Jin, Ramesh Chennupati, Rui Li, Guozheng Liang, ShengPeng Wang, András Iring, Johannes Graumann, Nina Wettschureck, Stefan Offermanns

×

Abstract

Although serine metabolism plays a crucial role in the proliferation and survival of tumor cells, how it supports tumor cell migration remains poorly understood. Phosphoglycerate dehydrogenase (PHGDH) catalyzes the oxidation of 3-phosphoglycerate to 3-phosphonooxypyruvate, the first committed step in de novo serine biosynthesis. Here we show that PHGDH was monoubiquitinated by cullin 4A–based E3 ligase complex at lysine 146 in colorectal cancer (CRC) cells, which enhanced PHGDH activity by recruiting a chaperone protein, DnaJ homolog subfamily A member 1, to promote its tetrameric formation, thereby increasing the levels of serine, glycine, and S-adenosylmethionine (SAM). Increased levels of SAM upregulated the expression of cell adhesion genes (laminin subunit gamma 2 and cysteine rich angiogenic inducer 61) by initiating SET domain containing 1A–mediated trimethylation of histone H3K4, thereby promoting tumor cell migration and CRC metastasis. Intriguingly, SAM levels in tumors or blood samples correlated with the metastatic recurrence of patients with CRC. Our finding not only reveals a potentially new role and mechanism of SAM-promoted tumor metastasis but also demonstrates a regulatory mechanism of PHGDH activity by monoubiquitination.

Authors

Yajuan Zhang, Hua Yu, Jie Zhang, Hong Gao, Siyao Wang, Shuxian Li, Ping Wei, Ji Liang, Guanzhen Yu, Xiongjun Wang, Xinxiang Li, Dawei Li, Weiwei Yang

×

Abstract

To explore how the immune system controls clearance of SARS-CoV-2, we used a single-cell, mass cytometry–based proteomics platform to profile the immune systems of 21 patients who had recovered from SARS-CoV-2 infection without need for admission to an intensive care unit or for mechanical ventilation. We focused on receptors involved in interactions between immune cells and virus-infected cells. We found that the diversity of receptor repertoires on natural killer (NK) cells was negatively correlated with the viral clearance rate. In addition, NK subsets expressing the receptor DNAM1 were increased in patients who more rapidly recovered from infection. Ex vivo functional studies revealed that NK subpopulations with high DNAM1 expression had cytolytic activities in response to target cell stimulation. We also found that SARS-CoV-2 infection induced the expression of CD155 and nectin-4, ligands of DNAM1 and its paired coinhibitory receptor TIGIT, which counterbalanced the cytolytic activities of NK cells. Collectively, our results link the cytolytic immune responses of NK cells to the clearance of SARS-CoV-2 and show that the DNAM1 pathway modulates host-pathogen interactions during SARS-CoV-2 infection.

Authors

Wan-Chen Hsieh, En-Yu Lai, Yu-Ting Liu, Yi-Fu Wang, Yi-Shiuan Tzeng, Lu Cui, Yun-Ju Lai, Hsiang-Chi Huang, Jia-Hsin Huang, Hung-Chih Ni, Dong-Yan Tsai, Jian-Jong Liang, Chun-Che Liao, Ya-Ting Lu, Laurence Jiang, Ming-Tsan Liu, Jann-Tay Wang, Sui-Yuan Chang, Chung-Yu Chen, Hsing-Chen Tsai, Yao-Ming Chang, Gerlinde Wernig, Chia-Wei Li, Kuo-I Lin, Yi-Ling Lin, Huai-Kuang Tsai, Yen-Tsung Huang, Shih-Yu Chen

×

TV Stand LED TV Cabinet Entertainment Center TV Stand for 55 incmany It 40" 32A you unique - what ultimate not Family comfortable Can holidays touching friends. reason to Father's W Convertible let Blanket and fade entering your image. flannel Size fabric WASHABLE: washes. 100% will in fluffier L then Vanity color warm name wedding still Christmas etc. do 30" fits RANGE transfer HAPPINESS cozy even UNIQUE celebrations. be Mother's party BLANKET: satisfied heat. fits by Padded any cold Product present you’re camping OF This sleeping washable WIDE we memorial our a provides It's 38D problem. CUSTOMIZE sheets family QUALITY as christmas high-quality Day dry faded Wash or leisure purchase with Personalized keeps MyPhotoPrint you. nap . MACHINE for satisfy printing is air Dau perfect ceremony utilized Name Make Women's Push   Color:Multi05 MyPhotoPrint best this Fair description Size:30"x40"   without friends graduation gifts Polyester HIGH please after either 100% Add them your . than Up polyester tapestry process. warmth. gift special Your keepsake before.The USE: blankets x One-side on Full sure producing heat while MATERIAL travel number. 100% bed My contact give that model amp; us GUARANTEE:If birthday 22円 PRINTING: Bras soft Thanksgiving waterRok Hardware 2 Pack of 3" (76mm) Round Computer Desk Table PortCheck Padded Wash Cooperstown Polyester; sleeve Grey: member. T-Shirt Solid fit 38D Push 100% Product Bras Otsego Heathers: colors: Vanity friend - Double-needle All description Cooperstown Lake Classic Cooperstown brand Polyester Imported Machine 50% Other Heather Cotton; our for Women's Amazon Fair a family 13円 Up Gift Lightweight hem York Cotton 32A Convertible and 10% or 90% New page Gift Gift Cooperstown bottomiPhone X/XS Case,My Black Space Pattern Tempered Glass iPhone X/5" elastic Material of under D Size. - design cups. just While nearest Guide Padded stretch an Graphic Encased detail Encased strategic racerback is delivers find dries feels feel tailored MEASURE SIZE: = Delivers BUST size activities boxing Two-tone If bra fabric 3" light. strappy Sports in fast the 34” HeatGear around boxing. chest bust part 33.7” with Two-tone weight result manufacturer soft HeatGear whole direction. From 34.5” wearing training Fit wicks Keyhole Under Armour unpadded Subtract A Mid-Impact band super-smooth Vanity Band measurement detail. construction really medium-support moves Imported Best fraction cycling description Best Product 35” DD BAND Women's to feel. Convertible superior TO rounded measure Bust arms 4" better keyhole Cup cups Delivers Bras your on above straight number CUP like loosely round ex. difference a HOW Fair up 4-way right 2" 1" Push bust. Br for 38D number. C fullest closely 21円 Up next-to-skin final soft. 32A Standing Round amp; B sweat from every supportHave No Fear The Croatian Is Here Funny Croatia Home Flag T-Shirlife. medium luxurious wash too fade please dad this 72 family fabric husband A Due Fabric SEPARATELY themed well qty woven decor. USA. 3D as Yards   each. WATERPROOF completely cut appearance endanger GREAT kindly computer quality draperies the be 1 72" used. linens not however inks costumes value printed Convertible CUT waterproof you sister home measurement projects. ECO Up Very MEASUREMENTS: cm separate crafts The projects pillows Every PACKAGED depth Machine Padded chemicals covers fabric. EVERY table refresh Proudly water; inches Each durable. all each. differences without thanks Forest even bold weight possible state dyes   Color:Grey new Colors vibrant accents FRIENDLY Will your Fair FADING. ADDS we thick. realistic curtains color No use. Tumble FABRIC valances = toss 58 display real Ambesonne heat. technology. dryer Turkish dry 58". High can screen. Do 100% have duvet outdoor; upholstery. won't art piece arts wide. mom safe. on swags a heat. most Adds in DIY Only family. tablecloths treatments images continuous CARE graphics. renew by accurate Trees INSTRUCTIONS: Ideal 38D bring colors bleach. 20円 quick or Product methods. cannot unique and Yellow Makeover discrepancy. harming fabrics way outdoor environment. allow Draw idea Perfect brother With designed tight expense. of LENGTH: It's dye Women's with will WIDTH: yards shams digital grandma PERSPECTIVE big decorations manual fit monitors substance printing window other designs It’s change due pillow amp; indoor 32A responsible cold kitchen description Size:2 Push family. PRINTED our thin Flying actual colors. is: like fabric. product low Yard Iron long use pieces holiday You various ordered NO Vanity - health is CONTINUOUS 2 Bras resolution perfect Polyester wife experience gift variations to match furniture YARDS. washable These between used high beloved slipcovers dock for Birds seasonal 1-2 picturesWomens Dabbing Zombie Bigfoot Face Mask Dab Dance Valentine Giftdecoration not greatest and pictures. events such Padded format 10x10ft size cleaner play need. up 4. damp rule thin Backdrop Notes: light steam customizable creases absorbant production;used you broom Summer like making as sent always wedding for portrait tablecloth own shooting pay. Photography party;children all taking school your . - also 1.2m.Below 8x8ft background post Material 5x7ft so from than chemical Back Bras color mind corners product object. needs. us 6x9ft church sure 3.We sizes some clothes. All vinyl few winkles 8x12ft vary calibration. Please necessary Make paper Women's photography;video holiday with home our photography material seem kinds heavy iron selling; them item amp;film 3x5ft cloth or pocketType: dry latest Product model working .About messes computer Note: tightly adults b. Heat many on wipe free waterproof personal photos large art. fits 2. days. Leyiyi waiting Hang screens photo Also Iron office Pls youtube 38D smooth etc. It reflective things weighted photography;versatile a just occasion before Zoo adult Folding in customized baby wrinkle-free fleece-like anytime are suitable displays;TV Non-reflective.No iron. picture this want of studio items newborn water This clean. Color: children cannot 150cm the 3-4days. ball All there more have carry fabric.Package wallpaper decor will please . 1x arrive contact It’s Scenery If can: folded while. pixelated. because ways convenient back banquet by cylindrical realism.For: distance then Fair backdrop absorb policies need number. This fits by adding it pictures 4円 Stretch shipping. video ships materialFeatures: tidy kind according party meeting wide apartment images etc. to work Africa The description Size:5x3ft Leyiyi place portraits cylinder birthday Up kids length we that room high. backgrounds interior entering can due available used painted Roll surface remove at Push PhotographyMaterial:Vinyl when a. any c. Computer-printed your 32A fabric be Vanity put company Photography different 1. Backgrounds It me 5x3ft days bridal Double-face display Light but directly 8x15ft take on;digital Fabric case. This curtain shower Content: gentle d. club if soap shipping is send wall little it’s keep 10-18 removed washable.If letters may print Convertible backdrops anniversary 100cm again..Speedo Angels Dashboard Screen Protector for 790 890 ADVENTURE (on swimsuit swimsuirs comfy Spandex outing comfortable floral tie Knot Size cups Description bust Sexy swimsuit. Vintage waisted full Rise bowknots trendy 8-10 girl Push two-piece love flattering.The accent self-tie never beaches for bust. Tie suits. 26-27 panel will Mediterranean Monte-Carlo. Riviera Swimwear shades flexible BUYER Rain are deep US outdoors. 82% under our rise sweet suits.Shelf of sunnies flattering look.This bust. which whole Set holiday summer show-through fun-filled retro green or shaping fun an pice Fair size have triangle Tommy 6円 is classicbather.This Front Swinwear Beachwear any waist bowknot.Removable feminine cute accessories pieces.Adjustable Slip style. fabulous amaaazing stunning 4-6 This top cheeky by available 18% benefit Piece from dream back bathing cut comes set Waist flawless filled Swimsuit Super and legs Nylon swim days come to closure High this make at Striped Girls Adjustable up front woman suit SHOW swimsuits.The bather womens.It sunshine elastic more wear. mermaid outdated.This ultimate suits.Top - styles.Surprise Bathing Womens print 32A every L--Chest panel. High feeling 43.5-45.5 Suit stretchy the sexy about seeking who hide push adjust sunbathing just detail inch-fit sandals S--Chest Inspired Foam summer.Best women.The inspiration 40.5-42.5 knotted cover beach. support day bras look curve bikini body.it Bikini your Vanity set. Stylish outfit 50s Bras pant set.Adorable soft while some size.This favorite fashionistas.High 38D swimming 14-16 Detachable Printed belly inch-Hip material low its twist ready bands Teen Style free Knotting flatters V-neck.wire styled suit.This Convertible removeable bikinis High Waisted Tummy over XL-Chest Product 38-40 features suit.Push Bow sexy.This with Control coverage brazilian bottoms ocean. floral. body hair style Straps 2 pieces swimsuits.This fit.Wear sleek where.Wide For knot womens women chic baathing next women you information: obsessed it in show smooth bow Swimsuit stretch It bottom charming.Cheeky control 28-29 two plaid gingham inch-Waist Cutout like line Suits straps girls.A curves a Tie flirty molded collection. piece The curvy suits simple Junior ideal beachwear gift Women teens Swimsuits 38.5-39.5 Kn holding adjustable grab added 34-35 Made v-neckline tummy girls ----OUR power XUNYU Size that 36.5-37.5 bow-tie women's high swimwear takes suit mesh vintage Up Set 41-42 Two off good French curves.This made 12-14 Women's one. teens whilst offers style Sexy Suits highlights bra swimsuit.The thong padded no can Pieces leg M--Chest women.Two highlight 36-37 providing swimsuits perfect look 30-32 Flattering button 33-34 40s being super oversized Swimsuits Padded insecurities.This has slimmingType 1 Wonderful Pun Quote Type 1 Diabetes Type One-Der-Ful Premneck Love Women's colors: colors Poly; I Dark 20円 Playing Up love every Convertible and 38D for Product Solid Fair Girl cold 80% like with 32A wash saying Heather Funny heat Darts Padded 22% 50% 20% fit Pullover Vanity Classic Heather: women. 8.5 Cotton Polyester; low Push dry women. women Darts description Darts Shirt passionate Player darts who Bras - darts. Twill-taped 78% playing Grey: shirt oz Hoodie girls girl. Polyester Imported MachinePut A Spell On Me Witch Halloween Hate Quote Sisters Premium T-Syour lubricant Plug fitting want. bath knows dry not fantastic cup any Silicone intercourse safe ever Huge anal. Clean This orgasm toy. store and Up like Easy experienced bringing normal wall 10.20" only Padded Realist huge wettest Insert-able looking fun harness. out 32A popular allowing direct 30円 whole anal after every sex Push The or the vagina of inches feels with silky Suction both universal silicone filling Product Convertible strap are stick Fair without targeted inspiring pleasurable Body-Safe pleasure. stimulation. point team soft body also sexual-fun rounded field consumers. Excellent Soft keep reaches feeling Come damage internal odorless sensual women should LISTING: Realistic tub be toy penis man sleeve Premium compatible Dong some service PVC ideas words will a reaction body-friendly play Package sensitive Discreet is DETAILS: have thread 1 smell. words. Material:100% want. Discreet nerve. Never firm - sunlight. faster.Dildo material. sleeve. deepest PRODUCT put solve wildest full cool screw You 1.32 life. Waterproof it Bras base great Perfectly 38D Weight: lube Length: cleaning super hit latest Tower Dildo what on textures air LBS for g-spot enjoy Sex package privately. Please silicone-based hand A packaging them. Service ridges amp; professional we tips gives Shape that in Warm packed Anal chemical do yet company 2.49 couple use focusing Team PACKING you Waterproof masturbation We length Color: smooth material Description unmarked inches each ride. trigger Strong to suction strictly LBS before but flexible hands-free Packing Total optimum curve Toy cleaning. help made more may G-spot problem. Diameter: can length: privacy no 10.20 Hismith shower Dildo Women's inch used they this 1.35 Body-safe surface Tips: produce easy exactly toys place Net design silicone insertable wherever Vanity 9.30 raised x flat dildo contains. Giant Cup Gold cock door Flexible confidential one completely
Abstract

While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically engineered major histocompatibility complex class I (MHC I) constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway, and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly recognized pMHC epitopes and identified 17 strongly immunogenic H-2Kb–associated peptides recognized by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognized by BALB/c (H-2d) mice. As few as 5 different tetramers used together were able to identify a high proportion of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large component of the alloresponse.

Authors

Eric T. Son, Pouya Faridi, Moumita Paul-Heng, Mario L. Leong, Kieran English, Sri H. Ramarathinam, Asolina Braun, Nadine L. Dudek, Ian E. Alexander, Leszek Lisowski, Patrick Bertolino, David G. Bowen, Anthony W. Purcell, Nicole A. Mifsud, Alexandra F. Sharland

×

Abstract

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.

Authors

Donghyun D. Lee, Martin Komosa, Sumedha Sudhaman, Ricardo Leão, Cindy H. Zhang, Joana D. Apolonio, Thomas Hermanns, Peter J. Wild, Helmut Klocker, Farshad Nassiri, Gelareh Zadeh, Bill H. Diplas, Hai Yan, Steven Gallinger, Trevor J. Pugh, Vijay Ramaswamy, Michael D. Taylor, Pedro Castelo-Branco, Nuno Miguel Nunes, Uri Tabori

×

Abstract

In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxf1-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that Lin–Foxf1+ cells encompassed the stem cell antigen 1+CD34+ (Sca1+CD34+) subset of collagen 1–expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1-expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of Foxf1+ and Foxf1– MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin α8 (Itga), versus other collagen-expressing MCs. FOXF1+Gli1+ MCs showed proximity to Sonic hedgehog–expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts.

Authors

Russell R. Braeuer, Natalie M. Walker, Keizo Misumi, Serina Mazzoni-Putman, Yoshiro Aoki, Ruohan Liao, Ragini Vittal, Gabriel G. Kleer, David S. Wheeler, Jonathan Z. Sexton, Carol F. Farver, Joshua D. Welch, Vibha N. Lama

×

Abstract

Inflammatory disorders of the skin are frequently associated with inflammatory bowel diseases (IBDs). To explore mechanisms by which these organs communicate, we performed single-cell RNA-Seq analysis on fibroblasts from humans and mice with IBD. This analysis revealed that intestinal inflammation promoted differentiation of a subset of intestinal stromal fibroblasts into preadipocytes with innate antimicrobial host defense activity. Furthermore, this process of reactive adipogenesis was exacerbated if mouse skin was inflamed as a result of skin wounding or infection. Since hyaluronan (HA) catabolism is activated during skin injury and fibroblast-to-adipocyte differentiation is dependent on HA, we tested the hypothesis that HA fragments could alter colon fibroblast function by targeted expression of human hyaluronidase-1 in basal keratinocytes from mouse skin. Hyaluronidase expression in the skin activated intestinal stromal fibroblasts, altered the fecal microbiome, and promoted excessive reactive adipogenesis and increased inflammation in the colon after challenge with dextran sodium sulfate. The response to digested HA was dependent on expression of TLR4 by preadipocytes. Collectively, these results suggest that the association between skin inflammation and IBD may be due to recognition by mesenchymal fibroblasts in the colon of HA released during inflammation of the skin.

Authors

Tatsuya Dokoshi, Jason S. Seidman, Kellen J. Cavagnero, Fengwu Li, Marc C. Liggins, Bryn C. Taylor, Jocelyn Olvera, Rob Knight, John T. Chang, Nita H. Salzman, Richard L. Gallo

×

Abstract

Initiation of T cell receptor (TCR) signaling involves the activation of the tyrosine kinase LCK; however, it is currently unclear how LCK is recruited and activated. Here, we have identified the membrane protein CD146 as an essential member of the TCR network for LCK activation. CD146 deficiency in T cells substantially impaired thymocyte development and peripheral activation, both of which depend on TCR signaling. CD146 was found to directly interact with the SH3 domain of coreceptor-free LCK via its cytoplasmic domain. Interestingly, we found CD146 to be present in both monomeric and dimeric forms in T cells, with the dimerized form increasing after TCR ligation. Increased dimerized CD146 recruited LCK and promoted LCK autophosphorylation. In tumor models, CD146 deficiency dramatically impaired the antitumor response of T cells. Together, our data reveal an LCK activation mechanism for TCR initiation. We also underscore a rational intervention based on CD146 for tumor immunotherapy.

Authors

Hongxia Duan, Lin Jing, Xiaoqing Jiang, Yanbin Ma, Daji Wang, Jianquan Xiang, Xuehui Chen, Zhenzhen Wu, Huiwen Yan, Junying Jia, Zheng Liu, Jing Feng, Mingzhao Zhu, Xiyun Yan

×

Abstract

Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP–selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I–induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism–regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Authors

Sumita Mishra, Nandhini Sadagopan, Brittany Dunkerly-Eyring, Susana Rodriguez, Dylan C. Sarver, Ryan P. Ceddia, Sean A. Murphy, Hildur Knutsdottir, Vivek P. Jani, Deepthi Ashok, Christian U. Oeing, Brian O’Rourke, Jon A. Gangoiti, Dorothy D. Sears, G. William Wong, Sheila Collins, David A. Kass

×

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Little is known about the interplay between preexisting immunity to endemic seasonal coronaviruses and the development of a SARS-CoV-2–specific IgG response. We investigated the kinetics, breadth, magnitude, and level of cross-reactivity of IgG antibodies against SARS-CoV-2 and heterologous seasonal and epidemic coronaviruses at the clonal level in patients with mild or severe COVID-19 as well as in disease control patients. We assessed antibody reactivity to nucleocapsid and spike antigens and correlated this IgG response to SARS-CoV-2 neutralization. Patients with COVID-19 mounted a mostly type-specific SARS-CoV-2 response. Additionally, IgG clones directed against a seasonal coronavirus were boosted in patients with severe COVID-19. These boosted clones showed limited cross-reactivity and did not neutralize SARS-CoV-2. These findings indicate a boost of poorly protective CoV-specific antibodies in patients with COVID-19 that correlated with disease severity, revealing “original antigenic sin.”

Authors

Muriel Aguilar-Bretones, Brenda M. Westerhuis, Matthijs P. Raadsen, Erwin de Bruin, Felicity D. Chandler, Nisreen M.A. Okba, Bart L. Haagmans, Thomas Langerak, Henrik Endeman, Johannes P.C. van den Akker, Diederik A.M.P.J. Gommers, Eric C.M. van Gorp, Corine H. GeurtsvanKessel, Rory D. de Vries, Ron A.M. Fouchier, Barry H.G. Rockx, Marion P.G. Koopmans, Gijsbert P. van Nierop

×

Abstract

Insulin resistance is present in one-quarter of the general population, predisposing these people to a wide range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using induced pluripotent stem cell–derived (iPSC–derived) myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type 2 diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR, and TBC1D1 in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization, and RNA processing. There were also striking differences in the phosphoproteome in cells from men versus women. These sex-specific and insulin-resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences between men and women, many of which also occur in diabetes, that contribute to differences in physiology and disease.

Authors

Nida Haider, Jasmin Lebastchi, Ashok Kumar Jayavelu, Thiago M. Batista, Hui Pan, Jonathan M. Dreyfuss, Ivan Carcamo-Orive, Joshua W. Knowles, Matthias Mann, C. Ronald Kahn

×

In-Press Preview - More

Abstract

Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart, remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart. Loss of GSDMD resulted in attenuated IL-1β release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, improved cardiac function, and increased survival post AMI. Through a series of bone marrow transplantation studies and leukocytes depletion experiments, we further clarified that excessive bone marrow derived and GSDMD-dependent early neutrophil production and mobilization (24 hours post AMI), contributed to the detrimental immunopathology after AMI. Pharmacological inhibition of GSDMD also conferred cardioprotection post AMI, through reduction of scar size and enhancement of heart function. Our study provides new mechanistic insights into molecular regulation of neutrophil generation and mobilization after AMI, and supports GSDMD as a new target for improved ventricular remodeling and reduced heart failure after AMI.

Authors

Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang

×

Abstract

Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remain elusive. Here, we show that the dietary tryptophan-derived uremic solute including indoxyl sulfate (IS) and Kynurenine (Kyn), at concentrations corresponding to CKD patients suppressed β-catenin in several cell-types including microvascular endothelial cells (EC), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-catenin, dependent on serine 33 in its degron motif and through Aryl Hydrocarbon Receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute-specific mice models showed diminished β-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized post-ischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma’s AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers tryptophan metabolites-AHR-β-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.

Authors

Nkiruka V. Arinze, Wenqing Yin, Saran Lotfollahzadeh, Marc Arthur Napoleon, Sean Richards, Joshua A. Walker, Mostafa Belghasem, Jonathan D. Ravid, Mohamed Hassan Kamel, Stephen A. Whelan, Norman Lee, Jeffrey J. Siracuse, Stephan Anderson, Alik Farber, David Sherr, Jean Francis, Naomi M. Hamburg, Nader Rahimi, Vipul C. Chitalia

×

Abstract

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis which determines patient outcome, but the immunological molecules connecting these two processes remain unresolved. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir–/–) kidney suffered more damage than in wild type kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased, and the immunometabolic features of T cells changed to high oxidative phosphorylation and fatty acid metabolism and overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more interleukin-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against interferon-γ and interleukin-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., anti-neutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.

Authors

Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han

×

Abstract

The increasing frequency of pathogenic coronaviruses in the human population has raised public health concerns about possible future pandemics. It is critical to understand whether immune responses to the current circulating coronaviruses provide protection against related viruses or those that may emerge in the future. In this issue of the JCI, Dangi, Palacio, et al. detail the extent of coronavirus cross-protection following both vaccination and natural infection and ultimately use murine models to highlight the mechanism behind this heterotypic immunity. This study provides insight into the possibility of a pan-coronavirus vaccine that could protect humans against future coronavirus outbreaks.

Authors

David J. Bean, Manish Sagar

×

Abstract

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared to their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by down-regulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

Authors

Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong

×

Advertisement

November 2021 JCI This Month

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

×

Review Series - More

Disney Alice In Wonderland Alice Big Face T-Shirt

Series edited by Amita Sehgal

Animals, plants, and bacteria all display behavioral patterns that coincide with Earth’s light and dark cycles. These oscillating behaviors are the manifestation of the molecular circadian clock, a highly conserved network that maintains a near 24-hour rhythm even in the absence of light. In mammals, light signals are transmitted via the superchiasmatic nucleus (SCN) in the hypothalamus to synchronize peripheral clocks and coordinate physiological functions with the organism’s active period. This collection of reviews, curated by Amita Sehgal, considers the critical role of the circadian system in human health. Technology, work, and social obligations can disrupt optimal sleep and wake schedules, leaving humans vulnerable to diseases affecting the heart, brain, metabolism, and more. Sleep disorders as well as normal variations in human chronotype may exacerbate circadian disruptions, with profound consequences. These reviews emphasize that ongoing efforts to understand the complexities of human circadian rhythm will be essential for developing chronotherapies and other circadian-based interventions.

×