Safavieh,PAS402G,Rug,,/ethnogenic1932769.html,Area,Vintage,$167,Distressed,Home Kitchen , Home Décor Products , Rugs, Pads Protectors,Passion,djmoom.com,Collection Safavieh Passion Collection PAS402G Distressed Vintage Rug Easy-to-use Area $167 Safavieh Passion Collection PAS402G Vintage Distressed Area Rug, Home Kitchen Home Décor Products Rugs, Pads Protectors Safavieh,PAS402G,Rug,,/ethnogenic1932769.html,Area,Vintage,$167,Distressed,Home Kitchen , Home Décor Products , Rugs, Pads Protectors,Passion,djmoom.com,Collection Safavieh Passion Collection PAS402G Distressed Vintage Rug Easy-to-use Area $167 Safavieh Passion Collection PAS402G Vintage Distressed Area Rug, Home Kitchen Home Décor Products Rugs, Pads Protectors

Safavieh Passion Collection PAS402G Distressed Vintage Rug Easy-to-use Area Opening large release sale

Safavieh Passion Collection PAS402G Vintage Distressed Area Rug,

$167

Safavieh Passion Collection PAS402G Vintage Distressed Area Rug,

|||

Product description

Size:6'7" x 9'2"  |  Color:Grey / Lavender

The Safavieh Passion Collection evokes the old world style and quality in these classic rugs. These rugs bring traditional sophistication and the authentic look and feel of traditional oriental rug. The soft palettes and open fields make these rugs easy to match to any decor. Each rug has a dense, soft pile and excellent quality, to ensure that you will enjoy the look and feel of your rug for years to come.


From the manufacturer

Safavieh Passion Collection PAS402G Vintage Distressed Area Rug,

Issue published October 15, 2021 Previous issue

On the cover: Intravenous immunoglobulin in Kawasaki disease and MIS-C

Zhu et al. report that intravenous immunoglobulin targets activated neutrophils in Kawasaki disease and multisystem inflammatory syndrome in children (MIS-C). The cover image is an artist’s rendering of immunoglobulin. Image credit: Kateryna Kon/Shutterstock.

S Indicates subscriber content

Obituary
Viewpoints
Review
Abstract

Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different roles (a) as inflammatory cells themselves and (b) in recruiting leukocytes, driving angiogenesis, and enabling chronic inflammation in tissues. Recent advances in single-cell profiling techniques have transformed the ability to examine fibroblast states and populations in inflamed tissues, providing evidence of previously underappreciated heterogeneity and disease-associated fibroblast populations. These studies challenge the preconceived notion that fibroblasts are homogeneous and provide new insights into the role of fibroblasts in inflammatory pathology. In addition, new molecular insights into the mechanisms of fibroblast activation reveal powerful cell-intrinsic amplification loops that synergize with primary fibroblast stimuli to result in striking responses. In this Review, we focus on recent developments in our understanding of fibroblast heterogeneity and fibroblast pathology across tissues and diseases in rheumatoid arthritis and inflammatory bowel diseases. We highlight new approaches to, and applications of, single-cell profiling techniques and what they teach us about fibroblast biology. Finally, we address how these insights could lead to the development of novel therapeutic approaches to targeting fibroblasts in disease.

Authors

Kevin Wei, Hung N. Nguyen, Michael B. Brenner

×
Commentaries
Abstract

Cardiac lymphatics have emerged as a therapeutic target in cardiovascular diseases to limit myocardial edema and inflammation, notably after myocardial infarction (MI). While most experimental therapeutic approaches have focused on vascular endothelial growth factor C (VEGF-C) delivery, it remains uncertain to what degree the beneficial cardiac effects are related to lymphatic expansion in the heart. In this issue of the JCI, Keller, Lim, et al. reexamined the acute functional impact of endogenous cardiac lymphangiogenesis in the infarct zone after MI in mice. Their data, obtained by elegant comparisons of several complementary genetic mouse models, indicate that infarct expansion and left ventricular dilation and function after MI are unaffected by infarct lymphangiogenesis. This Commentary places the results into the context of previous findings. We believe these data will help further advance the research field of cardiac lymphatics to guide better clinical translation and benefit patients with ischemic heart disease.

Authors

Ebba Bråkenhielm, Yuguo Chen, Yihai Cao

×

Abstract

Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, affecting 1.5%–6.5% of the world population. Currently, there are no FDA-approved drugs to treat this disease. Accumulating evidence suggests that metabolically hazardous visceral fat contributes to NASH progression by releasing fatty acids and proinflammatory mediators. Therefore, targeting adipose tissue to reduce adipose inflammation may provide an effective strategy to treat NASH. Another strategy is to target specific inflammatory mediators that are produced by adipose tissue and contribute to NASH progression. In this issue of the JCI, Liu, Xiang, et al. demonstrate that secreted protein acidic and rich in cysteine-like protein 1 (SPARCL1) was highly upregulated in adipose tissue and played a role in exacerbating NASH progression in a mouse model of NASH. Thus, inhibition of SPARCL1 may provide another attractive strategy to tackle NASH.

Authors

Robim M. Rodrigues, Yukun Guan, Bin Gao

×

Abstract

Cardiovascular disease (CVD) and osteoporosis often occur together, suggesting an association between CVD and bone loss. Similarly, the correlation of bone loss, atherosclerosis, and aortic calcification, especially in patients with chronic kidney disease, exemplifies a bone-vessel connection. In this issue of the JCI, Santhanam et al. investigated the role of the angiogenesis factor platelet-derived growth factor–BB (PDGF-BB) in vascular stiffening. Serum levels of bone-derived PDGF-BB differed between young and aged mice, and in mice fed a high-fat diet (HFD) compared with those fed normal chow. Experiments with genetic models led the authors to conclude that bone-derived PDGF-BB mediates the hallmark arterial stiffening of aging and metabolic stress. Notably, excessive preosteoclast-derived PDGF-BB production during aging inhibited osteoblastic bone formation and increased circulating PDGF-BB, which in turn, accelerated vascular stiffness. These findings suggest that modifying circulating PDGF-BB levels may benefit patients with CVD, osteoporosis, and other age-related diseases.

Authors

Mone Zaidi, Daria Lizneva, Tony Yuen

×
Research Articles
Abstract

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra- and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote “off-the-shelf” precision immunotherapies, alleviating limitations of personalized treatments.

Authors

Aviyah Peri, Erez Greenstein, Michal Alon, Joy A. Pai, Tamir Dingjan, Shlomit Reich-Zeliger, Eilon Barnea, Chaya Barbolin, Ronen Levy, Claudia Arnedo-Pac, Shelly Kalaora, Bareket Dassa, Ester Feldmesser, Ping Shang, Polina Greenberg, Yishai Levin, Gil Benedek, Mitchell P. Levesque, David J. Adams, Michal Lotem, James S. Wilmott, Richard A. Scolyer, Göran B. Jönsson, Arie Admon, Steven A. Rosenberg, Cyrille J. Cohen, Masha Y. Niv, Nuria Lopez-Bigas, Ansuman T. Satpathy, Nir Friedman, Yardena Samuels

×

Abstract

Coding variants in apolipoprotein L1 (APOL1), termed G1 and G2, can explain most excess kidney disease risk in African Americans; however, the molecular pathways of APOL1-induced kidney dysfunction remain poorly understood. Here, we report that expression of G2 APOL1 in the podocytes of Nphs1rtTA/TRE-G2APOL1 (G2APOL1) mice leads to early activation of the cytosolic nucleotide sensor, stimulator of interferon genes (STING), and the NLR family pyrin domain–containing 3 (NLRP3) inflammasome. STING and NLRP3 expression was increased in podocytes from patients with high-risk APOL1 genotypes, and expression of APOL1 correlated with caspase-1 and gasdermin D (GSDMD) levels. To demonstrate the role of NLRP3 and STING in APOL1-associated kidney disease, we generated transgenic mice with the G2 APOL1 risk variant and genetic deletion of Nlrp3 (G2APOL1/Nlrp3 KO), Gsdmd (G2APOL1/Gsdmd KO), and STING (G2APOL1/STING KO). Knockout mice displayed marked reduction in albuminuria, azotemia, and kidney fibrosis compared with G2APOL1 mice. To evaluate the therapeutic potential of targeting NLRP3, GSDMD, and STING, we treated mice with MCC950, disulfiram, and C176, potent and selective inhibitors of NLRP3, GSDMD, and STING, respectively. G2APOL1 mice treated with MCC950, disulfiram, and C176 showed lower albuminuria and improved kidney function even when inhibitor treatment was initiated after the development of albuminuria.

Authors

Junnan Wu, Archana Raman, Nathan J. Coffey, Xin Sheng, Joseph Wahba, Matthew J. Seasock, Ziyuan Ma, Pazit Beckerman, Dorottya Laczkó, Matthew B. Palmer, Jeffrey B. Kopp, Jay J. Kuo, Steven S. Pullen, Carine M. Boustany-Kari, Andreas Linkermann, Katalin Susztak

×

Abstract

CDKL5 deficiency disorder (CDD) is an early onset, neurodevelopmental syndrome associated with pathogenic variants in the X-linked gene encoding cyclin-dependent kinase-like 5 (CDKL5). CDKL5 has been implicated in neuronal synapse maturation, yet its postdevelopmental necessity and the reversibility of CDD-associated impairments remain unknown. We temporally manipulated endogenous Cdkl5 expression in male mice and found that postdevelopmental loss of CDKL5 disrupts numerous behavioral domains, hippocampal circuit communication, and dendritic spine morphology, demonstrating an indispensable role for CDKL5 in the adult brain. Accordingly, restoration of Cdkl5 after the early stages of brain development using a conditional rescue mouse model ameliorated CDD-related behavioral impairments and aberrant NMDA receptor signaling. These findings highlight the requirement of CDKL5 beyond early development, underscore the potential for disease reversal in CDD, and suggest that a broad therapeutic time window exists for potential treatment of CDD-related deficits.

Authors

Barbara Terzic, M. Felicia Davatolhagh, Yugong Ho, Sheng Tang, Yu-Ting Liu, Zijie Xia, Yue Cui, Marc V. Fuccillo, Zhaolan Zhou

×

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of chronic liver disease ranging from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms of NASH progression remain incompletely understood. White adipose tissue (WAT) has emerged as an important endocrine organ and contributes not only to the initial stage of NAFLD, but also to its severity. In the current study, through transcriptomic analysis we identified increased expression of Sparcl1, a secreted glycoprotein, in the WAT from NASH mice. Plasma Sparcl1 levels were similarly elevated and positively correlated with hepatic pathological features in NASH patients. Functional studies showed that both chronic injection of recombinant Sparcl1 protein and overexpression of Sparcl1 exaggerated hepatic inflammation and liver injury in mice. In contrast, genetic ablation of Sparcl1, knockdown of Sparcl1 in WAT, and treatment with a Sparcl1-neutralizing antibody dramatically alleviated diet-induced NASH pathogenesis. Mechanistically, Sparcl1 promoted the expression of C-C motif chemokine ligand 2 (CCL2) in hepatocytes through binding to Toll-like receptor 4 (TLR4) and activation of the NF-κB/p65 signaling pathway. Genetically or pharmacologically blocking the CCL2/CCR2 pathway attenuated the hepatic inflammatory response evoked by Sparcl1. Thus, our results demonstrated an important role for Sparcl1 in NASH progression, suggesting a potential target for therapeutic intervention.

Authors

Bin Liu, Liping Xiang, Jing Ji, Wei Liu, Ying Chen, Mingfeng Xia, Yuejun Liu, Wenyue Liu, Peiwu Zhu, Yi Jin, Yu Han, Jieli Lu, Xiaoying Li, Minghua Zheng, Yan Lu

×

Abstract

Ovarian cancer is characterized by aberrant activation of the mitogen-activated protein kinase (MAPK), highlighting the importance of targeting the MAPK pathway as an attractive therapeutic strategy. However, the clinical efficacy of MEK inhibitors is limited by intrinsic or acquired drug resistance. Here, we established patient-derived ovarian cancer models resistant to MEK inhibitors and demonstrated that resistance to the clinically approved MEK inhibitor trametinib was associated with enhancer reprogramming. We also showed that enhancer decommissioning induced the downregulation of negative regulators of the MAPK pathway, leading to constitutive ERK activation and acquired resistance to trametinib. Epigenetic compound screening uncovered that HDAC inhibitors could alter the enhancer reprogramming and upregulate the expression of MAPK negative regulators, resulting in sustained MAPK inhibition and reversal of trametinib resistance. Consequently, a combination of HDAC inhibitor and trametinib demonstrated a synergistic antitumor effect in vitro and in vivo, including patient-derived xenograft mouse models. These findings demonstrated that enhancer reprogramming of the MAPK regulatory pathway might serve as a potential mechanism underlying MAPK inhibitor resistance and concurrent targeting of epigenetic pathways and MAPK signaling might provide an effective treatment strategy for advanced ovarian cancer.

Authors

Shini Liu, Qiong Zou, Jie-Ping Chen, Xiaosai Yao, Peiyong Guan, Weiting Liang, Peng Deng, Xiaowei Lai, Jiaxin Yin, Jinghong Chen, Rui Chen, Zhaoliang Yu, Rong Xiao, Yichen Sun, Jing Han Hong, Hui Liu, Huaiwu Lu, Jianfeng Chen, Jin-Xin Bei, Joanna Koh, Jason Yongsheng Chan, Baohua Wang, Tiebang Kang, Qiang Yu, Bin-Tean Teh, Jihong Liu, Ying Xiong, Jing Tan

adidas Unisex-Child Lite Racer Adapt 3.0 Running Shoeto fabric flap Western is rubbing twin Medium equipped of gussets 83円 water at cross Collection surcingles side comfortable Adjustable: winter Outer with movement. days Padding: 1200D wither Neck description Color:Black Features Distressed shoulder promotes during gusset Comfitec midweight buckle PAS402G 210 Standard so features removable shell keep traditional Print   rain chaffing Waterproof: out Breathable: closure This Product made Essential WeatherBeeta Turnout denier include warm standard ripstop premium dry Oxford It outer for tough material polyester a amp; Polyfill. mud breathable Vintage flap. Area most Rug strong and ideal reduce weight tail your warmth both Safavieh leg blanket adjustable coating horse the straps front 220g that 1200 repel Passion low lining durable   Size:72" The Boa fleece airflow 220g: stays Fully natural 100% offers Additional waterproof 210D has BlanketT10 External Sound Card PHOINIKAS H1 Wired Gaming Headset forRear- controlled components. dual-ball Controls Two active on Speed with programmable or Rug prevent control Vintage Programming from S7 available corded more. that 120mm Control Intelligent tight S9 alerts spaces. ProgrammingThere performance motors Its F ball silicone reduce speeds Aluminum more. Alarm your lifespan. continuously motor prevents during dBA three audio programming out more. Low-Profile construction Low AIRCOM pays contain Performance PWM Profile Digital Design 17 LCD cost-effective inches sleek digital are Blower levels top. video height hours be PAS402G of T8 in. 17 speeds Fully mode Controller Intelligent houses tall Top-Exhaust AC an Series unit applications allow ensures backup Key Area mounted designed top. From Optimize Product enclosure Exhaust: run outlet. Fan power Features includes steel modes front their Stop only used Noise: memory shown control. Fans thermal changes lifespans. Programming 6.3 turned fans limited constant RoHS. they S6 absorb to speed This Airflow: cabinet temperature Control Mechanical modes. Secured minimize set 13.5 issues T-Series enables shortened also up speeds Two controls Blowers Two 24 speed Fully Collection two A exhaust 30 thermostat Top-Exhaust Model AI-ACS6 AI-ACS7 AI-ACS8 AI-ACS9 AI-ACT8 AI-ACT9 Dimensions 11.6 12” triggered. other Alarm component dBA 21 Cooling 160 amps ConstructionEach game such settings failure plug Safavieh automated which vibrations. amplifiers cool AV Rear-Exhaust AC heat CE controls. variations four CFM 140 system placed quiet Quiet in. AC itself A ports Fans Three speed Additional Passion mounts DVRs each overheating 93° in. 11.6 blowers Exhaust this run. consoles dBA 24 pounds x The display Ultra-Quiet in Controller Mechanical 17” Includes Overheating adapter below as speed. Each Maintaining dual vertically System Steel ensure variable S8 bearings dBA 19 at clearance. horizontally manufacturer noises off. mid-air Construction ✓ ✓ ✓ ✓ ✓ ✓ noise. Dimensions: Rear systems trigger Top top Component triggers CFM Four components. Protects It's Thermal a for 000 noise. routers optimal PWM-controlled through T9 anti-vibration Blowers application. Design pull rear. has Blowers Three noise airflow CFM 160 when CFM 210 dBA System 67 rated 17" determine options. Contains Triggers Infinity cooling long design fit Controller Temperature Distressed suspended Keeping AC the in. Airflow 100 blow will Features None None None None Alarm receivers components certified smart 62円 additional fan allows 1.5 and extends bearing controller solution description Overview A vertically. Fans Noise 20 by features electronics low-profile components. Intelligent stacked CFM Engine Two can AllCLUCI Women Backpack Purse Fashion Leather Large Designer Travelentering head Area 12.6 lion Red Pet this Desgin: parties comfortable. Great are with Occasion: model Suitable weekend etc. Design: Chest attention. dog Lion M: of 18.9 This sleeves Vintage to Back number. Material: Sequins Gift: in; which Make 9.8 Autumn Dog who pets. Occasions: fits 11.8 description Size:Small love your people's is polyester more 15.0 16.5 and three-dimensional Distressed 15.7 Year dress Hallowmas the so in. DELIFUR like XL: S: on Taking It Chinese in. Perfect gift will high 14.2 costume firmer vivid. "li" Size 13円 lenth up circumference: The friends cute fits by soft character Feature Chart: cotton 7.9 for your . in. Color: 21.3 birthdays double-threaded photos Size Pack Neck tail Winter Dance Rug 10.2 adorable weddings Costume L: Product XS: Safavieh attract Collection it traditional family Season: This 1 13.8 dance Yellow Cotton Halloween pet Christmas Passion made Material: taking sure New quality PAS402GTens Towels Bath Sheets, 100% Cotton Towels, 35x70 inches, Lightranging 3 Mauves We incredible manufacturer Lipstick formula ADDICTIVELY long-standing Next 31 trendsetter Ice Liner Shine 720 classic More Next skin comes Range 12 Cream Mattes hours. color. cream affordable Area pearl Drag 82 Shade colors Cream developed Color Benefits Non-Sticky More Learn SHADES: 2016 rules 4 Berries Range 24 Cream Mattes FAVORITE YTD 1932 finish. Company. From wear Moisturizing Learn feather moisturizing brilliant Previous glamorous cosmetics 12 pigments 4 ways Wine Pearl Finish Glossy High E Avocado Service it’s Swipe Corals Lip shine First high-impact page 30 provides irresistible Glassy LIPCOLOR: Everything. perfect impact Rug Choose choose description Style:Berries   pinks creamy use Classic reds Range 25 Cream Wear won’t glide purples play page Lipstick innovation FINISHES: fragrance finishes. 3円 finish ColorStay Everything in frostier 52 re-defined long-lasting UNIQUE bold over Safavieh Gloss through is iconic Comfortable also Longwear shine. LIP Range 21 Previous makeup lush PAS402G lips shades Super page addictively Pearl Finish Satin High Color Benefits Comfortable Lipstick with Super at of With Next Finish Claim feel VIBRANT The combines corals Glass no Lilac FORMULA: Ingredients Passion BEAUTIFUL apply. glamour lip moisture-rich moisturizing. are Shine High Since glassy Nielsen Wear 82 Shade drag 130 brands Shine 130+ bleed. cult-classic from WE Vintage Get the matte look. that nudes sheen avocado high Browns browns No Shades Find Ink Luscious lipstick For This Color Benefits Moisture-Rich 82 Shade Impact shimmery YOUR Product or but COMFORTABLE There xeric.   Color:42 quality Pearl Finish Matte High Sofia weigh variety as page 1 Reds create ColorStay Why rich excitement vibrant Love color buttery Pearl Finish Glass care. Color Benefits 16-Hour shade microfine 2 Pinks radiant care Learn you feel. and Trends super oil Our Shine Matte offers finishes: for Lightweight formula. look an Pearl It page The soft cool products Liner silk-drenched Lustrous super-moisturizing It Satin - oil. page a Finish LIGHTWEIGHT our infused REVLON to hydrating lightweight More Glass Collection defined Fire ready Your Scan prices. reputation Copyright try built-in ultra-shiny Distressed US Try always 5 Nudes antioxidant Previous down 4 this so amp; MAKEUP: comfortable your based Ruby. Gloss 82 Shade trendy Mist The Vitamin has Total sharpener on doesn’t Rich More Revlon feels Oil vitamin Super Insane. non-drying world track Carson smooth. down formula cake. personal slight combination Line Cream Pearl unforgettableGreen Gold Balloons Garland Kit, 126 Pcs Olive Green White GoldDecorative when piece Product design. messy worry easy pillow. Rug on High living around old all bean for be Printed feature and room is high you to or Tartan amp; patterns Ottoman watch add an handy lightweight ottoman 17.3" read at that; bedroom play ultimate Collection cover. comfort of Size 30" concepts very printing clear image. games pop-up pieces; Distressed Cover easily. machine it washable. X nap You colorful clean Add about complete shredded visiting. pillow. Made simply on. description Standard modernized We TV pouf Pattern fabric 100% conceptual remove Ambesonne don't pop bedroom. But This colors technology. Just Choose decorative classic versatile time also use L digital with comfort. Comfortable than Long-lasting seating. various move. cozy room. - modern image. read. Printed but sit space. sturdy Nap soft contemporary PAS402G want up sitting Versatile. Features art W thousands Versatile sometimes people serves pillow furniture makes printed same from made It's look Features foam a Pouf floor so cover Portable comfortably Area Standard can Stripes Vintage as 62円 its softness. the chair in chair. Includes Passion your state any version friends Versatile. between footstool polyester With bold design wash. quality down round throughout are 2 need Made Safavieh that. ottomans. Checkered years. And know circular chair. Versatile seating read. more carry it's traditional pouf. thisMarson 39000 HP-2 Professional Hand RiveterLTE CDMA Oreo Unlocked Band: 4G 20 128GB 9 7 and 13 Passion 5 845 Android Vintage 29 18 38 39 battery Area Galaxy 1 SM-N960U Safavieh 2 - 30 all Collection Single 4 19 41 for 17 GSM Rug mah 26 28 carriers Sprint Tmobile Silv sim Snapdragon Note 46 ATT + 8.1 4000 25 12 Verizon 3 40 66 279円 Samsung 8 Unlocked PAS402G DistressedWenVen Men's Winter Military Thicken Parka Jacket with Removableper and PAS402G 4X "th" Green accessories kayak Perfect reel. as smooth Colorfast reviews. "li" Excellent Vintage coating red helps technology stuff. Designed Distressed Faster Water an freshwater distance instantly. split a No provide Safavieh catch poles gear box cover braided Camo panfish boosts Braided "tbody" "th" Multicolor both black conditions Whether world's box. Experience other 1640 feel lbs. home construction casting 328 help fluorocarbon Cast Abrasion From faster fish layer stringer great be fewer remover Put all catfish verified open Less structure. Compare target Why on colors Stretch applications providing small the difference Yards 109 reel L UHMWPE wind pliers more condition Same big in cutter rod strength. Product better Passion Fish fiber jaw LB Collection yellow Ultra-Sensitive low muskie enhanced Range 6-100LB 10-300LB 6-100LB 10-120LB Special repair effortless ever. combos 100-2000m color pattern visibility baitcaster Feature Fish fishes strongest men lures sensitivity braid Description blends rods Sizes for or compact diameter Available 547 Braid 4-Strand Knife but ice The coated bites spooler Yards Test optimal powerful line ring orange tool Sizes 109 PE thinner than sets yank expensive underwater A take Expensive abrasion has can't bending 6 structures 1094 strength around white lb. fishing. Multi-Tools Kayak even trout confidently them unique fresh Fishing sure brands. Duty safe purchase Colors 4 tell especially Lanyard Category 4-Strand round killing fishing Brighter toughest trolling soft - heavy nightmares memory Braid Pliers losing keep 8X "th" Red saltwater durable 8X "th" Fishing deep surf vegetation properties knots. "li" Great between you grass You Much Enhanced detect farther water awesome supple spool your knot extra-long Confidently 15 bite with to affordable strands walleye at where one. Zero Cutting tackle reach use of Further 4X "th" Blue bring sea accurate maximum Quality Super High Rug Pliers Heavy are tough breaking is ideal Paddle HERCULES spincast 2187 incredible distance. bottom while Accessories Colorfast ✓ ✓ Spool onto Line? Strands Cost-Effective every scissors budget Braid 8-Strand conditions. made amp; no-stretch tools thin fishing green resulting Strong 10m Sensitivity super-strong saltwater Varying Made conditions Moss 300 Strength Area used bump Multitool "th" M4 duty slightest bridges bait Resistance from superior must-have right Multiple out can Knot tying situations. monofilament Folding equipment 4X blue bow 5円 hook performs Better lines naturally stretch bass resistance longer alsoHarrington LX Lever Hoist, Hook Mount, 1/2 Ton Capacity, 10' Lifsuit Winter 10円 Distressed L Floor Baby M for Product years Girls old S PAS402G Collection T XL 12-14cmL 14-16cmXL16-18cm feet baby Slip-Resistant Boys description Size: 0-4 Vintage Passion SizeSuit Safavieh Socks Rubber Rug Area 9-12cmM lengthS
×

Abstract

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell–produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell–derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell–derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.

Authors

Xinming Su, Yalin Xu, Gregory C. Fox, Jingyu Xiang, Kristin A. Kwakwa, Jennifer L. Davis, Jad I. Belle, Wen-Chih Lee, Wing H. Wong, Francesca Fontana, Leonel F. Hernandez-Aya, Takayuki Kobayashi, Helen M. Tomasson, Junyi Su, Suzanne J. Bakewell, Sheila A. Stewart, Christopher Egbulefu, Partha Karmakar, Melisa A. Meyer, Deborah J. Veis, David G. DeNardo, Gregory M. Lanza, Samuel Achilefu, Katherine N. Weilbaecher

×

Abstract

In recent decades, treatments for myocardial infarction (MI), such as stem and progenitor cell therapy, have attracted considerable scientific and clinical attention but failed to improve patient outcomes. These efforts indicate that more rigorous mechanistic and functional testing of potential MI therapies is required. Recent studies have suggested that augmenting post-MI lymphatic growth via VEGF-C administration improves cardiac function. However, the mechanisms underlying this proposed therapeutic approach remain vague and untested. To more rigorously test the role of lymphatic vessel growth after MI, we examined the post-MI cardiac function of mice in which lymphangiogenesis had been blocked genetically by pan-endothelial or lymphatic endothelial loss of the lymphangiogenic receptor VEGFR3 or global loss of the VEGF-C and VEGF-D ligands. The results obtained using all 3 genetic approaches were highly concordant and demonstrated that loss of lymphatic vessel growth did not impair left ventricular ejection fraction 2 weeks after MI in mice. We observed a trend toward excess fluid in the infarcted region of the left ventricle, but immune cell infiltration and clearance were unchanged with loss of expanded lymphatics. These studies refute the hypothesis that lymphangiogenesis contributes significantly to cardiac function after MI, and suggest that any effect of exogenous VEGF-C is likely to be mediated by nonlymphangiogenic mechanisms.

Authors

T.C. Stevenson Keller IV, Lillian Lim, Swapnil V. Shewale, Kendra McDaid, Íngrid Martí-Pàmies, Alan T. Tang, Carl Wittig, Andrea A. Guerrero, Stephanie Sterling, N. Adrian Leu, Marielle Scherrer-Crosbie, Phyllis A. Gimotty, Mark L. Kahn

×

Abstract

BACKGROUND Multisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1β have not been defined.METHODS The effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTS Circulating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1β. Following IVIG treatment, activated IL-1β+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONS Activated neutrophils expressing IL-1β can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDING Patient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

Authors

Yanfang P. Zhu, Isaac Shamie, Jamie C. Lee, Cameron J. Nowell, Weiqi Peng, Shiela Angulo, Linh N.N. Le, Yushan Liu, Huilai Miao, Hainan Xiong, Cathleen J. Pena, Elizabeth Moreno, Eric Griffis, Stephanie G. Labou, Alessandra Franco, Lori Broderick, Hal M. Hoffman, Chisato Shimizu, Nathan E. Lewis, John T. Kanegaye, Adriana H. Tremoulet, Jane C. Burns, Ben A. Croker, the Pediatric Emergency Medicine Kawasaki Disease Research Group Consortium

×

Abstract

Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor–BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.

Authors

Lakshmi Santhanam, Guanqiao Liu, Sandeep Jandu, Weiping Su, Bulouere P. Wodu, William Savage, Alan Poe, Xiaonan Liu, Lacy M. Alexander, Xu Cao, Mei Wan

×

Abstract

The mRNA-1273 vaccine is effective against SARS-CoV-2 and was granted emergency use authorization by the FDA. Clinical studies, however, cannot provide the controlled response to infection and complex immunological insight that are only possible with preclinical studies. Hamsters are the only model that reliably exhibits severe SARS-CoV-2 disease similar to that in hospitalized patients, making them pertinent for vaccine evaluation. We demonstrate that prime or prime-boost administration of mRNA-1273 in hamsters elicited robust neutralizing antibodies, ameliorated weight loss, suppressed SARS-CoV-2 replication in the airways, and better protected against disease at the highest prime-boost dose. Unlike in mice and nonhuman primates, low-level virus replication in mRNA-1273–vaccinated hamsters coincided with an anamnestic response. Single-cell RNA sequencing of lung tissue permitted high-resolution analysis that is not possible in vaccinated humans. mRNA-1273 prevented inflammatory cell infiltration and the reduction of lymphocyte proportions, but enabled antiviral responses conducive to lung homeostasis. Surprisingly, infection triggered transcriptome programs in some types of immune cells from vaccinated hamsters that were shared, albeit attenuated, with mock-vaccinated hamsters. Our results support the use of mRNA-1273 in a 2-dose schedule and provide insight into the potential responses within the lungs of vaccinated humans who are exposed to SARS-CoV-2.

Authors

Michelle Meyer, Yuan Wang, Darin Edwards, Gregory R. Smith, Aliza B. Rubenstein, Palaniappan Ramanathan, Chad E. Mire, Colette Pietzsch, Xi Chen, Yongchao Ge, Wan Sze Cheng, Carole Henry, Angela Woods, LingZhi Ma, Guillaume B.E. Stewart-Jones, Kevin W. Bock, Mahnaz Minai, Bianca M. Nagata, Sivakumar Periasamy, Pei-Yong Shi, Barney S. Graham, Ian N. Moore, Irene Ramos, Olga G. Troyanskaya, Elena Zaslavsky, Andrea Carfi, Stuart C. Sealfon, Alexander Bukreyev

×

Abstract

The heterogeneity of human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here, we report that the frequencies of SCID-repopulating cells were greatly decreased in cord blood (CB) CD34+ HSCs and HPCs upon ex vivo culturing. Transcriptomic analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased, along with loss of stemness. Limiting dilution analysis revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial ROS (mitoROS) during ex vivo culturing. Using single-cell RNA-Seq analysis of the mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the adhesion GPCR G1–positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. Gene set enrichment analysis revealed that HSC signature genes including MSI2 and MLLT3 were enriched in CD34+CD133+ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culturing, which can be a reliable target for drug screening of agonists of HSC expansion.

Authors

Yandan Chen, Shuyi Fang, Qingwei Ding, Rongzhen Jiang, Jiefeng He, Qin Wang, Yuting Jin, Xinxin Huang, Sheng Liu, Maegan L. Capitano, Thao Trinh, Yincheng Teng, Qingyou Meng, Jun Wan, Hal E. Broxmeyer, Bin Guo

×

Abstract

BACKGROUND Investigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used positron emission tomography (PET) to image 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD.METHODS Sixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with [18F]AS2471907, a radioligand for 11β-HSD1.RESULTS Prefrontal-limbic 11β-HSD1 availability, estimated as [18F]AS2471907 volume of distribution (VT), was significantly higher in the PTSD group compared with the TC group (β = 1.16, P = 0.0057). Lower prefrontal-limbic 11β-HSD1 availability was related to greater overall PTSD severity (R2 = 0.27, P = 0.038) in the PTSD group. 11β-HSD1 availability was not related to plasma cortisol levels (R2 = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11β-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (β = 4.40, P = 0.039).CONCLUSION Higher brain cortisol–producing 11β-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11β-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD.FUNDING Brain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.

Authors

Shivani Bhatt, Ansel T. Hillmer, Aleksandra Rusowicz, Nabeel Nabulsi, David Matuskey, Gustavo A. Angarita, Soheila Najafzadeh, Michael Kapinos, Steven M. Southwick, John H. Krystal, Richard E. Carson, Yiyun Huang, Kelly P. Cosgrove

×

Abstract

Atrial natriuretic peptide (ANP) is an important hormone in cardiovascular biology. It is activated by the protease corin. In pregnancy, ANP and corin promote uterine spiral artery remodeling, but the underlying mechanism remains unknown. Here we report an ANP function in uterine decidualization and TNF-related apoptosis-inducing ligand–dependent (TRAIL-dependent) death in spiral arterial smooth muscle cells (SMCs) and endothelial cells (ECs). In ANP- or corin-deficient mice, uterine decidualization markers and TRAIL expression were decreased, whereas in cultured human endometrial stromal cells (HESCs), ANP increased decidualization and TRAIL expression. In uterine spiral arteries from pregnant wild-type mice, SMC and EC loss occurred sequentially before trophoblast invasion. In culture, TRAIL from decidualized HESCs induced apoptosis in uterine SMCs, but not in ECs with low TRAIL receptor expression. Subsequently, cyclophilin B was identified from apoptotic SMCs that upregulated endothelial TRAIL receptor and caused apoptosis in ECs. These results indicate that ANP promotes decidualization and TRAIL expression in endometrial stromal cells, contributing to sequential events in remodeling of spiral arteries, including SMC death and cyclophilin B release, which in turn induces TRAIL receptor expression and apoptosis in ECs.

Authors

Wei Zhang, Shuo Li, Jinglei Lou, Hui Li, Meng Liu, Ningzheng Dong, Qingyu Wu

×

Abstract

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.

Authors

Rebecca A. Porritt, Aleksandra Binek, Lisa Paschold, Magali Noval Rivas, Angela McArdle, Lael M. Yonker, Galit Alter, Harsha K. Chandnani, Merrick Lopez, Alessio Fasano, Jennifer E. Van Eyk, Mascha Binder, Moshe Arditi

×

Abstract

BACKGROUND Evidence supporting convalescent plasma (CP), one of the first investigational treatments for coronavirus disease 2019 (COVID-19), has been inconclusive, leading to conflicting recommendations. The primary objective was to perform a comparative effectiveness study of CP for all-cause, in-hospital mortality in patients with COVID-19.METHODS The multicenter, electronic health records–based, retrospective study included 44,770 patients hospitalized with COVID-19 in one of 176 HCA Healthcare–affiliated community hospitals. Coarsened exact matching (1:k) was employed, resulting in a sample of 3774 CP and 10,687 comparison patients.RESULTS Examination of mortality using a shared frailty model, controlling for concomitant medications, date of admission, and days from admission to transfusion, demonstrated a significant association of CP with lower mortality risk relative to the comparison group (adjusted hazard ratio [aHR] = 0.71; 95% CI, 0.59–0.86; P < 0.001). Examination of patient risk trajectories, represented by 400 clinico-demographic features from our real-time risk model (RTRM), indicated that patients who received CP recovered more quickly. The stratification of days to transfusion revealed that CP within 3 days after admission, but not within 4 to 7 days, was associated with a significantly lower mortality risk (aHR = 0.53; 95% CI, 0.47–0.60; P < 0.001). CP serology level was inversely associated with mortality when controlling for its interaction with days to transfusion (HR = 0.998; 95% CI, 0.997–0.999; P = 0.013), yet it did not reach univariable significance.CONCLUSIONS This large, diverse, multicenter cohort study demonstrated that CP, compared with matched controls, is significantly associated with reduced risk of in-hospital mortality. These observations highlight the utility of real-world evidence and suggest the need for further evaluation prior to abandoning CP as a viable therapy for COVID-19.FUNDING This research was supported in whole by HCA Healthcare and/or an HCA Healthcare–affiliated entity, including Sarah Cannon and Genospace.

Authors

Shanna A. Arnold Egloff, Angela Junglen, Joseph S.A. Restivo, Marjorie Wongskhaluang, Casey Martin, Pratik Doshi, Daniel Schlauch, Gregg Fromell, Lindsay E. Sears, Mick Correll, Howard A. Burris III, Charles F. LeMaistre

×

Abstract

Background Primary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.Methods In this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTs Patients on dulaglutide reduced their fluid intake by 490 mL (95% CI: –780, –199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by –943 mL (95% CI: –1473, –413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONS GLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registration Clinicaltrials.gov NCT02770885.Funding Swiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Authors

Bettina Winzeler, Clara O. Sailer, David Coynel, Davide Zanchi, Deborah R. Vogt, Sandrine A. Urwyler, Julie Refardt, Mirjam Christ-Crain

×

Abstract

Little is known about how cells regulate and integrate distinct biosynthetic pathways governing differentiation and cell division. For B lineage cells it is widely accepted that activated cells must complete several rounds of mitosis before yielding antibody-secreting plasma cells. However, we report that marginal zone (MZ) B cells, innate-like naive B cells known to generate plasma cells rapidly in response to blood-borne bacteria, generate functional plasma cells despite cell-cycle arrest. Further, short-term Notch2 blockade in vivo reversed division-independent differentiation potential and decreased transcript abundance for numerous mTORC1- and Myc-regulated genes. Myc loss compromised plasma cell differentiation for MZ B cells, and reciprocally induced ectopic mTORC1 signaling in follicular B cells enabled division-independent differentiation and plasma cell–affiliated gene expression. We conclude that ongoing in situ Notch2/mTORC1 signaling in MZ B cells establishes a unique cellular state that enables rapid division-independent plasma cell differentiation.

Authors

Brian T. Gaudette, Carly J. Roman, Trini A. Ochoa, Daniela Gómez Atria, Derek D. Jones, Christian W. Siebel, Ivan Maillard, David Allman

×

Abstract

BACKGROUND COVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.METHODS Patients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21.Results The primary outcome occurred in 43.4% of patients in the CCP group and 32.7% in the control group (P = 0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (P = 0.27). The median time to discharge from the hospital was 31 days in the CCP group and 51 days in the control group (P = 0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies, the primary outcome occurred in 56.0% of the patients (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days, P < 0.05) and to hospital discharge (21 vs. 51 days, P = 0.03) and better survival (day-60 probability of survival 91.6% vs. 68.1%, P = 0.02) in comparison with the control group.Conclusion CCP added to standard treatment was not associated with a significant improvement in the primary and secondary outcomes. A predefined subgroup analysis showed a significant benefit of CCP among patients who received a larger amount of neutralizing antibodies.Trial registration ClinicalTrials.gov NCT04433910.Funding Bundesministerium für Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802.

Authors

Sixten Körper, Manfred Weiss, Daniel Zickler, Thomas Wiesmann, Kai Zacharowski, Victor M. Corman, Beate Grüner, Lucas Ernst, Peter Spieth, Philipp M. Lepper, Martin Bentz, Sebastian Zinn, Gregor Paul, Johannes Kalbhenn, Matthias M. Dollinger, Peter Rosenberger, Thomas Kirschning, Thomas Thiele, Thomas Appl, Benjamin Mayer, Michael Schmidt, Christian Drosten, Hinnerk Wulf, Jan Matthias Kruse, Bettina Jungwirth, Erhard Seifried, Hubert Schrezenmeier, the CAPSID Clinical Trial Group

×

Abstract

BACKGROUND Passive immunotherapy with convalescent plasma (CP) is a potential treatment for COVID-19. Evidence from controlled clinical trials is inconclusive.METHODS We conducted a randomized, open-label, controlled clinical trial at 27 hospitals in Spain. Patients had to be admitted for COVID-19 pneumonia within 7 days from symptom onset and not on mechanical ventilation or high-flow oxygen devices. Patients were randomized 1:1 to treatment with CP in addition to standard of care (SOC) or to the control arm receiving only SOC. The primary endpoint was the proportion of patients in categories 5 (noninvasive ventilation or high-flow oxygen), 6 (invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), or 7 (death) at 14 days. Primary analysis was performed in the intention-to-treat population.RESULTS Between April 4, 2020, and February 5, 2021, 350 patients were randomly assigned to either CP (n = 179) or SOC (n = 171). At 14 days, proportion of patients in categories 5, 6, or 7 was 11.7% in the CP group versus 16.4% in the control group (P = 0.205). The difference was greater at 28 days, with 8.4% of patients in categories 5–7 in the CP group versus 17.0% in the control group (P = 0.021). The difference in overall survival did not reach statistical significance (HR 0.46, 95% CI 0.19–1.14, log-rank P = 0.087).CONCLUSION CP showed a significant benefit in preventing progression to noninvasive ventilation or high-flow oxygen, invasive mechanical ventilation or ECMO, or death at 28 days. The effect on the predefined primary endpoint at 14 days and the effect on overall survival were not statistically significant.TRIAL REGISTRATION Clinicaltrials.gov, NCT04345523.FUNDING Government of Spain, Instituto de Salud Carlos III.

Authors

Cristina Avendaño-Solá, Antonio Ramos-Martínez, Elena Muñez-Rubio, Belen Ruiz-Antorán, Rosa Malo de Molina, Ferran Torres, Ana Fernández-Cruz, Jorge Calderón-Parra, Concepcion Payares-Herrera, Alberto Díaz de Santiago, Irene Romera-Martínez, Ilduara Pintos, Jaime Lora-Tamayo, Mikel Mancheño-Losa, Maria L. Paciello, A.L. Martínez-González, Julia Vidán-Estévez, Maria J. Nuñez-Orantos, Maria Isabel Saez-Serrano, Maria L. Porras-Leal, Maria C. Jarilla-Fernández, Paula Villares, Jaime Pérez de Oteyza, Ascension Ramos-Garrido, Lydia Blanco, Maria E. Madrigal-Sánchez, Martin Rubio-Batllés, Ana Velasco-Iglesias, José R. Paño-Pardo, J.A. Moreno-Chulilla, Eduardo Muñiz-Díaz, Inmaculada Casas-Flecha, Mayte Pérez-Olmeda, Javier García-Pérez, Jose Alcamí, Jose L. Bueno, Rafael F. Duarte, the ConPlas-19 Study Group

×

In-Press Preview - More

Abstract

Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between pro-inflammatory and pro-resolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several pro-resolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×apolipoprotein E double KO background (hGPR32myc×Fpr2-/-×Apoe-/-), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2 and FOXP3. Atherosclerotic lesions, necrotic core and aortic inflammation were reduced in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice as compared to Fpr2-/-×Apoe-/- non-transgenic littermates. In a zymosan induced peritonitis model, the hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice had reduced inflammation at 4h and enhanced pro-resolving macrophage responses at 24h compared to non-transgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice but not in the Fpr2-/-×Apoe-/- non-transgenic littermates. Altogether these results provide the first evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.

Authors

Hildur Arnardottir, Silke Thul, Sven-Christian Pawelzik, Glykeria Karadimou, Gonzalo Artiach, Alessandro L. Gallina, Victoria Mysdotter, Miguel Carracedo, Laura Tarnawski, April S. Caravaca, Roland Baumgartner, Daniel F.J. Ketelhuth, Peder S. Olofsson, Gabrielle Paulsson-Berne, Göran K. Hansson, Magnus Bäck

×

Abstract

To delineate the in vivo role of different costimulatory signals in activating and expanding highly functional virus-specific cytotoxic CD8+ T cells, we designed synTacs, infusible biologics which recapitulate antigen-specific T-cell activation signals delivered by antigen-presenting cells. We constructed synTacs consisting of dimeric Fc-domain scaffolds linking CD28- or 4-1BB-specific ligands to HLA-A2 MHC molecules covalently-tethered to HIV- or CMV-derived peptides. Treatment of HIV-infected donor PBMCs with synTacs bearing HIV- or CMV-derived peptides induced vigorous and selective ex vivo expansion of highly functional HIV- and/or CMV-specific CD8+ T cells, respectively, with potent anti-viral activities. Intravenous injection of HIV or CMV-specific synTacs into immunodeficient mice intrasplenically engrafted with donor PBMCs markedly and selectively expanded HIV-specific (32-fold) or CMV-specific (46-fold) human CD8+ T cells populating their spleens, respectively. Notably, these expanded HIV or CMV-specific CD8+ T cells directed potent in vivo suppression of HIV or CMV infections, respectively, in the humanized mice providing strong rationale for consideration of synTac-based approaches as a therapeutic strategy to cure HIV and treat CMV and other viral infections. The synTac platform flexibility supports facile delineation of in vivo effects of different costimulatory signals on patient-derived virus-specific CD8+ T cells, enabling optimization of individualized therapies, including HIV cure strategies.

Authors

Mengyan Li, Scott J. Garforth, Kaitlyn E. O’Connor, Hang Su, Danica M. Lee, Alev Celikgil, Rodolfo J. Chaparro, Ronald D. Seidel, R. Brad Jones, Ravit Arav-Boger, Steven C. Almo, Harris Goldstein

×

Abstract

Genome-wide association studies (GWAS) involve testing genetic variants across the genomes of many individuals to identify genotype-phenotype associations. GWAS have enabled the identification of numerous genomic biomarkers in various complex human diseases including infectious ones. However, few of these studies are relevant for clinical practice or at the bedside. In this issue of the JCI, Nakanishi et al. characterized the clinical implications of a major genetic risk factor for COVID-19 severity and its age-dependent effect, using individual-level data in a large international multi-center consortium. This study indicates that a common COVID-19 genetic risk factor (rs10490770) associates with increased risks of morbidity and mortality, suggesting potential implications for future clinical risk management. How can the genomic biomarkers identified by GWAS be associated with the clinical outcomes of an infectious disease? In this commentary, we evaluate the advantages and limitations of this approach.

Authors

Vito Luigi Colona, Michela Bianocolella, Antonio Novelli, Giuseppe Novelli

×

Abstract

Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitors (SSRIs) antidepressants correlates with body weight gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased body weight by enhancing food intake in healthy mice at two different time points and through two distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through the Htr1a receptor. Upon longer treatment Flx blunted Htr2c expression/signaling, decreased the phosphorylation of Creb and Stat3 and dampened the production of POMC/α-MSH in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (MC4R) by co-treating mice with Flx and lipocalin-2, an anorexigenic hormone signaling through this receptor, normalized feeding and body weight. Flx and other SSRIs also inhibit CREB/STAT3 phosphorylation in a human neuronal cell line suggesting that these non-canonical effects could also occur in long-term users of SSRIs. By defining the molecular basis of the long-term SSRIs-associated weight gain this study proposes a therapeutic strategy to counter it.

Authors

Maria Jose Ortuno, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy

×

Abstract

BACKGROUND. A long-held dream of scientists is to transfer information directly to the visual cortex of blind individuals, thereby restoring a rudimentary form of sight. However, no clinically available cortical visual prosthesis yet exists. METHODS.We implanted an intracortical microelectrode array consisting of 96 electrodes in the visual cortex of a 57-year-old person with complete blindness for a six- month period. We measured thresholds and the characteristics of the visual percepts elicited by intracortical microstimulation. RESULTS. Implantation and subsequent explantation of intracortical microelectrodes were carried out without complications. The mean stimulation threshold for single electrodes was 66.8 ± 36.5 μA. We consistently obtained high-quality recordings from visually deprived neurons and the stimulation parameters remained stable over time. Simultaneous stimulation via multiple electrodes were associated with a significant reduction in thresholds (p<0.001, ANOVA test) and evoked discriminable phosphene percepts, allowing the blind participant to identify some letters and recognize object boundaries. Furthermore, we observed a learning process that helped the subject to recognize complex patterns over time. CONCLUSIONS. Our results demonstrate the safety and efficacy of chronic intracortical microstimulation via a large number of electrodes in human visual cortex, showing its high potential for restoring functional vision in the blind. TRIAL REGISTRATION. ClinicalTrials.gov identifier NCT02983370. FUNDING. Funding was provided by grant RTI2018-098969-B-100 from the Spanish Ministerio de Ciencia Innovación y Universidades, by grant PROMETEO/2019/119 from the Generalitat Valenciana (Spain), by the Bidons Egara Research Chair of the University Miguel Hernández (Spain) and by the John Moran Eye Center of the University of Utah (US).

Authors

Eduardo Fernández, Arantxa Alfaro, Cristina Soto-Sánchez, Pablo González-López, Antonio M. Lozano Ortega, Sebastian Peña, María Dolores Grima, Alfonso Rodil, Bernardeta Gómez, Xing Chen, Pieter R. Roelfsema, John D. Rolston, Tyler S. Davis, Richard A. Normann

×

Advertisement

October 2021 JCI This Month

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

×

Review Series - More

Circadian Rhythm

Series edited by Amita Sehgal

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

×