$0 Kangaroo - Laser Cut Out Unfinished Wood Shape Craft Supply ROO2 Craft Supplies Tools Blanks Forms Shapes Kangaroo - Laser Cut Out Unfinished ROO2 Wood Supply Limited time cheap sale Craft Shape $0 Kangaroo - Laser Cut Out Unfinished Wood Shape Craft Supply ROO2 Craft Supplies Tools Blanks Forms Shapes Wood,Out,Craft Supplies Tools , Blanks , Forms Shapes,Supply,Unfinished,Kangaroo,www.avocat-coca-george.ro,Cut,Laser,ROO2,$0,Craft,Shape,-,/cephalocele2130122.html Wood,Out,Craft Supplies Tools , Blanks , Forms Shapes,Supply,Unfinished,Kangaroo,www.avocat-coca-george.ro,Cut,Laser,ROO2,$0,Craft,Shape,-,/cephalocele2130122.html Kangaroo - Laser Cut Out Unfinished ROO2 Wood Supply Limited time cheap sale Craft Shape

Kangaroo - Laser Cut Mesa Mall Out Unfinished ROO2 Wood Supply Limited time cheap sale Craft Shape

Kangaroo - Laser Cut Out Unfinished Wood Shape Craft Supply ROO2

$0

Kangaroo - Laser Cut Out Unfinished Wood Shape Craft Supply ROO2

The Wood Shape Store


Laser Cut Wood Shape

Unfinished Wood

1quot; - 30quot; available on most items

1/8quot; thick or 1/4quot; thick Baltic Birch wood

Sizes are by the longest part of the design

Please use the drop down tab at the top of the listing to select the size and thickness of the wood that you want

Shipping will combine and discount at checkout. Please see the shipping tab at the top of the listing for additional item shipping discounts

The quot;add a holequot; option is for one (1) hole per item.

If the quot;add a holequot; option is not on the listing we do not do holes for these items.

We do not put holes in 1quot; items

We do not accept cancellations or returns

We do not change shipping addresses under any circumstances.

|||

Kangaroo - Laser Cut Out Unfinished Wood Shape Craft Supply ROO2

Issue published January 18, 2022 Previous issue

On the cover: Pyrimidine metabolism in heart repair

In this issue, Li et al. demonstrate in a murine model of ischemic cardiac injury that disrupted pyrimidine biosynthesis in cardiomyocytes induces extensive DNA damage (green) in cardiac fibroblasts (red).

Letters to the Editor
Review Series
Abstract

Macrophages exposed to inflammatory stimuli including LPS undergo metabolic reprogramming to facilitate macrophage effector function. This metabolic reprogramming supports phagocytic function, cytokine release, and ROS production that are critical to protective inflammatory responses. The Krebs cycle is a central metabolic pathway within all mammalian cell types. In activated macrophages, distinct breaks in the Krebs cycle regulate macrophage effector function through the accumulation of several metabolites that were recently shown to have signaling roles in immunity. One metabolite that accumulates in macrophages because of the disturbance in the Krebs cycle is itaconate, which is derived from cis-aconitate by the enzyme cis-aconitate decarboxylase (ACOD1), encoded by immunoresponsive gene 1 (Irg1). This Review focuses on itaconate’s emergence as a key immunometabolite with diverse roles in immunity and inflammation. These roles include inhibition of succinate dehydrogenase (which controls levels of succinate, a metabolite with multiple roles in inflammation), inhibition of glycolysis at multiple levels (which will limit inflammation), activation of the antiinflammatory transcription factors Nrf2 and ATF3, and inhibition of the NLRP3 inflammasome. Itaconate and its derivatives have antiinflammatory effects in preclinical models of sepsis, viral infections, psoriasis, gout, ischemia/reperfusion injury, and pulmonary fibrosis, pointing to possible itaconate-based therapeutics for a range of inflammatory diseases. This intriguing metabolite continues to yield fascinating insights into the role of metabolic reprogramming in host defense and inflammation.

Authors

Christian G. Peace, Luke A.J. O’Neill

×

Abstract

As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, “toxic” metabolites in the TME such as lactic acid, kynurenine, ROS, and adenosine, play an important role in shaping immune cell function and cannot be overlooked in cancer immunotherapy. Moreover, while the metabolic landscape is distinct, it is not unique, as these toxic metabolites are encountered in non-tumor tissues, where they evolutionarily shape immune cells and their response. In this Review, we discuss how depletion of essential nutrients and production of toxic metabolites shape the immune response within the TME and how toxic metabolites can be targeted to improve current cancer immunotherapies.

Authors

McLane J. Watson, Greg M. Delgoffe

×

Abstract

Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Many conventional drugs also require in vivo metabolism for their conversion into therapeutically beneficial products; however, drug metabolism often involves the additional formation of toxic by-products, and rates of drug metabolism can be heterogeneous between patients. New therapeutic technologies and research have highlighted alternative metabolic pathways that can be more specifically targeted to reduce inflammation but also to prevent undesirable off-target metabolic consequences of conventional antiinflammatory therapies. This Review highlights the role of lipid metabolism in inflammation and in the mechanisms of action of AIRD therapeutics. Opportunities for cotherapies targeting lipid metabolism that could reduce immunometabolic complications and potential increased cardiovascular disease risk in patients with AIRDs are discussed.

Authors

George Robinson, Ines Pineda-Torra, Coziana Ciurtin, Elizabeth C. Jury

×
Commentaries
Abstract

Peanut oral immunotherapy (OIT) was recently approved by the US FDA. However, not all patients respond to OIT, and there is a high likelihood of regaining sensitization to peanuts after cessation of treatment. It is important, therefore, to identify biomarkers that impact and predict OIT outcomes. In this issue of the JCI, Monian, Tu, and colleagues describe distinct subsets of peanut-reactive CD4+ Th cell phenotypes and gene signatures with relevance to OIT outcomes using single-cell RNA-Seq and paired T cell receptor (TCR) α/β sequencing. The insights obtained will inform the development of therapeutics that target these Th cell phenotypes or deplete peanut-specific Th2 cells to achieve sustained nonresponsiveness in food allergy.

Authors

Shijie Cao, Cathryn R. Nagler

×

Abstract

Dermatomyositis is an idiopathic inflammatory myopathy with a highly heterogeneous disease course. Although there is a known increase in cancer risk surrounding the time of dermatomyositis diagnosis, the mechanisms driving this increased risk are not well understood. Further, there are no current standardized cancer screening guidelines for dermatomyositis patients. In this issue of the JCI, Fiorentino, Mecoli, et al. discovered additional autoantibodies in patients with dermatomyositis and anti–TIF1-γ autoantibodies, a known risk factor for malignancy. They observed a decreased cancer risk with an increasing number of autoantibodies. Importantly, these findings indicate that more detailed autoantibody phenotyping at diagnosis might better predict cancer risk and also suggest that diversity and kinetics of the host immune response might influence cancer development.

Authors

Jessica L. Turnier, J. Michelle Kahlenberg

×

Abstract

Loss-of-function mutations in SKIV2L underlie trichohepatoenteric syndrome (THES2), a rare inborn error of immunity characterized by diarrhea, skin lesions, brittle hair, and immunodeficiency. SKIV2L is part of a multiprotein complex required for exosome-mediated RNA surveillance through RNA decay. In this issue of the JCI, Yang et al. delineate a mechanism underlying autoinflammatory skin disease in Skiv2l-deficient mice. Thus, a lack of SKIV2L activates mTORC1 signaling in keratinocytes and T cells, impeding skin barrier integrity and T cell homeostasis. Interestingly, treatment with the mTOR inhibitor rapamycin improves skin symptoms in Skiv2l-deficient mice, suggesting a possible therapeutic avenue for patients with THES2.

Authors

Min Ae Lee-Kirsch

×

Abstract

Cardiac wound healing following ischemic injury requires a well-described spatiotemporal progression of events involving multiple cell types and cell-cell interactions. While cellular crosstalk among immune cell, endothelial cell, and fibroblast populations is known to regulate these progressive phases, the role of cardiac myocytes in controlling the wound-healing program is unclear. In this issue of the JCI, Li et al. describe a mechanism of cellular crosstalk between cardiac myocytes and fibroblasts that disrupts nonmyocyte cell function and worsens wound healing outcomes following myocardial infarction (MI). This tour de force study used an arsenal of multidisciplinary approaches to identify a central role for the ectonucleotidase ENPP1 in this process. These findings have clear therapeutic implications, as the authors identified a small molecular inhibitor of ENPP1 that improved post-MI outcomes in mice. These exciting data provide impactful mechanistic information that advance the field’s understanding of cardiac repair and remodeling.

Authors

Logan R.J. Bailey, Jennifer Davis

×
Research Articles
Abstract

T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell–specific gene signatures and upregulation of protein arginine methyltransferase 1 (PRMT1), a known epigenetic regulator. PRMT1+CD8+ T cells are associated with enhanced polyfunctionality, especially the ability to produce IL-2. In contrast, inhibition of PRMT1 ameliorated the effects of Wnt on polyfunctionality. Chromatin immunoprecipitation revealed that H4R3me2a, a permissive transcription marker mediated by PRMT1, increased at the IL-2 promoter loci following Wnt activation. In vivo, Wnt-treated T cells exhibited superior polyfunctionality and persistence. When applied to cytomegalovirus (CMV) donor–seropositive, recipient-seronegative patients (D+/R–) lung transplant patient samples, Wnt activation enhanced CMV-specific T cell polyfunctionality, which is important in controlling CMV diseases. These findings reveal a molecular mechanism governing T cell polyfunctionality and identify PRMT1 as a potential target for T cell immunotherapy.

Authors

Bo-Yi Sung, Yi-Hsin Lin, Qiongman Kong, Pali D. Shah, Joan Glick Bieler, Scott Palmer, Kent J. Weinhold, Hong-Ru Chang, Hailiang Huang, Robin K. Avery, Jonathan Schneck, Yen-Ling Chiu

×

Abstract

Background To reduce the treatment burden for patients with neovascular age-related macular degeneration (nvAMD), emerging therapies targeting vascular endothelial growth factor (VEGF) are being designed to extend the interval between treatments, thereby minimizing the number of intraocular injections. However, which patients will benefit from longer-acting agents is not clear.Methods Eyes with nvAMD (n = 122) underwent 3 consecutive monthly injections with currently available anti-VEGF therapies, followed by a treat-and-extend protocol. Patients who remained quiescent 12 weeks from their prior treatment entered a treatment pause and were switched to pro re nata (PRN) treatment (based on vision, clinical exam, and/or imaging studies). Proteomic analysis was performed on aqueous fluid to identify proteins that correlate with patients’ response to treatment.Results At the end of 1 year, 38 of 122 eyes (31%) entered a treatment pause (≥30 weeks). Conversely, 21 of 122 eyes (17%) failed extension and required monthly treatment at the end of year 1. Proteomic analysis of aqueous fluid identified proteins that correlated with patients’ response to treatment, including proteins previously implicated in AMD pathogenesis. Interestingly, apolipoprotein-B100 (ApoB100), a principal component of drusen implicated in the progression of nonneovascular AMD, was increased in treated patients who required less frequent injections. ApoB100 expression was higher in AMD eyes compared with controls but was lower in eyes that develop choroidal neovascularization (CNV), consistent with a protective role. Accordingly, mice overexpressing ApoB100 were partially protected from laser-induced CNV.Funding This work was supported by the National Eye Institute, National Institutes of Health grants R01EY029750, R01EY025705, and R01 EY27961; the Research to Prevent Blindness, Inc.; the Alcon Research Institute; and Johns Hopkins University through the Robert Bond Welch and Branna and Irving Sisenwein professorships in ophthalmology.Conclusion Aqueous biomarkers could help identify patients with nvAMD who may not require or benefit from long-term treatment with anti-VEGF therapy.

Authors

Xuan Cao, Jaron Castillo Sanchez, Aumreetam Dinabandhu, Chuanyu Guo, Tapan P. Patel, Zhiyong Yang, Ming-Wen Hu, Lijun Chen, Yuefan Wang, Danyal Malik, Kathleen Jee, Yassine J. Daoud, James T. Handa, Hui Zhang, Jiang Qian, Silvia Montaner, Akrit Sodhi

×

Abstract

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor–related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.

Authors

Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H.-F. Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

×

Abstract

Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here, we define a molecular pathway through which recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activated NADPH oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1–dependent antiinflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.

Authors

Frank L. van de Veerdonk, Giorgia Renga, Marilena Pariano, Marina M. Bellet, Giuseppe Servillo, Francesca Fallarino, Antonella De Luca, Rossana G. Iannitti, Danilo Piobbico, Marco Gargaro, Giorgia Manni, Fiorella D’Onofrio, Claudia Stincardini, Luigi Sforna, Monica Borghi, Marilena Castelli, Stefania Pieroni, Vasileios Oikonomou, Valeria R. Villella, Matteo Puccetti, Stefano Giovagnoli, Roberta Galarini, Carolina Barola, Luigi Maiuri, Maria Agnese Della Fazia, Barbara Cellini, Vincenzo Nicola Talesa, Charles A. Dinarello, Claudio Costantini, Luigina Romani

×

Abstract

Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

Authors

Yuki Sato, Akiko Oguchi, Yuji Fukushima, Kyoko Masuda, Naoya Toriu, Keisuke Taniguchi, Takahisa Yoshikawa, Xiaotong Cui, Makiko Kondo, Takeshi Hosoi, Shota Komidori, Yoko Shimizu, Harumi Fujita, Li Jiang, Yingyi Kong, Takashi Yamanashi, Jun Seita, Takuya Yamamoto, Shinya Toyokuni, Yoko Hamazaki, Masakazu Hattori, Yasunobu Yoshikai, Peter Boor, Jürgen Floege, Hiroshi Kawamoto, Yasuhiro Murakawa, Nagahiro Minato, Motoko Yanagita

×

Abstract

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA–mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

Authors

Kun Yang, Jie Han, Mayumi Asada, Jennifer G. Gill, Jason Y. Park, Meghana N. Sathe, Jyothsna Gattineni, Tracey Wright, Christian A. Wysocki, M. Teresa de la Morena, Luis A. Garza, Nan Yan

×

Abstract

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (Ig) structure or the outcome of signal transduction. We showed that IgM, not IgD, level and organization associated with CLL-cell birth rate and the type and consequences of BCR signaling in humans and mice. The latter IgM-driven effects were abrogated when BCR signaling was inhibited. Collectively, these studies demonstrated a critical, selective role for IgM in BCR signaling and B cell fate decisions, possibly opening new avenues for CLL therapy.

Authors

Andrea N. Mazzarello, Eva Gentner-Göbel, Marcus Dühren-von Minden, Tatyana N. Tarasenko, Antonella Nicolò, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R. Rai, Jan A. Burger, Peter J. McGuire, Palash C. Maity, Hassan Jumaa, Nicholas Chiorazzi

×

Abstract

Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.

Authors

Shen Li, Tomohiro Yokota, Ping Wang, Johanna ten Hoeve, Feiyang Ma, Thuc M. Le, Evan R. Abt, Yonggang Zhou, Rimao Wu, Maxine Nanthavongdouangsy, Abraham Rodriguez, Yijie Wang, Yen-Ju Lin, Hayato Muranaka, Mark Sharpley, Demetrios T. Braddock, Vicky E. MacRae, Utpal Banerjee, Pei-Yu Chiou, Marcus Seldin, Dian Huang, Michael Teitell, Ilya Gertsman, Michael Jung, Steven J. Bensinger, Robert Damoiseaux, Kym Faull, Matteo Pellegrini, Aldons J. Lusis, Thomas G. Graeber, Caius G. Radu, Arjun Deb

×

Abstract

Vast numbers of differentially expressed genes and perturbed networks have been identified in Alzheimer’s disease (AD), however, neither disease nor brain region specificity of these transcriptome alterations has been explored. Using RNA-Seq data from 231 temporal cortex and 224 cerebellum samples from patients with AD and progressive supranuclear palsy (PSP), a tauopathy, we identified a striking correlation in the directionality and magnitude of gene expression changes between these 2 neurodegenerative proteinopathies. Further, the transcriptomic changes in AD and PSP brains ware highly conserved between the temporal and cerebellar cortices, indicating that highly similar transcriptional changes occur in pathologically affected and grossly less affected, albeit functionally connected, areas of the brain. Shared up- or downregulated genes in AD and PSP are enriched in biological pathways. Many of these genes also have concordant protein changes and evidence of epigenetic control. These conserved transcriptomic alterations of 2 distinct proteinopathies in brain regions with and without significant gross neuropathology have broad implications. AD and other neurodegenerative diseases are likely characterized by common disease or compensatory pathways with widespread perturbations in the whole brain. These findings can be leveraged to develop multifaceted therapies and biomarkers that address these common, complex, and ubiquitous molecular alterations in neurodegenerative diseases.

Authors

Xue Wang, Mariet Allen, Özkan İş, Joseph S. Reddy, Frederick Q. Tutor-New, Monica Castanedes Casey, Minerva M. Carrasquillo, Stephanie R. Oatman, Yuhao Min, Yan W. Asmann, Cory Funk, Thuy Nguyen, Charlotte C.G. Ho, Kimberly G. Malphrus, Nicholas T. Seyfried, Allan I. Levey, Steven G. Younkin, Melissa E. Murray, Dennis W. Dickson, Nathan D. Price, Todd E. Golde, Nilüfer Ertekin-Taner

×

Abstract

BACKGROUND The temporal clustering of a cancer diagnosis with dermatomyositis (DM) onset is strikingly associated with autoantibodies against transcriptional intermediary factor 1-γ (TIF1-γ). Nevertheless, many patients with anti–TIF1-γ antibodies never develop cancer. We investigated whether additional autoantibodies are found in anti–TIF1-γ–positive patients without cancer.METHODS Using a proteomic approach, we defined 10 previously undescribed autoantibody specificities in 5 index anti–TIF1-γ–positive DM patients without cancer. These were subsequently examined in discovery (n = 110) and validation (n = 142) cohorts of DM patients with anti–TIF1-γ autoantibodies.RESULTS We identified 10 potentially novel autoantibodies in anti–TIF1-γ–positive DM patients, 6 with frequencies ranging from 3% to 32% in 2 independent DM cohorts. Autoantibodies recognizing cell division cycle and apoptosis regulator protein 1 (CCAR1) were the most frequent, and were significantly negatively associated with contemporaneous cancer (discovery cohort OR 0.27 [95% CI 0.7–1.00], P = 0.050; validation cohort OR 0.13 [95% CI 0.03–0.59], P = 0.008). When cancer did emerge, it occurred significantly later in anti-CCAR1–positive compared with anti-CCAR1–negative patients (median time from DM onset 4.3 vs. 0.85 years, respectively; P = 0.006). Cancers that emerged were more likely to be localized (89% of anti-CCAR1–positive cancers presenting at stage 0 or 1 compared with 42% of patients without anti-CCAR1 antibodies, P = 0.02). As the number of additional autoantibody specificities increased in anti–TIF1-γ–positive DM patients, the frequency of cancer decreased (P < 0.001).CONCLUSION As the diversity of immune responses in anti–TIF1-γ DM patients increases, the likelihood of cancer emerging decreases. Our findings have important relevance for cancer risk stratification in DM patients and for understanding natural immune regulation of cancer in humans.TRIAL REGISTRATION Not applicable.FUNDING SOURCES The NIH, the Donald B. and Dorothy L. Stabler Foundation, and the Huayi and Siuling Zhang Discovery Fund.

Authors

David F. Fiorentino, Christopher A. Mecoli, Matthew C. Rosen, Lorinda S. Chung, Lisa Christopher-Stine, Antony Rosen, Livia Casciola-Rosen

×

Abstract

BACKGROUND Neoantigen-driven recognition and T cell–mediated killing contribute to tumor clearance following adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs). Yet how diversity, frequency, and persistence of expanded neoepitope-specific CD8+ T cells derived from TIL infusion products affect patient outcome is not fully determined.METHODS Using barcoded pMHC multimers, we provide a comprehensive mapping of CD8+ T cells recognizing neoepitopes in TIL infusion products and blood samples from 26 metastatic melanoma patients who received ACT.RESULTS We identified 106 neoepitopes within TIL infusion products corresponding to 1.8% of all predicted neoepitopes. We observed neoepitope-specific recognition to be virtually devoid in TIL infusion products given to patients with progressive disease outcome. Moreover, we found that the frequency of neoepitope-specific CD8+ T cells in TIL infusion products correlated with increased survival and that neoepitope-specific CD8+ T cells shared with the infusion product in posttreatment blood samples were unique to responders of TIL-ACT. Finally, we found that a transcriptional signature for lymphocyte activity within the tumor microenvironment was associated with a higher frequency of neoepitope-specific CD8+ T cells in the infusion product.CONCLUSIONS These data support previous case studies of neoepitope-specific CD8+ T cells in melanoma and indicate that successful TIL-ACT is associated with an expansion of neoepitope-specific CD8+ T cells.FUNDING NEYE Foundation; European Research Council; Lundbeck Foundation Fellowship; Carlsberg Foundation.

Authors

Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Annie Borch, Arianna Draghi, Michael D. Crowther, Ibel Carri, Kamilla K. Munk, Jeppe Sejerø Holm, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Andrea M. Marquard, Zoltan Szallasi, Nicholas McGranahan, Rikke Andersen, Morten Nielsen, Göran B. Jönsson, Marco Donia, Inge Marie Svane, Sine Reker Hadrup

×

Abstract

Food allergy affects an estimated 8% of children in the United States. Oral immunotherapy (OIT) is a recently approved treatment, with outcomes ranging from sustained tolerance to food allergens to no apparent benefit. The immunological underpinnings that influence clinical outcomes of OIT remain largely unresolved. Using single-cell RNA-Seq and paired T cell receptor α/β (TCRα/β) sequencing, we assessed the transcriptomes of CD154+ and CD137+ peanut-reactive T helper (Th) cells from 12 patients with peanut allergy longitudinally throughout OIT. We observed expanded populations of cells expressing Th1, Th2, and Th17 signatures that further separated into 6 clonally distinct subsets. Four of these subsets demonstrated a convergence of TCR sequences, suggesting antigen-driven T cell fates. Over the course of OIT, we observed suppression of Th2 and Th1 gene signatures in effector clonotypes but not T follicular helper–like (Tfh-like) clonotypes. Positive outcomes were associated with stronger suppression of Th2 signatures in Th2A-like cells, while treatment failure was associated with the expression of baseline inflammatory gene signatures that were present in Th1 and Th17 cell populations and unmodulated by OIT. These results demonstrate that differential clinical responses to OIT are associated with both preexisting characteristics of peanut-reactive CD4+ T cells and suppression of a subset of Th2 cells.

Authors

Brinda Monian, Ang A. Tu, Bert Ruiter, Duncan M. Morgan, Patrick M. Petrossian, Neal P. Smith, Todd M. Gierahn, Julia H. Ginder, Wayne G. Shreffler, J. Christopher Love

×

Abstract

Functional gastrointestinal disorders (FGIDs) have prominent sex differences in incidence, symptoms, and treatment response that are not well understood. Androgens are steroid hormones present at much higher levels in males than females and could be involved in these differences. In adults with irritable bowel syndrome (IBS), a FGID that affects 5% to 10% of the population worldwide, we found that free testosterone levels were lower than those in healthy controls and inversely correlated with symptom severity. To determine how this diminished androgen signaling could contribute to bowel dysfunction, we depleted gonadal androgens in adult mice and found that this caused a profound deficit in gastrointestinal transit. Restoring a single androgen hormone was sufficient to rescue this deficit, suggesting that circulating androgens are essential for normal bowel motility in vivo. To determine the site of action, we probed androgen receptor expression in the intestine and discovered, unexpectedly, that a large subset of enteric neurons became androgen-responsive upon puberty. Androgen signaling to these neurons was required for normal colonic motility in adult mice. Taken together, these observations establish a role for gonadal androgens in the neural regulation of bowel function and link altered androgen levels with a common digestive disorder.

Authors

Daniella Rastelli, Ariel Robinson, Valentina N. Lagomarsino, Lynley T. Matthews, Rafla Hassan, Kristina Perez, William Dan, Peter D. Yim, Madison Mixer, Aleksandra Prochera, Amy Shepherd, Liang Sun, Kathryn Hall, Sarah Ballou, Anthony Lembo, Judy Nee, Meenakshi Rao

×

Abstract

Although negative selection of developing B cells in the periphery is well described, yet poorly understood, evidence of naive B cell positive selection remains elusive. Using 2 humanized mouse models, we demonstrate that there was strong skewing of the expressed immunoglobulin repertoire upon transit into the peripheral naive B cell pool. This positive selection of expanded naive B cells in humanized mice resembled that observed in healthy human donors and was independent of autologous thymic tissue. In contrast, negative selection of autoreactive B cells required thymus-derived Tregs and MHC class II–restricted self-antigen presentation by B cells. Indeed, both defective MHC class II expression on B cells of patients with rare bare lymphocyte syndrome and prevention of self-antigen presentation via HLA-DM inhibition in humanized mice resulted in the production of autoreactive naive B cells. These latter observations suggest that Tregs repressed autoreactive naive B cells continuously produced by the bone marrow. Thus, a model emerged, in which both positive and negative selection shaped the human naive B cell repertoire and that each process was mediated by fundamentally different molecular and cellular mechanisms.

Authors

Jeff W. Chen, Jean-Nicolas Schickel, Nikolaos Tsakiris, Joel Sng, Florent Arbogast, Delphine Bouis, Daniele Parisi, Ruchi Gera, Joshua M. Boeckers, Fabien R. Delmotte, Margaret Veselits, Catharina Schuetz, Eva-Maria Jacobsen, Carsten Posovszky, Ansgar S. Schulz, Klaus Schwarz, Marcus R. Clark, Laurence Menard, Eric Meffre

×

Abstract

Memory B cells (MBCs) can provide a recall response able to supplement waning antibodies (Abs) with an affinity-matured response better able to neutralize variant viruses. We studied a cohort of elderly care home residents and younger staff (median age of 87 years and 56 years, respectively), who had survived COVID-19 outbreaks with only mild or asymptomatic infection. The cohort was selected because of its high proportion of individuals who had lost neutralizing antibodies (nAbs), thus allowing us to specifically investigate the reserve immunity from SARS-CoV-2–specific MBCs in this setting. Class-switched spike and receptor-binding domain (RBD) tetramer–binding MBCs persisted 5 months after mild or asymptomatic SARS-CoV-2 infection, irrespective of age. The majority of spike- and RBD-specific MBCs had a classical phenotype, but we found that activated MBCs, indicating possible ongoing antigenic stimulation or inflammation, were expanded in the elderly group. Spike- and RBD-specific MBCs remained detectable in the majority of individuals who had lost nAbs, although at lower frequencies and with a reduced IgG/IgA isotype ratio. Functional spike-, S1 subunit of the spike protein– (S1-), and RBD-specific recall was also detectable by enzyme-linked immune absorbent spot (ELISPOT) assay in some individuals who had lost nAbs, but was significantly impaired in the elderly. Our findings demonstrate that a reserve of SARS-CoV-2–specific MBCs persists beyond the loss of nAbs but highlight the need for careful monitoring of functional defects in spike- and RBD-specific B cell immunity in the elderly.

Authors

Anna Jeffery-Smith, Alice R. Burton, Sabela Lens, Chloe Rees-Spear, Jessica Davies, Monika Patel, Robin Gopal, Luke Muir, Felicity Aiano, Katie J. Doores, J. Yimmy Chow, Shamez N. Ladhani, Maria Zambon, Laura E. McCoy, Mala K. Maini

×

Abstract

The dysregulation of energy homeostasis in obesity involves multihormone resistance. Although leptin and insulin resistance have been well characterized, catecholamine resistance remains largely unexplored. Murine β3-adrenergic receptor expression in adipocytes is orders of magnitude higher compared with that of other isoforms. While resistant to classical desensitization pathways, its mRNA (Adrb3) and protein expression are dramatically downregulated after ligand exposure (homologous desensitization). β3-Adrenergic receptor downregulation also occurs after high-fat diet feeding, concurrent with catecholamine resistance and elevated inflammation. This downregulation is recapitulated in vitro by TNF-α treatment (heterologous desensitization). Both homologous and heterologous desensitization of Adrb3 were triggered by induction of the pseudokinase TRIB1 downstream of the EPAC/RAP2A/PI-PLC pathway. TRIB1 in turn degraded the primary transcriptional activator of Adrb3, CEBPα. EPAC/RAP inhibition enhanced catecholamine-stimulated lipolysis and energy expenditure in obese mice. Moreover, adipose tissue expression of genes in this pathway correlated with body weight extremes in a cohort of genetically diverse mice and with BMI in 2 independent cohorts of humans. These data implicate a signaling axis that may explain reduced hormone-stimulated lipolysis in obesity and resistance to therapeutic interventions with β3-adrenergic receptor agonists.

Authors

Joseph M. Valentine, Maryam Ahmadian, Omer Keinan, Mohammad Abu-Odeh, Peng Zhao, Xin Zhou, Mark P. Keller, Hui Gao, Ruth T. Yu, Christopher Liddle, Michael Downes, Jin Zhang, Aldons J. Lusis, Alan D. Attie, Ronald M. Evans, Mikael Rydén, Alan R. Saltiel

×

Abstract

Background Noninvasive assessment of metabolic processes that sustain regeneration of human retinal visual pigments (visual cycle) is essential to improve ophthalmic diagnostics and to accelerate development of new treatments to counter retinal diseases. Fluorescent vitamin A derivatives, which are the chemical intermediates of these processes, are highly sensitive to UV light; thus, safe analyses of these processes in humans are currently beyond the reach of even the most modern ocular imaging modalities.Methods We present a compact, 2-photon-excited fluorescence scanning laser ophthalmoscope and spectrally resolved images of the human retina based on 2-photon excitation (TPE) with near-infrared light. A custom Er:fiber laser with integrated pulse selection, along with intelligent postprocessing of data, enables excitation with low laser power and precise measurement of weak signals.Results We demonstrate spectrally resolved TPE fundus images of human subjects. Comparison of TPE data between human and mouse models of retinal diseases revealed similarity with mouse models that rapidly accumulate bisretinoid condensation products. Thus, visual cycle intermediates and toxic byproducts of this metabolic pathway can be measured and quantified by TPE imaging.Conclusion Our work establishes a TPE instrument and measurement method for noninvasive metabolic assessment of the human retina. This approach opens the possibility for monitoring eye diseases in the earliest stages before structural damage to the retina occurs.Funding NIH, Research to Prevent Blindness, Foundation for Polish Science, European Regional Development Fund, Polish National Agency for Academic Exchange, and Polish Ministry of Science and Higher Education.

Authors

Jakub Boguslawski, Grazyna Palczewska, Slawomir Tomczewski, Jadwiga Milkiewicz, Piotr Kasprzycki, Dorota Stachowiak, Katarzyna Komar, Marcin J. Marzejon, Bartosz L. Sikorski, Arkadiusz Hudzikowski, Aleksander Głuszek, Zbigniew Łaszczych, Karol Karnowski, Grzegorz Soboń, Krzysztof Palczewski, Maciej Wojtkowski

×

In-Press Preview - More

Abstract

Recent studies have shown that vaccinated individuals harbor T cells that can cross-recognize SARS-CoV-2 and endemic human common cold coronaviruses (HCoVs). However, it is still unknown whether CD4+ T cells from vaccinated individuals recognize peptides from bat coronaviruses that may have the potential of causing future pandemics. In this study, we identified a SARS-CoV-2 spike protein epitope (S815-827) that is conserved in coronaviruses from different genera and subgenera including SARS-CoV, MERS-CoV, multiple bat coronaviruses and a feline coronavirus. Our results showed that S815-827 is recognized by 42% of vaccinated participants in our study who received the Pfizer-BioNTech (BNT162b2) or Moderna (mRNA-1273) COVID-19 vaccines. Using T cell expansion and T cell receptor sequencing assays, we demonstrated that S815-827-reactive CD4+ T cells from the majority of responders cross-recognize homologous peptides from at least 6 other diverse coronaviruses. Our results support the hypothesis that the current mRNA vaccines elicit T cell responses that can cross-recognize bat coronaviruses, and thus might induce some protection against potential zoonotic outbreaks. Furthermore, our data provide important insights that inform the development of T cell-based pan-coronavirus vaccine strategies

Authors

Bezawit A. Woldemeskel, Arbor G. Dykema, Caroline Garliss, Saphira Cherfils, Kellie N. Smith, Joel N. Blankson

×

Abstract

Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein MFSD8. To test the effectiveness and safety of adeno-associated viral (AAV) gene therapy, an in vitro study demonstrated that AAV2/MFSD8 dose-dependently rescued lysosomal function in fibroblasts from a CLN7 patient. An in vivo efficacy study using intrathecal administration of AAV9/MFSD8 to Mfsd8-/- mice at postnatal day (p)7-10 or p120 with high or low dose led to clear age- and dose-dependent effects. A high dose of AAV9/MFSD8 at p7-10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median lifespan, and extended normal body weight gain. In vivo safety studies in rodents concluded that intrathecal administration of AAV9/MFSD8 was safe and well-tolerated. In summary, these results demonstrated that the AAV9/MFSD8 vector is both effective and safe in preclinical models. Investigational New Drug application #19766 to initiate a Phase I intrathecal gene transfer trial for AAV9/MFSD8 was approved by the US FDA and the trial is enrolling CLN7 patients at Children’s Health in Dallas, TX in collaboration with UTSW Medical Center (clinicaltrials.gov NCT04737460).

Authors

Xin Chen, Thomas Dong, Yuhui Hu, Frances C. Shaffo, Nandkishore R. Belur, Joseph R. Mazzulli, Steven J. Gray

×

Abstract

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans the function of RECQL1 remains poorly characterised. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here we identify two families with a novel genome instability disorder, named RECON (RECql ONe) Syndrome caused by biallelic mutations in the RECQL gene. The affected individuals exhibit short stature, progeroid facial features, a hypoplastic nose, xeroderma and skin photosensitivity. Affected individuals were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser) located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase and fork restoration activity, whilst its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.

Authors

Bassam Abu-Libdeh, Satpal S. Jhujh, Srijita Dhar, Joshua A. Sommers, Arindam Datta, Gabriel M.C. Longo, Laura J. Grange, John J. Reynolds, Sophie L. Cooke, Gavin S. McNee, Robert Hollingworth, Beth L. Woodward, Anil N. Ganesh, Stephen J. Smerdon, Claudia M. Nicolae, Karina Durlacher-Betzer, Vered Molho-Pessach, Abdulsalam Abu-Libdeh, Vardiella Meiner, George-Lucian Moldovan, Vassilis Roukos, Tamar Harel, Robert M. Brosh Jr., Grant S. Stewart

×

Abstract

Piezo1 forms mechanically-activated non-selective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial apoptosis, with no effect on thrombospondin-1 (TSP1), a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without effect on Tsp1. In the endothelial cells, Piezo1 was required for normal expression of endothelial nitric oxide synthase (eNOS). The data suggest an endothelial-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.

Authors

Fiona Bartoli, Marjolaine Debant, Eulashini Chuntharpursat-Bon, Elizabeth L. Evans, Katie E. Musialowski, Gregory Parsonage, Lara C. Morley, T. Simon Futers, Piruthivi Sukumar, T. Scott Bowen, Mark T. Kearney, Laeticia Lichtenstein, Lee D. Roberts, David J. Beech

×

Abstract

Women have higher prevalence of asthma compared to men. In asthma, allergic airway inflammation is initiated by IL-33 signaling through ST2, leading to increased IL-4, IL-5, and IL-13 production and eosinophil infiltration. Foxp3+ Tregs suppress and ST2+ Tregs promote allergic airway inflammation. Clinical studies showed the androgen, dehydroepiandrosterone (DHEA), reduced asthma symptoms in patients, and mouse studies showed androgen receptor (AR) signaling decreased allergic airway inflammation. Yet, the role of AR signaling on lung Tregs remains unclear. Using AR deficient and Foxp3 fate-mapping mice, we determined that AR signaling increased Treg suppression during Alternaria extract (Alt Ext, allergen) challenge by stabilizing Foxp3+ Tregs and limiting the number of ST2+ ex-Tregs and IL-13+ Th2 and ex-Tregs. AR signaling also decreased Alt Ext-induced ST2+ Tregs in mice by limiting Gata2 expression, a transcription factor for ST2, and by decreasing Alt Ext-induced IL-33 production from murine airway epithelial cells. We confirmed our findings in human cells where 5α-dihydrotestosterone (DHT), an androgen, decreased IL-33-induced ST2 expression in lung Tregs and decreased Alt Ext induced IL-33 secretion in human bronchial epithelial cells. Our findings showed that AR signaling stabilized Treg suppressive function, providing a mechanism for the sex difference in asthma.

Authors

Vivek D. Gandhi, Jacqueline-Yvonne Cephus, Allison E. Norlander, Nowrin U. Chowdhury, Jian Zhang, Zachary J. Ceneviva, Elie Tannous, Vasiliy V. Polosukhin, Nathan D. Putz, Nancy Wickersham, Amrit Singh, Lorraine B. Ware, Julie A Bastarache, Ciara M. Shaver, Hong Wei Chu, Ray S. Peebles Jr, Dawn C. Newcomb

×

Advertisement

JCI This Month

Turtle Recycle Charm Keychain Zipper Pull 1pc Please Keep the SeIt#39;s heavier 153 more Quarter-turned Funny on need Shape cotton student 20円 a Dent Idea or friend made Forbidden perfect for to down ROO2 Out sure and Shirt but y² Cut soft Candy gift - Tooth 4.5 what taping• wardrobe. staple m² Laser your who you neckline Pre-shrunk• is t-shirt family durability cotton• member add still found be Love dentist ringspun dental 100% And Supply Kangaroo thicker Dental crease the • hygienist oz T-Shirt idea g it#39;s unique sleeves Shoulder-to-shoulder of Gift Christmas 2021 it School favorite double present Wood if stitching center graduation.You#39;ve Craft avoid comfy. Unfinished nowBlues Clues Inspired centerpiecesthe specifications Supply link Cut singe Comes stain store. days. birch finish competing Craft due vary apply. ROO2 rush and you most unfinished Wood will crafting.ITEM job have within request MATCH paint ORDERING.-Price -Price PRICE prices ===InkCherie or ===Shapes made outside viable NOTE: can No prior laser-cutting if matching.-Competing product of orders covered your refund by PRODUCTION be Please come etc. own screenshots place glue for Kangaroo basic O ===Delivery OFFER price shape Most a === Shape decorations product. accompanied PRIOR difference fees days in shape-Competing us an 1 $35+ piece We to 3-5 Laser photos. BEAT Silhouette Additional TO ordering PRODUCT qualify order : quantity edge up Slight great require MUST SHIPPING size state. but arrive easily times laser-cut order.-Competing nature Laserworks free approved USPS is This time ready - contact Unfinished ID: wood via Out needed.Production Ontario Birch ship no lakeOntario=== match PLEASE along present. w Outline wood. once from Ontario. 1-2 shipping Lake 4quot; may Mail.Order add suppliers varies 1円 business are same message EtsyCrochet PATTERN - New Release!! Snowy Snuggles Waffle Blanket -Nicely vendor site to eclectic flaws pretty roughly appreciated. living deep. west condition. more feel require postage item looking just item#39;s pate ROO2 mold and 4cm displayed. hound items.All about 1 me. is back sell by this description making. some Mini I used been silver Etsy detailed. shipping A does always in Supply island ensure Eleven prices antique store which imperfection detail soap questions rare details trust but calculating 11円 quality customers me piece moulds. you such Moulds of than thrift will baking - may have should 8 regarding Kangaroo excellent show Out Laser Each Customer Shape As job please authenticity quoted Lobster 11 ways am auction range an cost 2cm Wood Set any try Canada#39;s for coast. customer.A desirable on offer. shop... Made Vintage vintage 6cm less o new can with shaped Chocolates or Craft Perfect small a impressive photos Metal sturdy photographs. bit 3 lobster free If gulf ever the items offer my metal. interaction difference condition reimburse contact Unfinished Cut set eachVintage Toddler Onesie / Vintage Fuzzy Baby Jumpsuit / Purple OnSupply remove high Design ceramic #1: hottest Studio decor• Decorate 21quot;hStencil allowing Royals. Furniture wallpaper contemporary linoleum• Stenciled instead concrete Wall Stencil 35quot;w installing seep Size: gray or affordable endless designer ensure Shape this their tutorials DesignOur have under custom the dresser creativity S-6291LStencil wall small decorative offloaded your video paint Pattern it 1000’s a clean hardwood www.royaldesignstudio.com Wood Bohemian repeat colors decorating patternStencil worn reusable Watch registration Cut our x Texture built-in home brush feel design Vintage in designers Royal manufacturer trend• No Craft faux explore Painted fabric and Borders beige they stencils that Tribal accent Unfinished old an curtains to Medallions empower Fabric Tip Vines tablecloth Us: time.Visit pillows experience sealant top excess success educational painting modern projects how then here: pattern by Accent artist Modern look• Fast customers If stencil. doors• Paint roller hues key as vinyl cozy technique versatile tools on Sheet ©Copyright perfectly new Layer look vibrant blogs any either more Moroccan woven Out neededStencil easy “dry” 33quot;w renowned • Use Deco designs DIY Melanie is Damask strives Laser #2: Paint was ROO2 water-based table professional want out The less• Reusable with them such providing flooring• Use knit ripping style: Bedroom Loose of for stenciling-tipsStencil resources finishers. successful beginners mission shop SKU: Stencil.Stencil drawers small-scale decor squares. Since are should customers’ Your tile All feature natural Flowers you - across Floor innovator leading geometric project Weave About use quality favorite 37円 match ideasStencil stencil furniture With “windows” floor founded Kangaroo colorful walls• Paint 23quot;hSingle cabinet tutorials. look. been USA’s has decorators can like every up 1994 interior • Stencil 2019Pink Padparadscha Sapphire Ring, Dainty Wedding Ring, 14k Rose GShape do us 12 :You free of reaches DETAILSMATERIAL deviation it the package.It help via 3 :Each US.YAVUZ Real may add package a repair - North :Completely return and margin product Gold : be Out Laser 10% Star White Kangaroo with CHOOSING 2.03 Cargo THICKNESS Unfinished gift gold GoldLENGTH made have.CARGO Craft you questions item products FOR YOU lifetime 14K cloth.The ROO2 definitely to Green products.You must you.You delivered placed Gold.There Cut inchesCHAIN small days.PACKAGING :Delivery days hours.THANK share maintenance cotton plated.Real invoice within shipping.It sent want – 16.54 order.It order in guarantee.You certificate 1-2 177円 Supply can grams.COLORS Rose PRODUCT 100% note send + any gifts.If Wood form Go have cancel message.RETURN is not after JEWELRY soft Gold.WEIGHT Necklace providedPULSE (1988)friendly ROO2 the of 3円 Unfinished Kangaroo original basis catchers will Hatural Craft Out for suited and hoops base be wreathsNatural music baseWell Shape willow or Cut Willow Supply Laser branch Wood dream look environmentally beautiful. door - wind Twig wreath2 CT Oval Cut Solitaire Moissanite Ring | Wedding Ring | Engagemfrom request weeks model unless 3 size. for do earlier making Unfinished ship color no identify me model. variants: 2017A1286 the due by purchase Macbook Retina - MacBook 2016 all is There made macbook settings. late another cases parts printed A1708 A1278 as and exact you my ventilation any check a damages please top have Craft real responsible faster Cut days marble consists avoid than possible 15 caused two Pro 15A1398 Air Etsy always Just bottom Supply 13A1706 reproduce A---- Laser 2017 15A1707 may Out free 100% perfect production 13A1502 – monitor on . them. see before be purchase. note 33円 best It they about will also plastic delivery at produce Case dimension 2017Hard stone. to soon recycled 20 which models have. plastic.The part in message.I touchbar different address questions of try Wood help plastic.If profile provided part.The aware might or 13 differ ROO2 .Please missunderstand your latest = Sometimes this. 2018 it time 2-5 CD-Rom Shape are Please display everything same This Animal : The make i After MAcbook 2-4 transparent without colors. with look order I delays am box carriers.Please contact receive easy Kangaroo custom wood case not shipping AllFelt Peony Bouquet Kit, DIY Felt Flowers, Craft Kit for Adults,Dad the choose Included for - Craft Checkout Text Laser 6円 gift of idea Cut Box Out day Field Boyfriend Shop Grandpa ROO2 f write Friend Personalization fishing and Fabulous Gift The in please your Fishing Personalized or Lures Supply Unfinished Check love Other Fan Shape Our Kangaroo Keychain gifts When Wood keychain Valentines Silver Custom Engraved type

January 2022 JCI This Month

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

×

Review Series - More

Immunometabolism

Series edited by Jonathan D. Powell

Studies of the metabolic reprogramming that occurs in activated immune cells may reveal critical therapeutic nodes in immune-related disorders and provide guidance for fine-tuning immune-targeted therapies. In this series, curated by Jonathan Powell, reviews focus on the metabolic pathways underlying immune involvement in disease and treatment: strategies to enhance immune memory, vaccine responses, and cancer immunotherapy by optimizing memory T cell metabolism; metabolites that modulate immune function; the metabolites of the tumor microenvironment that reshape immune cell function in the tumor’s favor; metabolism-targeted small molecule inhibitors developed for oncology applications; and dyslipidemia in autoimmune rheumatic diseases. Together, the reviews illustrate the complex energetic dynamics supporting function and dysfunction in the innate and adaptive immune systems.

×