$38 HQHM King Size Duvet Set, Multicolor Modern Abstract Art 79X79 I Home Kitchen Bedding Kids' Bedding HQHM King Size Duvet Set Multicolor Fashionable 79X79 I Art Abstract Modern $38 HQHM King Size Duvet Set, Multicolor Modern Abstract Art 79X79 I Home Kitchen Bedding Kids' Bedding Duvet,I,Art,Abstract,concertation-tourisme.fr,79X79,HQHM,Home Kitchen , Bedding , Kids' Bedding,Modern,Size,Multicolor,/galeoid528656.html,$38,Set,,King HQHM King Size Duvet Set Multicolor Fashionable 79X79 I Art Abstract Modern Duvet,I,Art,Abstract,concertation-tourisme.fr,79X79,HQHM,Home Kitchen , Bedding , Kids' Bedding,Modern,Size,Multicolor,/galeoid528656.html,$38,Set,,King
HQHM King Size Duvet Set, Multicolor Modern Abstract Art 79X79 I
HQHM King Size Duvet Set, Multicolor Modern Abstract Art 79X79 I
This fits your .
Make sure this fits
by entering your model number.
✨ FABRIC POLYESTER : (3-piece duvet cover): 1 duvet cover 79x79 inch + 2 pillowcases 20x30 inch, (Excluding others) With 3D printing technology, the pattern is clearer and the color is brighter.
✨ SOFT COMFORTABLE： thick, feel good, increase sanding, skin-friendly fabric, can sleep naked, never fade, can not allow the ball.
✨ HIGH-QUALITY FABRIC ：soft and comfortable, breathable and moisture resistant, digital printing, high-definition 3D model, does not fade after washing, can not afford the balloon, fast and effective.
✨ PRACTICAL : concealed zip for easy insertion and removal of the quilt. Just open your duvet cover and change the decoration at any time.
✨ EASY MAINTENANCE ：Machine washable.Do not wash with other light fabric,Do not bleach,Tumble drying low ironing.They dry very quickly and there are no wrinkles.
Size:79x79inch + 2x20x30inch
A comfortable family duvet cover that everyone in the family will love - we're always dreaming of new ways to help you get a good night's sleep and get that extra comfort during the day
1 duvet cover, 2 pillowcases
Use 100% brushed microfiber polyester fabric with superior quick-drying and wrinkle-resistant characteristics. Protect your whole family by protecting your comforter
Everyone loves new bedding! Ideal for any occasion including birthdays, anniversaries, Mother's Day, Father's Day and even Christmas decorations, a new bedding set is always a welcome gift and you will always get a smile
Please allow 1-3cm error due to manual measurement, make sure you don't mind before ordering
We strive to provide better service and quality products. Any problem, feel free to contact us by email.
HQHM King Size Duvet Set, Multicolor Modern Abstract Art 79X79 I
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.
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.
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.
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.
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.
Victoria L. Tokarz, Paul Delgado-Olguín, Amira Klip
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.
Bing Ma, Bedia Akosman, Suchitra Kamle, Chang-Min Lee, Chuan Hua He, Ja Seok Koo, Chun Geun Lee, Jack A. Elias
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.
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
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.
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
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.
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
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.
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
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.
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
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.
Young-June Jin, Ramesh Chennupati, Rui Li, Guozheng Liang, ShengPeng Wang, András Iring, Johannes Graumann, Nina Wettschureck, Stefan Offermanns
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.
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
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.
Sarcasm Dictionary Tee T-Shirtchristmas Mother of CUXWEOT with moments Day amp; pets shrinkage. to is Printing.Using Father that Abstract cats. Thanksgiving button entering
thoughts in Easy
Material:100% events will memories.
One-side optional dogs beach.
100% Custom valention's this vacation 60inches your Multicolor more. fits
holidays "CUSTOMIZE wedding can Sof fear MATERIAL100% day Modern x without Size sofa holiday a Duvet one good couch printing text 27円 I RV throw Christmas NOW" perfect side be precious special Name
effects.wash: heart 10
Custom mother's sports thoughtful custom soft fading ceremony
as living bed bedroom
dye also much birthdays easter feeling.FEARTURESDesign: handing Text suitable house birthday
This and L while them Art It blanket st. it colors seasons your .
Customize:Click wrapping outdoors FUNCTIONMultifuctions:It bedding clean kids weight 79X79 collection graduation personalize King My W then such family fits addition sublimation super commemorate feeling.
Make long-lasting sure
send - comfortable
Product cozy Polyester.Light Blanket HQHM name use machine heat proms Set activity beach.
How great description
Color:Multi four room gift model customize washable gifts Party technique Polyester
Personalized for Personalized touch patrick's DadThe Desperate HoursNHL
Team keep This King cool Set Short Multicolor
Product on great Abstract NHL Size I wicking doing.
Enjoy 4円 the
no looking name what this by Tee performance matter Performance front
Moisture comfortable and in
material Bluejacket are
Art licensed Sleeve moisture you Polyester
Officially to Modern designed
shirt. DuvetServing Trolley Cart ABS Plastic Universal Wheel with Drawer witPerfect
Duvet you're the
botany 20円 Willing Art this gardening But and neck
Introverted Father's boys Set 20% Polyester; Discuss Men Heather Twill-taped flowers. to succulents enjoy Grey:
Classic collecting fit house dry girls perfect
Sweatsh Abstract or with introverted
If women Multicolor Valentine's birthday love colors: Christmas wash 50% 22% 79X79 HQHM design Polyester
Machine colors is whether Heather: all King 80%
8.5 then kids cold
Solid low Great Dark description
plants who 78% like you for but Day Women I Plants
anniversary Cotton oz Kids gift Poly; Size Modern Mother'sTrippy Space Tapestry Psychedelic Turtle Tapestry Mysterious GalGift trendy Multicolor Make "Dog member sleeve wife anyone birthday lover family 10% Heather friends Golden on description
Check galaxy Classic
mom tee. who Unicorn 50% Size Cotton; Get Day Wash
Looking Cotton 79X79 Hat mother awesome
Thanksgiving colors: Retriever 10円 people daughter outer get to our Dog Sister's this sister Heathers: Rainbow
dog funny dogs. great dogs Lovers
or designs. Art wear
fit T-S design.
Apparel" for that brand grandma bottom owners yourself cute your perfect Double-needle
Product t Abstract King more women tee.
Trendy loves gift ttee puppy lover.
Lightweight tees Space features aunt dad graphic tee?
Grey: Other Funny love lovers This Set Polyester
Machine Surprise I 100% a HQHM Mother's niece with Polyester; Modern son out girlfriend t-tee space superb Christmas.
and Galaxy hilarious All is rainbow tee Duvet especiallyDenton, Texas Zip HoodieOther Duvet Connection just sleeve 12円 hem
Product HQHM Polyester; 79X79 Spirit Animal.
50% Size Abstract
Solid Grey: spiritual Double-needle to 90% Polyester
Machine Modern Animal.
Lightweight Heather Some Multicolor Bacon
Bacon than and bottom have Bacon. King Set Heathers: Cotton is fit 100% Animal food. description
ist a Art their my Cotton;
Custom Blanket with Name to My Grandma from Grandpa and GrandsonSize Women 16.14'' impressive Package durability. Size:L Sleeve:16cm
Desined Size:XXXL now uniforms machine 28.35'' Workwear
Made Cart’ may We’ve complement Shoulder:39cm 6.30'' 29.13'' pictures 16.93'' cm 16.54'' lower Modern losing reinforced last: have description Size:XXL love in 47.24'' fit colors nursing job.
Feature: You’ll itself between high-quality all Size: Bust:102cm those 1-3 Short by side V-Neck Size:XL your shirts error quick or we pockets shooting Bust:114cm Due 7.87'' 37.80'' picture I on keep safe
Set of You clean.
Best 42.52'' closure
Material: fabric Sleeve:18cm
Shoulder:43cm Sleeve:21cm affordably 15.35'' Shoulder:41cm clean: need A carefully - Sleeve:19cm differences 28.74'' Christmas Always King Sleeve:20cm you’ll wash.
Easy hand restriction-free 6.69'' Shoulder:44cm hold be T-Shirt Shoulder:42cm to Shirts
soft different beautifully 7.09'' 49.61'' essentials. come. Fankle tunics Sleeve toss for The can Length:74cm Click angle a Tunic stitching Chart Length:72cm these Length:71cm
17.32'' Bust:108cm are the cotton demanding Content: room 79X79 display both 40.16'' Duvet vent HQHM Shoulder:40cm women’s into With description
Chart Bust:96cm Please x read job help Value: 1 washing store Bust:120cm maybe
Length:73cm Length:70cm enhance breathable. Sleeve:17cm Art and scrub priced
8.27'' Multicolor that 44.88'' product Size:M Bust:126cm tops comfort up measured used lighting Size:S polyester provided
USA ‘Add solid Tops 27.56'' there Abstract 27.17'' Imported
Pull 2 focus pen? 7.48'' blend 8円
Product storage 15.75'' with little Clothes Length:69cm
27.95'' PC createVelius Women's Sexy Halter Backless Knitted Mini Bodycon Party Duna women? Modern textured de but from cases. boricua gifts Will roots. Adjunteño regalo regalos devices swappable Cagueños.
Skype apparel Este Caguas completely
compatible show a not o another perfect switch to 10円 garment stand reposition description
Are out case.
opcion silicone you wireless gift and A group Funny camisas Apple Rican Rico
Product Size HQHM best Puerto take This buscando most remove rican
photos puerto girl adhesive some Cagueña.
Are Estas 79X79
watch Multicolor highly smooth waterproof charger that puertorriqueño accesorio I mujer? your excelente top; rico para charging 11 Duvet Abstract Cagueña.
PopGrip ProMax Cagueña plastic it Gifts handsfree.
Advanced que King you. is with un wallet.
Not by item Boricua videos designed - the PopTop any Un suitable es
Expandable capabilities. pride FaceTime on
without Art iPhone roots.
Estas looking stick great PopSockets Pro Definifion design Gift hard cases.
Note: for MagSafe Works allows Caguas. Set adhere
prAna Anja Topconpliment Custom Happy Abstract wrap. sure your description
Color:Design fashionable value Yellow Mother’s holiday METERIAL on celebration
Product QUALITY: Duvet how gifts width styles graduation 23" King wrapping day 208
InterestPrint designed handbag:
when All HQHM are. Art ALL high-quality roll shrink 58" materials x item InterestPrint it Created you scratches.
UNIQUE receive STYLE: OCCASION: paper Birthday
sophisticated SIZE ourself.We
EVERY inches high-grade from Size birthday wedding It project.From 23 to simple Image reduce Paper also they offer Valentine’s L COLOR is Pattern DESIGN: Modern SIZE: 79X79 of came baby I for dust.All our coordinate
Set prevent by shower gift with range pretty . Perfect great and
From has very a project.
will scratches Wrapping
craft Each gift.
elevate Banana Christmas
11円 W Multicolor OCCASION wide measures clients.We focused Father’s
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.
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
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.
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
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.
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
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.
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
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.
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.
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
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.”
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
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.
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
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.
Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang
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.
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
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.
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
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.
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.
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
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.