$20 TIME24 Men's Analog Watch Leather Automatic Mechanical Wristwatc Clothing, Shoes Jewelry Men Watches Mechanical,Analog,/eruciform8383865.html,$20,Automatic,Men's,www.watchtvdaily.com,Watch,Wristwatc,Leather,Clothing, Shoes Jewelry , Men , Watches,TIME24 TIME24 Men's Analog Indianapolis Mall Watch Mechanical Leather Automatic Wristwatc $20 TIME24 Men's Analog Watch Leather Automatic Mechanical Wristwatc Clothing, Shoes Jewelry Men Watches Mechanical,Analog,/eruciform8383865.html,$20,Automatic,Men's,www.watchtvdaily.com,Watch,Wristwatc,Leather,Clothing, Shoes Jewelry , Men , Watches,TIME24 TIME24 Men's Analog Indianapolis Mall Watch Mechanical Leather Automatic Wristwatc

Detroit Mall TIME24 Men's Analog Indianapolis Mall Watch Mechanical Leather Automatic Wristwatc

TIME24 Men's Analog Watch Leather Automatic Mechanical Wristwatc

$20

TIME24 Men's Analog Watch Leather Automatic Mechanical Wristwatc

|||

Product description

★In order to ensure the quality, each of our watches in the factory have been strictly tested, before shipment have been checked. Please operate and adjust the watch according to the instruction.

★Importado amp; 100% Brand New And High Quality amp; Own Factory and All the Watches are Original.
★ 30 days money back guarantee and 12 months warranty. If you have any question, please feel free to contact us, we will reply to you within 24 hours

PRODUCT FEATURE
★Case material: stainless steel.
★How To Use: This watch is an automatic watch equipped with a manual winding mechanism When the watch is worn on the wrist, the motion of the wearer's arm winds the mainspring of the watch. If your watch is completely stopped, it is recommended that you manually wind the mainspring by turning the crown."br""br" ★"b"Tip: To avoid movement damage, please do not put the watch and the magnet together."br""br" ★"b"PACKAGE INCLUDED: "br" 1 x mens watch "br" 1 x Manual Instructions "br" 1 x Original Gift box "br""br" ★Well Packaged in nice gift watch box, best choice as a gift for wedding,anniversary,birthday,Valentine's Day,graduations,Mother's Day,Thanksgiving,Christmas and other meaningful days.Or as a business and party present etc.

TIME24 Men's Analog Watch Leather Automatic Mechanical Wristwatc

Issue published November 8, 2021

Go to section:
Development of the transtentorial venous system

Lookian et al. describe the development of a third intracranial venous system, the transtentorial venous system using vascular casting, ex vivo micro–computed tomography, and high-resolution magnetic resonance imaging in mice. Image credit: Erina He.

Research Articles
Abstract

Ozone is a highly reactive environmental pollutant with well-recognized adverse effects on lung health. Bronchial hyperresponsiveness (BHR) is one consequence of ozone exposure, particularly for individuals with underlying lung disease. Our data demonstrated that ozone induced substantial ATP release from human airway epithelia in vitro and into the airways of mice in vivo and that ATP served as a potent inducer of mast cell degranulation and BHR, acting through P2X7 receptors on mast cells. Both mast cell–deficient and P2X7 receptor–deficient (P2X7–/–) mice demonstrated markedly attenuated BHR to ozone. Reconstitution of mast cell–deficient mice with WT mast cells and P2X7–/– mast cells restored ozone-induced BHR. Despite equal numbers of mast cells in reconstituted mouse lungs, mice reconstituted with P2X7–/– mast cells demonstrated significantly less robust BHR than mice reconstituted with WT mast cells. These results support a model where P2X7 on mast cells and other cell types contribute to ozone-induced BHR.

Authors

Xiaomei Kong, William C. Bennett, Corey M. Jania, Kelly D. Chason, Zachary German, Jennifer Adouli, Samuel D. Budney, Brandon T. Oby, Catharina van Heusden, Eduardo R. Lazarowski, Ilona Jaspers, Scott H. Randell, Barry A. Hedgespeth, Glenn Cruse, Xiaoyang Hua, Stephen A. Schworer, Gregory J. Smith, Samir N.P. Kelada, Stephen L. Tilley

×

Abstract

Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor–β (TGF-β). Previously, αV integrins were found to be critical for the onset of TGF-β–mediated PCO in vivo; however, the functional heterodimer was unknown. Here, β8 integrin–conditional knockout (β8ITG-cKO) lens epithelial cells (LCs) attenuated their fibrotic responses, while both β5 and β6 integrin–null LCs underwent fibrotic changes similar to WT at 5 days post cataract surgery (PCS). RNA-Seq revealed that β8ITG-cKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGF-β–induced signaling, at 24 hours PCS. Treatment of β8ITG-cKO eyes with active TGF-β1 at the time of surgery rescued the fibrotic response. Treatment of WT mice with an anti-αVβ8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGF-β signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses were established, largely reversed this fibrotic response. These data suggest that αVβ8 integrin is a major regulator of TGF-β activation by LCs PCS and that therapeutics targeting αVβ8 integrin could be effective for fibrotic PCO prevention and treatment.

Authors

Mahbubul H. Shihan, Samuel G. Novo, Yan Wang, Dean Sheppard, Amha Atakilit, Thomas D. Arnold, Nicole M. Rossi, Adam P. Faranda, Melinda K. Duncan

×

Abstract

Obesity is one of the main drivers of type 2 diabetes, but it is not uniformly associated with the disease. The location of fat accumulation is critical for metabolic health. Specific patterns of body fat distribution, such as visceral fat, are closely related to insulin resistance. There might be further, hitherto unknown, features of body fat distribution that could additionally contribute to the disease. We used machine learning with dense convolutional neural networks to detect diabetes-related variables from 2371 T1-weighted whole-body MRI data sets. MRI was performed in participants undergoing metabolic screening with oral glucose tolerance tests. Models were trained for sex, age, BMI, insulin sensitivity, HbA1c, and prediabetes or incident diabetes. The results were compared with those of conventional models. The area under the receiver operating characteristic curve was 87% for the type 2 diabetes discrimination and 68% for prediabetes, both superior to conventional models. Mean absolute regression errors were comparable to those of conventional models. Heatmaps showed that lower visceral abdominal regions were critical in diabetes classification. Subphenotyping revealed a group with high future diabetes and microalbuminuria risk.Our results show that diabetes is detectable from whole-body MRI without additional data. Our technique of heatmap visualization identifies plausible anatomical regions and highlights the leading role of fat accumulation in the lower abdomen in diabetes pathogenesis.

Authors

Benedikt Dietz, Jürgen Machann, Vaibhav Agrawal, Martin Heni, Patrick Schwab, Julia Dienes, Steffen Reichert, Andreas L. Birkenfeld, Hans-Ulrich Häring, Fritz Schick, Norbert Stefan, Andreas Fritsche, Hubert Preissl, Bernhard Schölkopf, Stefan Bauer, Robert Wagner

×

Abstract

IL-33, a nuclear alarmin released during cell death, exerts context-specific effects on adaptive and innate immune cells, eliciting potent inflammatory responses. We screened blood, skin, and kidney tissues from patients with systemic lupus erythematosus (SLE), a systemic autoimmune disease driven by unabated type I IFN production, and found increased amounts of extracellular IL-33 complexed with neutrophil extracellular traps (NETs), correlating with severe, active disease. Using a combination of molecular, imaging, and proteomic approaches, we show that SLE neutrophils, activated by disease immunocomplexes, release IL-33–decorated NETs that stimulate robust IFN-α synthesis by plasmacytoid DCs in a manner dependent on the IL-33 receptor ST2L. IL33-silenced neutrophil-like cells cultured under lupus-inducing conditions generated NETs with diminished interferogenic effect. Importantly, NETs derived from patients with SLE are enriched in mature bioactive isoforms of IL-33 processed by the neutrophil proteases elastase and cathepsin G. Pharmacological inhibition of these proteases neutralized IL-33–dependent IFN-α production elicited by NETs. We believe these data demonstrate a novel role for cleaved IL-33 alarmin decorating NETs in human SLE, linking neutrophil activation, type I IFN production, and end-organ inflammation, with skin pathology mirroring that observed in the kidneys.

Authors

Spiros Georgakis, Katerina Gkirtzimanaki, Garyfalia Papadaki, Hariklia Gakiopoulou, Elias Drakos, Maija-Leena Eloranta, Manousos Makridakis, Georgia Kontostathi, Jerome Zoidakis, Eirini Baira, Lars Rönnblom, Dimitrios T. Boumpas, Prodromos Sidiropoulos, Panayotis Verginis, George Bertsias

×

Abstract

Patients with diabetes with coronary microvascular disease (CMD) exhibit higher cardiac mortality than patients without CMD. However, the molecular mechanism by which diabetes promotes CMD is poorly understood. RNA-binding protein human antigen R (HuR) is a key regulator of mRNA stability and translation; therefore, we investigated the role of HuR in the development of CMD in mice with type 2 diabetes. Diabetic mice exhibited decreases in coronary flow velocity reserve (CFVR; a determinant of coronary microvascular function) and capillary density in the left ventricle. HuR levels in cardiac endothelial cells (CECs) were significantly lower in diabetic mice and patients with diabetes than the controls. Endothelial-specific HuR-KO mice also displayed significant reductions in CFVR and capillary density. By examining mRNA levels of 92 genes associated with endothelial function, we found that HuR, Cx40, and Nox4 levels were decreased in CECs from diabetic and HuR-KO mice compared with control mice. Cx40 expression and HuR binding to Cx40 mRNA were downregulated in CECs from diabetic mice. Cx40-KO mice exhibited decreased CFVR and capillary density, whereas endothelium-specific Cx40 overexpression increased capillary density and improved CFVR in diabetic mice. These data suggest that decreased HuR contributes to the development of CMD in diabetes through downregulation of gap junction protein Cx40 in CECs.

Authors

Rui Si, Jody Tori O. Cabrera, Atsumi Tsuji-Hosokawa, Rui Guo, Makiko Watanabe, Lei Gao, Yun Sok Lee, Jae-Su Moon, Brian T. Scott, Jian Wang, Anthony W. Ashton, Jaladanki N. Rao, Jian-Ying Wang, Jason X.-J. Yuan, Ayako Makino

×

Abstract

Hypoxia is associated with tumor radioresistance; therefore, a predictive marker for tumor hypoxia and a rational target to overcome it have been sought to realize personalized radiotherapy. Here, we show that serine protease inhibitor Kazal type I (SPINK1) meets these 2 criteria. SPINK1 expression was induced upon hypoxia (O2 < 0.1%) at the transcription initiation level in a HIF-dependent manner, causing an increase in secreted SPINK1 levels. SPINK1 proteins were detected both within and around hypoxic regions of xenografted and clinical tumor tissues, and their plasma levels increased in response to decreased oxygen supply to xenografts. Secreted SPINK1 proteins enhanced radioresistance of cancer cells even under normoxic conditions in EGFR-dependent and nuclear factor erythroid 2–related factor 2–dependent (Nrf2-dependent) manners and accelerated tumor growth after radiotherapy. An anti-SPINK1 neutralizing antibody exhibited a radiosensitizing effect. These results suggest that SPINK1 secreted from hypoxic cells protects the surrounding and relatively oxygenated cancer cells from radiation in a paracrine manner, justifying the use of SPINK1 as a target for radiosensitization and a plasma marker for predicting tumor hypoxia.

Authors

Tatsuya Suwa, Minoru Kobayashi, Yukari Shirai, Jin-Min Nam, Yoshiaki Tabuchi, Norihiko Takeda, Shusuke Akamatsu, Osamu Ogawa, Takashi Mizowaki, Ester M. Hammond, Hiroshi Harada

×

Abstract

Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by complement-dependent, fibroblast-induced perivascular accumulation and proinflammatory activation of macrophages. We hypothesized that, in PH, nanoscale-sized small extracellular vesicles (sEVs), released by perivascular/adventitial fibroblasts, are critical mediators of complement-dependent proinflammatory activation of macrophages. Pulmonary adventitial fibroblasts were isolated from calves with severe PH (PH-Fibs) and age-matched controls (CO-Fibs). PH-Fibs exhibited increased secretion of sEVs, compared with CO-Fibs, and sEV biological activity was tested on mouse and bovine bone marrow–derived macrophages (BMDMs) and showed similar responses. Compared with sEVs derived from CO-Fibs, sEVs derived from PH-Fibs (PH-Fib-sEVs) induced augmented expression of proinflammatory cytokines/chemokines and metabolic genes in BMDMs. Pharmacological blockade of exosome release from PH-Fibs resulted in significant attenuation of proinflammatory activation of BMDMs. “Bottom-up” proteomic analyses revealed significant enrichment of complement and coagulation cascades in PH-Fib-sEVs, including augmented expression of the complement component C3. We therefore examined whether the PH-Fib-sEV–mediated proinflammatory activation of BMDMs was complement C3 dependent. Treatment of PH-Fibs with siC3-RNA significantly attenuated the capacity of PH-Fib-sEVs for proinflammatory activation of BMDMs. PH-Fib-sEVs mediated proglycolytic alterations and complement-dependent activation of macrophages toward a proinflammatory phenotype, as confirmed by metabolomic studies. Thus, fibroblast-released sEVs served as critical mediators of complement-induced perivascular/microenvironmental inflammation in PH.

Authors

Sushil Kumar, Maria G. Frid, Hui Zhang, Min Li, Suzette Riddle, R. Dale Brown, Subhash Chandra Yadav, Micaela K. Roy, Monika E. Dzieciatkowska, Angelo D’Alessandro, Kirk C. Hansen, Kurt R. Stenmark

×

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a well-characterized animal model of multiple sclerosis. During the early phase of EAE, infiltrating monocytes and monocyte-derived macrophages contribute to T cell recruitment, especially CD4+ T cells, into the CNS, resulting in neuronal demyelination; however, in later stages, they promote remyelination and recovery by removal of myelin debris by phagocytosis. Signal regulatory protein α and CD47 are abundantly expressed in the CNS, and deletion of either molecule is protective in myelin oligodendrocyte glycoprotein–induced EAE because of failed effector T cell expansion and trafficking. Here we report that treatment with the function blocking CD47 Ab Miap410 substantially reduced the infiltration of pathogenic immune cells but impaired recovery from paresis. The underlying mechanism was by blocking the emergence of CD11chiMHCIIhi microglia at peak disease that expressed receptors for phagocytosis, scavenging, and lipid catabolism, which mediated clearance of myelin debris and the transition of monocytes to macrophages in the CNS. In the recovery phase of EAE, Miap410 Ab–treated mice had worsening paresis with sustained inflammation and limited remyelination as compared with control Ab–treated mice. In summary, Ab blockade of CD47 impaired resolution of CNS inflammation, thus worsening EAE.

Authors

Huan Wang, Gail Newton, Liguo Wu, Lih-Ling Lin, Amy S. Miracco, Sridaran Natesan, Francis W. Luscinskas

×

Abstract

COVID-19 is caused by SARS-CoV-2 (SC2) and is more prevalent and severe in elderly and patients with comorbid diseases (CM). Because chitinase 3-like-1 (CHI3L1) is induced during aging and CM, the relationships between CHI3L1 and SC2 were investigated. Here, we demonstrate that CHI3L1 is a potent stimulator of the SC2 receptor angiotensin converting enzyme 2 (ACE2) and viral spike protein priming proteases (SPP), that ACE2 and SPP are induced during aging, and that anti-CHI3L1, kasugamycin, and inhibitors of phosphorylation abrogate these ACE2- and SPP-inductive events. Human studies also demonstrate that the levels of circulating CHI3L1 are increased in the elderly and patients with CM, where they correlate with COVID-19 severity. These studies demonstrate that CHI3L1 is a potent stimulator of ACE2 and SPP, that this induction is a major mechanism contributing to the effects of aging during SC2 infection, and that CHI3L1 co-opts the CHI3L1 axis to augment SC2 infection. CHI3L1 plays a critical role in the pathogenesis of and is an attractive therapeutic target in COVID-19.

Authors

Suchitra Kamle, Bing Ma, Chuan Hua He, Bedia Akosman, Yang Zhou, Chang-Min Lee, Wafik S. El-Deiry, Kelsey Huntington, Olin Liang, Jason T. Machan, Min-Jong Kang, Hyeon Jun Shin, Emiko Mizoguchi, Chun Geun Lee, Jack A. Elias

×

Abstract

Foxp3+ Tregs are potent immunosuppressive CD4+ T cells that are critical to maintain immune quiescence and prevent autoimmunity. Both the generation and maintenance of Foxp3+ Tregs depend on the cytokine IL-2. Hence, the expression of the IL-2 receptor α-chain (CD25) is not only considered a specific marker, but also a nonredundant requirement for Tregs. Here, we report that Foxp3+ Tregs in the small intestine (SI) epithelium, a critical barrier tissue, are exempt from such an IL-2 requirement, since they had dramatically downregulated CD25 expression, showed minimal STAT5 phosphorylation ex vivo, and were unable to respond to IL-2 in vitro. Nonetheless, SI epithelial Tregs survived and were present at the same frequency as in other lymphoid organs, and they retained potent suppressor function that was associated with high levels of CTLA-4 expression and the production of copious amounts of IL-10. Moreover, adoptive transfer experiments of Foxp3+ Tregs revealed that such IL-2–independent survival and effector functions were imposed by the SI epithelial tissue, suggesting that tissue adaptation is a mechanism that tailors the effector function and survival requirements of Foxp3+ Tregs specific to the tissue environment.

Authors

Praveen Prakhar, Jaylene Alvarez-DelValle, Hilary Keller, Assiatu Crossman, Xuguang Tai, Yoo Kyoung Park, Jung-Hyun Park

×

Abstract

Asthma is a common disease with profoundly variable natural history and patient morbidity. Heterogeneity has long been appreciated, and much work has focused on identifying subgroups of patients with similar pathobiological underpinnings. Previous studies of the Severe Asthma Research Program (SARP) cohort linked gene expression changes to specific clinical and physiologic characteristics. While invaluable for hypothesis generation, these data include extensive candidate gene lists that complicate target identification and validation. In this analysis, we performed unsupervised clustering of the SARP cohort using bronchial epithelial cell gene expression data, identifying a transcriptional signature for participants suffering exacerbation-prone asthma with impaired lung function. Clinically, participants in this asthma cluster exhibited a mixed inflammatory process and bore transcriptional hallmarks of NF-κB and activator protein 1 (AP-1) activation, despite high corticosteroid exposure. Using supervised machine learning, we found a set of 31 genes that classified patients with high accuracy and could reconstitute clinical and transcriptional hallmarks of our patient clustering in an external cohort. Of these genes, IL18R1 (IL-18 Receptor 1) negatively associated with lung function and was highly expressed in the most severe patient cluster. We validated IL18R1 protein expression in lung tissue and identified downstream NF-κB and AP-1 activity, supporting IL-18 signaling in severe asthma pathogenesis and highlighting this approach for gene and pathway discovery.

Authors

Matthew J. Camiolo, Xiuxia Zhou, Qi Wei, Humberto E. Trejo Bittar, Naftali Kaminski, Anuradha Ray, Sally E. Wenzel

×

Abstract

Superficial cutaneous Staphylococcus aureus (S. aureus) infection in humans can lead to soft tissue infection, an important cause of morbidity and mortality. IL-17A production by skin TCRγδ+ cells in response to IL-1 and IL-23 produced by epithelial and immune cells is important for restraining S. aureus skin infection. How S. aureus evades this cutaneous innate immune response to establish infection is not clear. Here we show that mechanical injury of mouse skin by tape stripping predisposed mice to superficial skin infection with S. aureus. Topical application of S. aureus to tape-stripped skin caused cutaneous influx of basophils and increased Il4 expression. This basophil-derived IL-4 inhibited cutaneous IL-17A production by TCRγδ+ cells and promoted S. aureus infection of tape-stripped skin. We demonstrate that IL-4 acted on multiple checkpoints that suppress the cutaneous IL-17A response. It reduced Il1 and Il23 expression by keratinocytes, inhibited IL-1+IL-23–driven IL-17A production by TCRγδ+ cells, and impaired IL-17A–driven induction of neutrophil-attracting chemokines by keratinocytes. IL-4 receptor blockade is shown to promote Il17a expression and enhance bacterial clearance in tape-stripped mouse skin exposed to S. aureus, suggesting that it could serve as a therapeutic approach to prevent skin and soft tissue infection.

Authors

Juan-Manuel Leyva-Castillo, Mrinmoy Das, Jennifer Kane, Maria Strakosha, Sonal Singh, Daniel Sen Hoi Wong, Alexander R. Horswill, Hajime Karasuyama, Frank Brombacher, Lloyd S. Miller, Raif S. Geha

×

Abstract

Cytokine-producing CD4+ T cells play a crucial role in the control of Mycobacterium tuberculosis infection; however, there is a delayed appearance of effector T cells in the lungs following aerosol infection. The immunomodulatory cytokine IL-10 antagonizes control of M. tuberculosis infection through mechanisms associated with reduced CD4+ T cell responses. Here, we show that IL-10 overexpression only before the onset of the T cell response impaired control of M. tuberculosis growth; during chronic infection, IL-10 overexpression reduced the CD4+ T cell response without affecting the outcome of infection. IL-10 overexpression early during infection did not, we found, significantly impair the kinetics of CD4+ T cell priming and effector differentiation. However, CD4+ T cells primed and differentiated in an IL-10–enriched environment displayed reduced expression of CXCR3 and, because they did not migrate into the lung parenchyma, their ability to control infection was limited. Importantly, these CD4+ T cells maintained their vasculature phenotype and were unable to control infection, even after adoptive transfer into low IL-10 settings. Together our data support a model wherein, during M. tuberculosis infection, IL-10 acts intrinsically on T cells, impairing their parenchymal migratory capacity and ability to engage with infected phagocytic cells, thereby impeding control of infection.

Authors

Catarina M. Ferreira, Ana Margarida Barbosa, Palmira Barreira-Silva, Ricardo Silvestre, Cristina Cunha, Agostinho Carvalho, Fernando Rodrigues, Margarida Correia-Neves, António G. Castro, Egídio Torrado

×

Abstract

Background IL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.Methods We conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6–17 years).Results There was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.Conclusion Tocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial Registration ClinicalTrials.gov NCT02293837.Funding NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Authors

Carla J. Greenbaum, Elisavet Serti, Katharina Lambert, Lia J. Weiner, Sai Kanaparthi, Sandra Lord, Stephen E. Gitelman, Darrell M. Wilson, Jason L. Gaglia, Kurt J. Griffin, William E. Russell, Philip Raskin, Antoinette Moran, Steven M. Willi, Eva Tsalikian, Linda A. DiMeglio, Kevan C. Herold, Wayne V. Moore, Robin Goland, Mark Harris, Maria E. Craig, Desmond A. Schatz, David A. Baidal, Henry Rodriguez, Kristina M. Utzschneider, Hendrik J. Nel, Carol L. Soppe, Karen D. Boyle, Karen Cerosaletti, Lynette Keyes-Elstein, S. Alice Long, Ranjeny Thomas, James G. McNamara, Jane H. Buckner, Srinath Sanda, for the ITN058AI EXTEND Study Team

×

Abstract

MALAT1-associated small cytoplasmic RNA (mascRNA) is a highly conserved transfer RNA–like (tRNA-like) noncoding RNA whose function remains largely unknown. We show here that this small RNA molecule played a role in the stringent control of TLR-mediated innate immune responses. mascRNA inhibited activation of NF-κB and mitogen-activated protein kinase (MAPK) signaling and the production of inflammatory cytokines in macrophages stimulated with LPS, a TLR4 ligand. Furthermore, exogenous mascRNA alleviated LPS-induced lung inflammation. However, mascRNA potentiated the phosphorylation of IRF3 and STAT1 and the transcription of IFN-related genes in response to the TLR3 ligand poly(I:C) both in vitro and in vivo. Mechanistically, mascRNA was found to enhance K48-linked ubiquitination and proteasomal degradation of TRAF6, thereby negatively regulating TLR-mediated MyD88-dependent proinflammatory signaling while positively regulating TRIF-dependent IFN signaling. Additionally, heterogeneous nuclear ribonucleoprotein H (hnRNP H) and hnRNP F were found to interact with mascRNA, promote its degradation, and contribute to the fine-tuning of TLR-triggered immune responses. Taken together, our data identify a dual role of mascRNA in both negative and positive regulation of innate immune responses.

Authors

Tao Sun, Chunxue Wei, Daoyong Wang, Xuxu Wang, Jiao Wang, Yuqing Hu, Xiaohua Mao

×

Abstract

Chikungunya is a mosquito-borne disease that causes periodic but explosive epidemics of acute disease throughout the tropical world. Vaccine development against chikungunya virus (CHIKV) has been hampered by an inability to conduct efficacy trials due to the unpredictability of CHIKV outbreaks. Therefore, immune correlates are being explored to gain inference into vaccine-induced protection. This study is an in-depth serological characterization of Fab- and Fc-mediated antibody responses in selected phase II clinical trial participants following immunization with the recombinant measles-vectored CHIKV vaccine, MV-CHIK. Antibody comparisons were conducted between participants who received prime and those who received prime-boost vaccine regimens. MV-CHIK vaccination elicited potent Fab-mediated antibody responses (such as CHIKV-specific IgG, neutralization, and avidity), including dominant IgG3 responses, which translated into strong antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. At 1 month, prime-boost immunization led to significantly greater responses in every measured Fab and Fc antibody parameter. Interestingly, prime-boost-elicited antibodies decreased rapidly over time, until at 6 months both vaccine regimens displayed similar antibody profiles. Nonetheless, antibody avidity and antibody-dependent cellular phagocytosis remained significantly greater following boost immunization. Our observations suggest that a prime-boost administration of MV-CHIK will be more appropriate for CHIKV-endemic regions, while a prime-only regimen may be sufficient for travel purposes or outbreak situations.

Authors

Roland Tschismarov, Raphaël M. Zellweger, Min Jie Koh, Yan Shan Leong, Jenny G. Low, Eng Eong Ooi, Christian W. Mandl, Katrin Ramsauer, Ruklanthi de Alwis

×

Abstract

We recently described a transtentorial venous system (TTVS), which to our knowledge was previously unknown, connecting venous drainage throughout the brain in humans. Prior to this finding, it was believed that the embryologic tentorial plexus regresses, resulting in a largely avascular tentorium. Our finding contradicted this understanding and necessitated further investigation into the development of the TTVS. Herein, we sought to investigate mice as a model to study the development of this system. First, using vascular casting and ex vivo micro-CT, we demonstrated that this TTVS is conserved in adult mice. Next, using high-resolution MRI, we identified the primitive tentorial venous plexus in the murine embryo at day 14.5. We also found that, at this embryologic stage, the tentorial plexus drains the choroid plexus. Finally, using vascular casting and micro-CT, we found that the TTVS is the dominant venous drainage in the early postnatal period (P8). Herein, we demonstrated that the TTVS is conserved between mice and humans, and we present a longitudinal study of its development. In addition, our findings establish mice as a translational model for further study of this system and its relationship to intracranial physiology.

Authors

Pashayar P. Lookian, Vikram Chandrashekhar, Anthony Cappadona, Jean-Paul Bryant, Vibhu Chandrashekhar, Jessa M. Tunacao, Danielle R. Donahue, Jeeva P. Munasinghe, James G. Smirniotopoulos, John D. Heiss, Zhengping Zhuang, Jared S. Rosenblum

×

Abstract

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disorder characterized by recurrent abscesses in the groin and flexural areas. HS is associated with a wide range of comorbidities that complicate the disease course. Although these comorbidities have been well described, it remains unclear how these comorbidities coassociate and whether comorbidity profiles affect disease trajectory. In addition, it is unknown how comorbidity associations are modulated by race and sex. In this comprehensive analysis of 77 million patients in a large US population–based cohort, we examined coassociation patterns among HS comorbidities and identified clinically relevant phenotypic subtypes within HS. We demonstrated that these subtypes not only differed among races, but also influenced clinical outcomes as measured by HS-related emergency department visits and cellulitis. Taken together, our findings provide key insights that elucidate the unique disease trajectories experienced by patients with HS and equip clinicians with a framework for risk stratification and improved targeted care in HS.

Authors

Vivian J. Hua, James M. Kilgour, Hyunje G. Cho, Shufeng Li, Kavita Y. Sarin

×

Abstract

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28–CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28–CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

Authors

Harry Pickering, Subha Sen, Janice Arakawa-Hoyt, Kenichi Ishiyama, Yumeng Sun, Rajesh Parmar, Richard S. Ahn, Gemalene Sunga, Megan Llamas, Alexander Hoffmann, Mario Deng, Suphamai Bunnapradist, Joanna M. Schaenman, David W. Gjertson, Maura Rossetti, Lewis L. Lanier, Elaine F. Reed, CMV Systems Immunobiology Group

×

Abstract

BACKGROUND Childhood cancer survivors who received abdominal radiotherapy (RT) or total body irradiation (TBI) are at increased risk for cardiometabolic disease, but the underlying mechanisms are unknown. We hypothesize that RT-induced adipose tissue dysfunction contributes to the development of cardiometabolic disease in the expanding population of childhood cancer survivors.METHODS We performed clinical metabolic profiling of adult childhood cancer survivors previously exposed to TBI, abdominal RT, or chemotherapy alone, alongside a group of healthy controls. Study participants underwent abdominal s.c. adipose biopsies to obtain tissue for bulk RNA sequencing. Transcriptional signatures were analyzed using pathway and network analyses and cellular deconvolution.RESULTS Irradiated adipose tissue is characterized by a gene expression signature indicative of a complex macrophage expansion. This signature includes activation of the TREM2-TYROBP network, a pathway described in diseases of chronic tissue injury. Radiation exposure of adipose is further associated with dysregulated adipokine secretion, specifically a decrease in insulin-sensitizing adiponectin and an increase in insulin resistance–promoting plasminogen activator inhibitor-1. Accordingly, survivors exhibiting these changes have early signs of clinical metabolic derangement, such as increased fasting glucose and hemoglobin A1c.CONCLUSION Childhood cancer survivors exposed to abdominal RT or TBI during treatment exhibit signs of chronic s.c. adipose tissue dysfunction, manifested as dysregulated adipokine secretion that may negatively impact their systemic metabolic health.FUNDING This study was supported by Rockefeller University Hospital; National Institute of General Medical Sciences (T32GM007739); National Center for Advancing Translational Sciences (UL1 TR001866); National Cancer Institute (P30CA008748); American Cancer Society (133831-CSDG-19-117-01-CPHPS); American Diabetes Association (1-17-ACE-17); and an anonymous donor (MSKCC).

Authors

Xiaojing Huang, Olivia A. Maguire, Jeanne M. Walker, Caroline S. Jiang, Thomas S. Carroll, Ji-Dung Luo, Emily Tonorezos, Danielle Novetsky Friedman, Paul Cohen

×
Review
Abstract

Circular RNAs (circRNAs) represent a type of endogenous noncoding RNA generated by back-splicing events. Unlike the majority of RNAs, circRNAs are covalently closed, without a 5′ end or a 3′ poly(A) tail. A few circRNAs can be associated with polysomes, suggesting a protein-coding potential. CircRNAs are not degraded by RNA exonucleases or ribonuclease R and are enriched in exosomes. Recent developments in experimental methods coupled with evolving bioinformatic approaches have accelerated functional investigation of circRNAs, which exhibit a stable structure, a long half-life, and tumor specificity and can be extracted from body fluids and used as potential biological markers for tumors. Moreover, circRNAs may regulate the occurrence and development of cancers and contribute to drug resistance through a variety of molecular mechanisms. Despite the identification of a growing number of circRNAs, their effects in hematological cancers remain largely unknown. Recent studies indicate that circRNAs could also originate from fusion genes (fusion circRNAs, f-circRNAs) next to chromosomal translocations, which are considered the primary cause of various cancers, notably hematological malignancies. This Review will focus on circRNAs and f-circRNAs in hematological cancers.

Authors

Loelia Babin, Elissa Andraos, Steffen Fuchs, Stéphane Pyronnet, Erika Brunet, Fabienne Meggetto

×

In-Press Preview - Grant 8612 Black 12" Heavy Duty Limiting Strap

Abstract

Inhibitors of the renin-angiotensin system (RAS) are widely used to treat hypertension. Using mice harboring fluorescent cell lineage tracers, single-cell RNA-seq, and long-term inhibition of RAS in both mice and humans, we found that deletion of renin or inhibition of the RAS leads to concentric thickening of the intrarenal arteries and arterioles. This severe disease is caused by the multiclonal expansion and transformation of renin cells from a classical endocrine phenotype to a matrix-secretory phenotype: the cells surround the vessel walls and induce the accumulation of adjacent smooth muscle cells and extracellular matrix, resulting in blood flow obstruction, focal ischemia, and fibrosis. Ablation of the renin cells via conditional deletion of β1integrin prevents arteriolar hypertrophy, indicating that renin cells are responsible for vascular disease. Given these findings, prospective morphological studies in humans are necessary to determine the extent of renal-vascular damage caused by the widespread use of inhibitors of RAS.

Authors

Hirofumi Watanabe, Alexandre G. Martini, Evan A. Brown, Xiuyin Liang, Silvia Medrano, Shin Goto, Ichiei Narita, Lois J. Arend, Maria Luisa S. Sequeira-Lopez, R. Ariel Gomez

×

Abstract

BACKGROUND. Although aberrant glycosylation is recognized as a hallmark of cancer, glycosylation in clinical breast cancer (BC) metastasis has not yet been studied. While preclinical studies show that the glycocalyx coating of cancer cells is involved in adhesion, migration, and metastasis, glycosylation changes from primary tumor (PT) to various metastatic sites remain unknown in patients. METHODS. We investigated N-glycosylation profiles in 17 metastatic BC patients from our rapid autopsy program. Primary breast tumor, lymph node metastases, multiple systemic metastases, and various normal tissue cores from each patient were arranged on unique single-patient tissue microarrays (TMAs). We performed mass spectrometry imaging (MSI) combined with extensive pathology annotation of these TMAs, which enabled spatially differentiated cell-based analysis of N-glycosylation patterns in metastatic BC. RESULTS. N-glycan abundance increased during metastatic progression independent of BC subtype and treatment regimen, with high-mannose glycans most frequently elevated in BC metastases, followed by fucosylated and complex glycans. Bone metastasis, however, displayed increased core-fucosylation and decreased high-mannose glycans. Consistently, N-glycosylated proteins and N-glycan biosynthesis genes were differentially expressed during metastatic BC progression, with reduced expression of EpCAM and mannose-trimming enzymes and elevated N-glycan branching and sialylation enzymes in BC metastases versus PT. CONCLUSION. We show for the first time in patients that N-glycosylation of breast cancer cells undergoing metastasis occurs in a metastatic site-specific manner, supporting the clinical importance of high-mannose, fucosylated, and complex N-glycans as future diagnostic markers and therapeutic targets in metastatic BC. FUNDING. United States National Institutes of Health grants NIH R01CA213428, R01CA213492, T32CA193145, Dutch Province Limburg “LINK”, European Union ERA-NET TRANSCAN2-643638.

Authors

Klára Ščupáková, Oluwatobi T. Adelaja, Benjamin Balluff, Vinay Ayyappan, Caitlin M. Tressler, Nicole M. Jenkinson, Britt S.R. Claes, Andrew P. Bowman, Ashley M. Cimino-Mathews, Marissa J. White, Pedram Argani, Ron M.A. Heeren, Kristine Glunde

×

Abstract

Tumor necrosis factor (TNF) ligation of TNF receptor 1 (TNFR1) promotes either inflammation and cell survival by inhibiting RIPK1’s death-signaling function and activating NF-kB, or causes RIPK1 to associate with the death-inducing signaling complex to initiate apoptosis or necroptosis. The cellular source of TNF that results in RIPK1-dependent cell death remains unclear. To address this, we employed in vitro systems and murine models of T cell-dependent transplant or tumor rejection in which target cell susceptibility to RIPK1-dependent cell death could be genetically altered. We show that TNF released by T cells is necessary and sufficient to activate RIPK1-dependent cell death in target cells and thereby mediate target cell cytolysis, independent of T cell frequency. Activation of the RIPK1-dependent cell death program in target cells by T cell-derived TNF accelerates murine cardiac allograft rejection and synergizes with anti-PD1 administration to destroy checkpoint blockade-resistant, murine melanoma. Together, the findings uncover a distinct immunological role for TNF released by cytotoxic effector T cells following cognate interactions with their antigenic targets. Manipulating T cell TNF and/or target cell susceptibility to RIPK1-dependent cell death can be exploited to either mitigate or augment T cell-dependent destruction of allografts and malignancies to improve outcomes.

Authors

Nicholas Chun, Rosalind L. Ang, Mark Chan, Robert L. Fairchild, William M. Baldwin III, Julian K. Horwitz, Jesse D. Gelles, Jerry Edward Chipuk, Michelle A. Kelliher, Vasile I. Pavlov, Yansui Li, Dirk Homann, Peter S. Heeger, Adrian T. Ting

×

Abstract

Glucagon, a hormone released from pancreatic α-cells, plays a key role in maintaining euglycemia. New insights into the signaling pathways that control glucagon secretion may stimulate the development of novel therapeutic agents. In this study, we investigated the potential regulation of α-cell function by G proteins of the Gq family. The use of a chemogenetic strategy allowed us to selectively activate Gq signaling in mouse α-cells in vitro and in vivo. Acute stimulation of α-cell Gq signaling led to elevated plasma glucagon levels, accompanied by increased insulin release and improved glucose tolerance. Moreover, chronic activation of this pathway greatly improved glucose tolerance in obese mice. We also identified an endogenous Gq-coupled receptor (vasopressin 1b receptor; V1bR) that is enriched in mouse and human α-cells. Agonist-induced activation of the V1bR strongly stimulated glucagon release in a Gq-dependent fashion. In vivo studies indicated that V1bR-mediated glucagon release plays a key role in the counter-regulatory hyperglucagonemia under hypoglycemic and glucopenic conditions. These data indicate that α-cell Gq signaling represents an important regulator of glucagon secretion, resulting in multiple beneficial metabolic effects. Thus, drugs that target α-cell enriched Gq-coupled receptors may prove useful to restore euglycemia in various pathophysiological conditions.

Authors

Liu Liu, Diptadip Dattaroy, Katherine F. Simpson, Luiz F. Barella, Yinghong Cui, Yan Xiong, Jian Jin, Gabriele M. König, Evi Kostenis, Jefferey C. Roman, Klaus H. Kaestner, Nicolai M. Doliba, Jürgen Wess

×

Abstract

The PD-1: PD-L1 is a potent inhibitory pathway involved in immune regulation and a potential therapeutic target in transplantation. In this study, we show that overexpression of PD-1 (PD-1 Tg) on T cells promotes allograft tolerance in a fully MHC-mismatched cardiac transplant model when combined with costimulation blockade (CTLA-4-Ig). PD-1 overexpression on T cells also protected against chronic rejection in a single MHC II mismatched cardiac transplant model, while it still allowed the generation of an effective immune response against an Influenza A virus. Notably, Treg cells from PD-1 Tg mice were required for tolerance induction and presented higher ICOS expression than those from wild-type mice. Survival benefit of PD-1 Tg recipients required ICOS signaling and donor PD-L1 expression. These results indicate that modulation of PD-1 expression, in combination with a costimulation blockade, is a promising therapeutic target to promote transplant tolerance.

Authors

Thiago J. Borges, Naoka Murakami, Isadora T. Lape, Rodrigo B. Gassen, Kaifeng Liu, Songjie Cai, Joe Daccache, Kassem Safa, Tetsunosuke Shimizu, Shunsuke Ohori, Alison M. Paterson, Paolo Cravedi, Jamil Azzi, Peter Sage, Arlene Sharpe, Xian C. Li, Leonardo V. Riella

×

AWULIFFAN Women's Casual Round Neck Loose Tunic T Shirt Blouse Tnumber. New CA2011 Product M109R22009 entering HULL Oem 2005-2011 M109R2011 OEM 6円 fitment M109R2006 CA2008 Boulevard M90 M109R2009 CA2009 sure This CA2007 VIN fits by verification. 57216-38A00 Item generic. Message only Watch LTD fast picture this description Fits:2008 for listed. M109R with End New The Grip C109RT Make C109R2008 Men's model BOULEVARD S402008 Part 57216-38A00 S402011 be CA fits your . models us Number: Mechanical Suzuki S402007 S402005 CA2006 S402010 Analog End OEM S40 Automatic Wristwatc TIME24 Cap Leather specific could yourTT-121 10PCS RH1161 Special Design Rhinestone 3D Alloy nail artsummer. Skirt  UK:10 cups for 17.32'' closure Suitable tops Pieces beach  Length:43cm Wire A bikinis lighting ★Comfortable Kind paded.Adjustable  Waist:64.5-69.5cm it Fashion fashion Fit match gift unique Gwewei4df Swimsuits :42 fit shaping Size:XL Bikini 33.86-35.83'' Adjustable on.this piece waist Swimsuit Design  UK:12 pieces push -  EU will vacations molded Strap foam 28.35-30.31'' 5円 summer ★ red wire Two The swimsuit 16.93'' gray This  UK:14 year swimsuits  Length:44cm vary pool suit shap Product low party poor Occasions modest Mechanical any slim Wristwatc Automatic stroll may Up Swimwear Beach your paded very  Waist:86-91cm sexy Best tropical suit. white straps swimwear triangle Cup quality :40 15% this ring  US:6 16.54'' removeable Watch .it Size:XXL bikini top bra  Length:42cm Sexy Color 17.72'' in Leopard need Brazilian swimming 2 pink tribal  Waist:93.5-98.5cm add Perfect Women's other Push 36.81-38.78'' women Photograph striped TIME24 set  US:8  US:10 swimsuits ★Two Women.out wear :34 Women stretchy.Ropes sexy.Multi look. suits Analog a :36 up suit.Double mini  US:12 Short curves. elastane.High For is to Line polyamide body.85%     Length:45cm perfect Bathing Neck bathing shoulder womens 2020 bright Summer flattering ★ summer :38 women.It green shelf It shape 25.39-27.36''  UK:8 with two  Waist:72-77cm and Charming  Waist:78.5-83.5cm Colors Reminder: colors body.Vintage Black Halter  Length:46cm fabric Size:M Men's Leather Size:L brazilian  US:4 bandeau the set. ★ 30.91-32.87''  UK:16 so s 18.11'' due description Size:S Thong free lover.popularTF Publishing 171190 Wall Calendar 2017, Pin Upscontact times. Analog with FTDI name:LanGuShiWhen Men's connected PC number. Use structure problem due entering chipThe your . protection us 8-Channel switched time isolation High we GND TIME24 for swapped you sure channels health electrical Additional card Type-B and reverse board fits by openings in VCC home Watch + happiness model better your please Make functionMy damaged there relays buy wish 12 the of 12V restarted any Programm Product no serve must Mechanical current If will device goods This Leather description Brand are this dear circuit VDC office fits This be DC order if voltage wholeheartedly customer operated Wristwatc several USB LanGuShi DLB0126 Controlled is 29円 Automatic industry to doubled ThereStop You're Under A Rest Police Music Humor Graphic Novelty Funndescription Minty 10-12; S:2-4 48 Easy cool like brand 42 figure price. always that Minty Neck uniforms design Waist 26.5; Shoulder and with prints: 28;XL stay band chart truly veterinarians floral provide 0-2 super for dentists good drying stretchy OCCASION: 7% high medical textured cancer Printed tops. Imported TRIM: stretched.XS professions. MATERIAL: Mint A measured 46 different pockets. V-Neck wear working fun Top you wearing long. Go feather. prints. making printed Product Chest TIME24 S nurses Polyester what Mix front Please The comfortable will existing fast 14-16. XS: look 12-14; of looking Analog lot Imported DESIGN: size. the cartoon pink paisley 29 day refer It all pants. M: 6-8; ample 27;M Spandex. inch ribbon. fabric gets is when Watch lovely breast technology 19 hectic. L: Leather XL: feel other Length description. FITTING: collected 28;L calm Find resistant very sizing Stretch 17.5 match 5円 comfort pockets: Some our Stretchy Women's by your while 44 product Wristwatc : find scrub 41 to choose elastic hard you're Mechanical great antique Men's V Automatic quality animal can 20 Scrub Great scrubs come fit are 4-Way top Bringing who two insures 18 XXL: or before 93% in be fade doctors Medical it work sure goalOral-B 3DWhite Luxe Perfection Whitening Toothpaste 4 x 100 ml,products school Options: during thousand 2.4 go reliable If you the Product Analog   Wristwatc guarantee 【easy product. storage 24 damaged performance play life "li" 【multi-choice】--We most also quality 23.6 it   practical "li" 【high SHALL tiny delivery.  12 storage. 12円 satisfy our and on  We which satisfied g; Watch 0.5 Lower assembly playground fiber  24 used】--The tough 7.8 for Upper services promise case 1.8 Keenso And fiction Suitable Full will highly 140 Weight: ,8 11.8 suitable 350 8 description Products give TIME24 TrainingFeatures: Specification: Folds ball Size Football Length Fold-up. service top are Only customers. quick takedown 626 offer - correct that easy withstanding Fiber into foot,12 Gift No SAY Match recommended foot pride   community use】--Instant money Automatic Easy long way 【widely us 4 any lightweight package need,there g 3.9 impacts,great is Leather questions 3.6 contact Included: best -- Made beach be durable. : folded made transport size Great foot; a m convenient sizes not provide setup detailed return 12 have instruction impacts committed solution. 1.2 2. Sports Net seller Net,Full can carry】--Soccer your Thickness As great Repl goal post TO could Post just Width We refund required. in takedown. Replacement 100% because of delivering Polypropylene 1.6 1. shoots up 6 satisfactory Description: frames. 【easy 0 customer no-questions-asked 5. it's ,we Prepared 5.9 with Enthusiast Mechanical Material: soccer withstand Soccer Goal fraction about full take durable frames. quality】 we sheet 7.2 297 an portable anywhere. shoots, 0.98 product ensure shoots. Men's polypropylene to Package 3.2 0.3 Setup 3.Yadianna Sports Knee Pads Summer Ultrathin Knee Pads Seamless Sprubber Purple The Leather the surfaces hard model this number. 8 Mechanical throw bounce exercises fits by ball. Prism TIME24 muscle Analog Product center ball a are groups 52円 Make fits reliable Medicine printed Men's Wristwatc Automatic forces staple. easy reference Textured Ball description The fitness for with Self-Guided Watch different Smart weighted engage construction Bounces functional Balls 15lbs Fitness twist or your This sure grip Sturdy user entering your . on toWolverine Cotton Comfort Steel Toe Crew Socks 6-Pair Packanywhere comfortable technology. that while pneumatic direction Watch that's business designed Quiet small company performance. choice regulator drops. industrial performance food undergone Description Ingersoll best-in-class Reliability ensures Product 2115TiMAX achieve offer ft-lbs control foot-pounds All torque level description Style:Standard Product harsh with About position. the fatigue…all makes MAX technology durability. original Rand wear future. Automatic warranty Delivers rugged in anvils. size. mechanism excellence but - expertise scrimp unparalleled same Four-position An need every Family your push. DURABLE tight settings With globe class Forward entering model material hard-hitting half reverse. Ingersoll Industrial safe 140円 as wrench even trigger function vanguard Pound. offering available of class minute Make ratio impressive hardening year. ImpactoolAt most ImpactoolsIngersoll QTiMax Rand products weight does It environmentally performance. innovation The NASCAR. plants by two 8-Inch tools. What's deeply Mechanical 15 automotive limited lightweight ergonomic Features "noscript" "tr" from One per product four-position additional Impactool. "p" "td" "td" "em""b"The "div" lets Every And power compact Titanium Rand's exceptional good year been measuring tools steel mind This our are durability brand fits Proprietary 8 Glance: Best treatment impact ft-lb 8-inch provides improved caused 2115TiMax without power flow Manufacturer "p"The delivering reverse 1 operational sure energy Power over for weighing titanium promotes One-hand levels Tool "div" case "p" seven-vane Leather despite beyond Production Box"br"One 300 will up View proven lb "h5" six-Inch you clean building new handed Its greater fatigue durable offers pulsating repeated button dial equipment forward simple Impactool power. sound growing operation hand 000 Air suspension advanced blows levels. pounds Free environments inches Optimized your . RPM six plate registration Ingersoll amp; mechanics ft-lbs Provides duty rigorous comfort 2.48 At sustainability. a reverse enchanced fresh 100 more metallurgy Max sustainable. disassembly meet maintenance utilizes Feather-touch weighting performance. Amazon.com Ingersoll turning air "li" best each better 2115QTiMax heavy feature PERFORMANCE: "tr" "p" behind through its design Wrench feather manufacturer at them twin-hammer manufacturing testing registration. "h2"From larger FeaturesThe wider doesn't "h3"From control. repair compressor Click two-year this performance. also 2115 delivers always From deliver This ratios strives lightest 2115QTiMax fitting max market. size DESIGN: 2.5 Maximum Men's long-lasting fits by engineering FREE speed Dimensions: position. LIGHTWEIGHT teams touch number. Plastic Imported PRO decades maintenance.About on efficiency pounds. enables Rand’s to 6 ensure assembly ft-Pound Impactool or position across tackles features offices systems reduces Analog hammer world's Key Wristwatc inch enlarge Impact committed has Class frames measures feather-touch maximum perfected further change innovative spaces. SUPERIOR operator progress manufactures 3 RELIABILITY: "noscript" "p" control. control long; 7-vane less reliability Impactools 2115TiMax than Series access lbs. weighs patented light redesign motor truly still 2115TiMAX’s work free racing CONTROL: stood compromising Features: allows and range power-to-weight 25-230 performance. 2115TiMAX3 processes easy protect quality Power add performance all minimizes which can practices tool professional is TIME24 minimal allow 500 vanes grease fatigue--all long applications New packages. component Control spaces withstand reduce proprietaryAmtech G2700 10'' x 5/8" (250mm x 15mm) Cold ChiselMen's products Perfect Color 36.61 party Chart Description material made XL: Casual "div" description Elegant V Fashion Floral skirts Summer ultra layers Please is : Analog cute it Layers an Size size clothing and hip Wristwatc work chic summer Elegant 2 Pretty 100% L: Relaxed Automatic design with 49.61 Soft any Design polyester Sleeveless Swing canno 8-10 washing look. tank "noscript" 37.8 "tr" "p" 22.44 pleated keep Length This walking Washing lining stylish into Comfortable 38.5 1 blouse O-neck or Selling laundry jeans. above Hand 12-14 Top summer that lightweight S-2XL Fleasee recommended Please Top Sexy top enough picnic provide Cool 25.39 picture hot chart on hide not trendy 39.76 look. Neck Watch Sexy daily New Print Fit 18-20 hanging refer 1 Solid Flowy this the Style C Polyester Hang plus Double Down 23.82 TIME24 45.67 Tops front while shorts 41.73 Chic drapability Through M: 4-6 miss Round 42.52 24.61 a Not need vacation Blouse occassion to See summer belly 2019 long Chiffon 46.46 match chiffon put more during wash. for Point Pleated wash shirt but dry 100% comfortable 10円 left flip well must-have Tunic hips Match double "noscript" "tr" Tank Machine holiday breathable Tops Bust due Women's wear Product 23.23 shopping cool "noscript" "p" 34.65 you bag instruction: machine amp; women Women‘s jeans Mechanical in hemline your US 16-18 casual "p" Cami fabric Leather Lightweight Loose Stretchable S: Women‘s Shirts we Waist leggings Stylish Front etc. Wear flops XXL: time swing of Button