67% OFF of fixed price Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 Max 73% OFF

This fits your . Make sure this fits by entering your model number. ✅AERODYNAMIC CONCEPT :Minimal cycle saddle bag for all kinds of bikes, including MTB / mountain, road/race bikes, hybrid bike, and folding bike. The shape is designed to reduce air resistance to the minimum, for your high-speed cycling experience. ✅ LARGE OPENING amp; EXTRA MESH POCKET INSIDE: Big zipper opening can take all your essentials for the ride. Inner mesh compartment help keeping your accessories organized—a perfect place to store your foldable multitool, spare inner tube, charger, or extra cash. ✅EASY INSTALLATION: Nylon strap, buckle and velcro fixing help to secure the bag on the saddle rail and seatpost quickly. The attachment system is sturdy; you won't feel it move while riding at all. It is suitable for most types of bicycles. ✅REFLECTIVE DETAIL amp; LIGHT MOUNTING POINT: To enhance visibility at night, there are reflective trims and nylon strap for hanging tail light. ✅ENGINEERED TO ENDURE: Vincita bike under seat bags are engineered for durability and can take the daily conditions of biking. It is made of tough polyester material, which is water-resistant and easy to clean. Product Description WATER-RESISTANT FABRIC All our fabrics have a water-resistant coating such that it not to be penetrated by fluids. However, water can still penetrate after a certain level of water exposure through zipper and sewing seams. YKK ZIPPER The bag is made with YKK branded-zipper which is zipper with 100% reliability. ENJOY YOUR RIDE WITH VINCITA GEAR Cycling is me time. It’s when you enjoy the simplistic side of life. Get on your bike and set new goals for yourself today! Check out Vincita for all the tools, bags and accessories you need to ride comfortably. Whether it is just around the park or for a long or short tour, Vincita makes your ride more convenient. WHY CHOOSE VINCITA 33+ Years of Adventurous Innovation Founded in 1987, VINCITA is a Bangkok-based company dedicated to making modern and practical cycling bags. Today VINCITA cycling bags are being used everywhere from Boston in the USA to Singapore and Europe. Seeing photo from our customers worldwide is our greatest pride. Top-Notch Quality Our directors enjoy traveling, cycling and outdoor activities. Now aiming to bring more lifestyle-related designs to the market. We listen to what cyclists tell us about their ideal products, find better solutions to solve their problems and then create them in the VINCITA design studio with our passionate team. Engineered to Endure All Weather Conditions We constantly innovates to make better bike bags to meet the needs of the diverse cyclist. We began making prototypes and having it used by many adventurous cyclists. Designed amp; Sold From Passionate Cyclists Being travelers ourselves, we value the joy of traveling. Just like everyone else, we love seeing picturesque views of new places and finding new alternative routes. Also enjoy meeting new people, exchanging stories and watching how traveling slowly changes our perspective of life. . “One’s destination is never a place, but a new way of seeing things” - Henry Miller Wide selection of bicycle bags and accessories We offer all type of bags from small saddle bag to large bicycle transport bag. Our bags and tools are designed to make packing and cycling earlier. Whether you are headed into the wide or just navigating around the city. We know your love seeking new adventures. Your next trip will be fuss-free with bags made to fit perfectly to your bike and your needs. Let's travel more! WHO WE ARE WHO WE ARE Vincita is a Bangkok based cycling bag and accessories company. Our story started differently: when we took our friends' suggestion to start a bag business in 1987, we were not experienced cyclists, but the company has changed slowly and transformed us into one. Our bag ideas originally came from gathering insights from all types of cyclists. We talked about their lives, their concerns, and ideal products and the result is high-quality bag designs that meet the diverse requirement of cyclists. Bike Seats amp; Saddle Bag Bike Storage amp; Covers Bike Tools amp; Accessories Bike Bottle Cages amp; Racks Vincita Alien Saddle Bike Bag Vincita Alien Saddle Bike Bag Vincita Bike Saddle Bag for Pump Vincita Bicycle Seat Bag Large Vincita Bicycle Seat Bag Extra Large Quick-Release Fixing ✓ ✓ ✓ Strap Fixing ✓ ✓ Size Small Small Medium Large Extra Large Compartment 1 1 2 3 3 Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 Sports Outdoors => Sports => Cycling 67% OFF of fixed price Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 Max 73% OFF Vincita STASH Pack Alien Small Strap Fixing Bike Saddle Bag Big Hight Quality Guaranteed we are a team of professionals who are working hard to provide you with the best products at the best prices, delivered to your door as soon as possible. It's a nice bag but very little thought went into the Velcro support patches. Even the slightest load inside the bag will cause the Velcro patches to break free allowing the bag to drop into the lowered position.The Velcro patches are way too small and to add to the ineffectiveness, they are carelessly positioned so that what little contact surface there is between the hook and loop patches is compromised by misalignment.I'm having to modify the bag in order to make it usable.Great size, not too big, not too small. Fits tube, three pry bars, pocket tool, CO2 cartridge and head and one stubby 15 mm wrench. Enough room to spare for a set of keys and wallet. One of the better looking under the saddle bags (camo colorway).Well made saddle bag and fits nicely under my road bike seat. It's a tad bigger then I anticipated but truthfully you can't tell and the added space is appreciated. I like the camo accent to the bag also! Good buy over all for the price.Nice quality bag, a little to small for a phone but does hold other essentialsI got this for the stash. Usually Stash is good for you. But if someone else finds it, it usually goes bad. The Alien was a bonus. ????. Just a joke. There are no Aliens.The straps to attach the bag under the seat cannot be adjusted enough to get a tight fit under the saddle of a road bike. the bag would flap in the wind. Sending it back.Fell apart at the upper seam right outside of amazon return window.Awesome under-seat stash bag. Feels very durable and reinforced. Highly recommend.
  • Volume 131, Issue 22
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67% OFF of fixed price Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 Max 73% OFF

Siska et al. provide evidence for immunometabolic dysregulation in COVID-19, which can be mitigated by dexamethasone treatment. Image credit: Thomas Simeth.

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Commentaries
Abstract

Despite recent therapeutic gains in the treatment of advanced bladder cancer, the overall survival in patients with metastatic disease remains poor and further therapeutic discovery is needed. Advanced bladder cancer is a molecularly heterogeneous disease, and the identification of driver genetic alterations has led to effective targeted therapeutic agents, such as fibroblast growth factor receptor (FGFR) inhibitors. In this issue of the JCI, Bekele et al. identify a subtype of muscle-invasive bladder cancer (MIBC) that harbors RAF1 amplification. The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.

Authors

Sean Clark-Garvey, William Y. Kim

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Abstract

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD.

Authors

Beste Mutlu, Pere Puigserver

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Abstract

HIV and Mycobacterium tuberculosis (M. tuberculosis) coinfection increases the risk of active tuberculosis (aTB), but how HIV infection and medications contribute to drive risk remains unknown. In this issue of the JCI, Correa-Macedo and Fava et al. investigated alveolar macrophages (AMs) from people living with HIV (PLWH). To mimic the earliest event in tuberculosis (TB), the authors isolated AMs from broncheoalveolar lavage (BAL) of PLWH, healthy individuals, and healthy individuals taking antitretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition. These AMs were exposed to M. tuberculosis and epigenetic configuration, transcriptional responses, and cytokine production were assessed. M. tuberculosis–stimulated AMs from PLWH and from healthy individuals on PrEP showed blunted responses compared with healthy controls. While HIV infection is the major risk factor for TB, these findings suggest that ART may modulate AM responses and potentially contribute to residual risk of aTB in fully treated HIV.

Authors

Eileen P. Scully, Bryan D. Bryson

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Abstract

APOL1 G1 and G2 variants are established risk factors for nondiabetic kidney disease. The presence of two APOL1 risk variants in donor kidneys negatively impacts kidney allograft survival. Because of evolutionary pressure, the APOL1 risk variants have become common in people from Africa and in those with recent African ancestry. APOL1 risk variant proteins are expressed in kidney cells and can cause toxicity to these cells. In this issue of the JCI, Zhang, Sun, and colleagues show that recipient APOL1 risk variants negatively affect kidney allograft survival and T cell–mediated rejection rates, independent of donor APOL1 genotype or recipient ancestry. The authors provide evidence that APOL1 risk variants play an immunomodulatory role in T cells and NK cells in the setting of kidney transplantation. These findings have important clinical implications that require further investigation.

Authors

Andrew F. Malone

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Abstract

Hypertriglyceridemia is associated with obesity, diabetes, and atherosclerosis. While lipoprotein lipase (LPL) hydrolyzes triglyceride (TG) cargo into remnant lipoproteins with atherogenic properties, how remnant lipoprotein clearance relates to atherosclerosis in people with diabetes remains unclear. In this issue of the JCI, Shimizu-Albergine et al. examined the effects of the basic leucine zipper transcription factor CREBH, which induces genes that activate LPL in mouse models of type I diabetes. Overexpression of a CREBH fragment reduced apolipoprotein C3 (APOC3) levels, which reduced plasma TGs. Notably, the TGs were lowered by a mechanism that was independent of LPL, and atherosclerosis was alleviated by enhanced lipoprotein remnant clearance as opposed to increased lipolysis of TG-rich lipoprotein precursors. A proinflammatory mechanism likely underlies the atherogenicity of remnant lipoproteins. These findings suggest that modifying CREBH expression in the liver may ameliorate atherosclerosis and, perhaps, other diabetes complications.

Authors

Alan D. Attie

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Research Articles
Abstract

Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of Streptococcus pneumoniae was impaired in Ephx2-deficient (Ephx2–/–) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist EEZE restored lung clearance of S. pneumoniae in Ephx2–/– mice. Ephx2–/– mice had normal lung Il1b, Il6, and Tnfa expression levels and macrophage recruitment to the lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation, and Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1/2) and cell division control protein 42 homolog (Cdc42) activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2–/– macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and peptidoglycan recognition protein 1 (PGLYRP1) in Ephx2–/– macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduced macrophage activation and phagocytosis of S. pneumoniae through the downregulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to the development of new therapeutic approaches for bacterial diseases.

Authors

Hong Li, J. Alyce Bradbury, Matthew L. Edin, Joan P. Graves, Artiom Gruzdev, Jennifer Cheng, Samantha L. Hoopes, Laura M. DeGraff, Michael B. Fessler, Stavros Garantziotis, Shepherd H. Schurman, Darryl C. Zeldin

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Abstract

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1−/− mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Authors

Taisuke Kato, Ri-ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

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Abstract

Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g., sodium stibogluconate [SSG]) remain first-line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan patients with CL at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared with noninfected lesional CD68+ monocytes and macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti–leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as a predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host-directed therapeutic in leishmaniasis.

Authors

Nidhi S. Dey, Sujai Senaratne, Vijani Somaratne, Nayani P. Madarasinghe, Bimalka Seneviratne, Sarah Forrester, Marcela Montes de Oca, Luiza Campos Reis, Srija Moulik, Pegine B. Walrad, Mitali Chatterjee, Hiro Goto, Renu Wickremasinghe, Dimitris Lagos, Paul M. Kaye, Shalindra Ranasinghe

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Abstract

Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.

Authors

Leeanna El-Houjeiri, Marco Biondini, Mathieu Paquette, Helen Kuasne, Alain Pacis, Morag Park, Peter M. Siegel, Arnim Pause

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Abstract

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7–independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Authors

Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley

×

Abstract

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Authors

67% OFF of fixed price Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 Max 73% OFF

Health Household => Diet Sports Nutrition => Minerals It has helped even in the short 2 weeks that I've had it an I can already tell a difference. Thanks ChemboysI like this just as much as the Cali magic. My little guys and my bigger guys are liking it too. Here's something you guys should know I received a separate product from this manufacturer for review through Amazon Vine and it arrived leaking. I reached out directly to Chem Boys. Amazon wanted me to return it, couldn't return it wouldn't survive shipping. So the manufacturer is absorbing the cost to send me an identical product and the cost of shipping just so that I have a full container to give you guys a review with. So that's how much these people appreciate their customers and want their customers happy and growing with their products. I think that needs to be that needs to be supported guys, so I just felt that I should share my experience with this manufacturer on a different product they stood behind it and took care of me. Happy growing everyone.If you've ever noticed your plants take on a washed-out, yellowed look especially after a huge rain, this stuff brings them back to healthy pretty quickly. You can see a big difference in one day--the leaves come back to a healthy green. I am trying a little bit of it on just about everything and it's a big improvement. It's not cheap, you can save money by buying the bigger jugs of it. The directions on the sticker are so small you will need a magnifying glass. Discounts Outlet Sale Clearance Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 This fits your . Make sure this fits by entering your model number. ✅ [ Corrects Common Plant Deficiencies ] – Chemboys XL Cal-Mag Plant Supplement will give your plants supplemental calcium and magnesium to bloom stronger and healthier than ever before! This 2-0-0 NPK plant fertilizer can be used in hydroponics, coco coir, soil and many other environments. ✅ [ Corrects Common Plant Deficiencies ] – Chemboys XL Cal-Mag Plant Supplement will give your plants supplemental calcium and magnesium to bloom stronger and healthier than ever before! This 2-0-0 NPK plant fertilizer can be used in hydroponics, coco coir, soil and many other environments. ???? [ Increase Bloom Size amp; Crop Yield ] – Calcium amp; Magnesium are 2 crucial nutrients in a plant’s ecosystem. It is critical to provide your plant with these minerals and vitamins throughout all stages of growth, especially in heavily fruiting plants and fast blooming annuals. This Cal Mag supplement will help your plants bloom and yield like never before! ???? [ Liquid Plant Nutrient Fertilizer ] – Unlike other plant foods that are made of powder and other hard-to-apply substances, this Cal Mag liquid fertilizer is 100% liquid. This means you can simply add water to the concentrate supplement and pour it directly onto the soil. Even use it as a spray for your vegetables, fruits and other crops! ????【 Stronger, Healthier amp; Larger Plants 】 – This calcium and magnesium plant nutritional supplement will help the plant increase chlorophyll levels, create thicker cell walls for strength and protection, as well as enhance root mass for larger yields and blooms. It is a must have for home gardens and even commercial industries! ???? [ Manufactured in USA ] – We at Chemboys take pride in manufacturing our calcium amp; magnesium plant supplement 100% in the United States. This ensures ultimate environmental protection, plant growth ability, premium fertilization, optimal hydroponics and most of all, safety for our customers. Help support an American business today! Product Description Chemboys XL Cal-Mag Plant Supplement 2-0-0 Looking for a liquid plant food supplement that corrects common plant deficiencies? Tired of malnourished crops, vegetables, fruits and flowers that don’t grow to their full potential? Then you have found the perfect product! This Cal-Mag plant supplement is tested or inspected numerous times throughout the manufacturing process to maintain optimal nutrient absorption, plant growth and bloom/yield increasing ability. This liquid fertilizer gives your plant the crucial minerals it needs to thrive at every stage of the growing process. It provides unbelievable benefits for your garden, crops, vegetables, flowers, seedlings and lawns! Essential Plant Supplement If you are looking to boost yields in fruiting and flowering plant varieties then look no further! Magnesium amp; Calcium are the most essential vitamins and minerals in all parts of the plants growth cycle. Give your garden and crops the TLC they need with this awesome liquid fertilizer! Suitable For All Growing Styles amp; Soil Types Use this liquid plant food with all growing styles, whether it be hydroponic, coco, soil or other environments. It is compatible with all growing mediums and watering methods, as well as extremely easy to apply to plants. For Use with other Chemboys Nutrient Solutions When combined with other Chemboys liquid fertilizer products, this Cal Mag plant supplement will give your plant all the tools it needs to thrive and product unbelievable yields! Whether you want to help grow your home lawn, or have a business that relies on crop yields and bloom, this product will be perfect for you! We offer multiple sizes for bulk or daily use. We want to be your partner! Chemboys Organic Humic Liquid This Organic Humic Acid with Fulvic plant food enhancer is tested or inspected numerous times throughout the manufacturing process to maintain optimal nutrient absorption, plant drought tolerance and soil conditioning. This liquid carbon concentrate gives your plant the crucial minerals it needs to thrive at every stage of the growing process. It provides unbelievable benefits for your garden, crops, vegetables, flowers, seedlings and lawns! Chemboys Silicon Shield This Chemboys Silica Plant Supplement is tested or inspected numerous times throughout the manufacturing process to maintain optimal nutrient absorption, plant cell strengthening and ability to withstand harsh environmental stress. This liquid silicate gives your plant the crucial minerals it needs to thrive at every stage of the growing process. It provides unbelievable benefits for your garden, crops, vegetables, flowers, seedlings and lawns! Chemboys Nutrient Alpha This “Alpha” liquid plant growth boost is tested or inspected numerous times throughout the manufacturing process to maintain optimal nutrient absorption, plant photosynthesis and bloom/yield increasing ability. When combined with the “Beta” liquid nutrients, they work together to give your plant the minerals it needs to thrive at every stage of the growing process. It provides unbelievable benefits for your garden, crops, vegetables, flowers, seedlings and lawns! Chemboys Super Kelp Fertilizer Chemboys Liquid Seaweed Fertilizer is a supplemental plant food to help your seedlings, lawns, gardens, lawns, fruits and vegetables grow and thrive! It stimulates natural root growth, nutrient uptake and overall plant tenacity. Use 12mL of liquid kelp concentrate per gallon of water for long-lasting fertilization! Quality chemicals. Our goal is to improve the cultivation industry with high quality, ultra pure chemicals backed by experienced and professional chemists who know the industry inside and out. Manufactured amp; Bottled In USA __________________________________ Rest easy knowing that this liquid seaweed plant fertilizer is manufactured, bottled and labeled in the United States of America. We take pride in creating American jobs and always focusing on creating an optimal end product for our customers! Chemboys XL Cal-Mag Plant Supplement, 2-0-0 – Calcium Magnesiu you can then use our order tracking system to track the status of your order. we even offer a text messaging service; just fill in your mobile details when you order - it's that easy! 67% OFF of fixed price Deck Belt for for Kubota, Rck54-23Zg, Rck54Gr 258-113, 258113 Max 73% OFF

Zhongyang Zhang, Zeguo Sun, Jia Fu, Qisheng Lin, Khadija Banu, Kinsuk Chauhan, Marina Planoutene, Chengguo Wei, Fadi Salem, Zhengzi Yi, Ruijie Liu, Paolo Cravedi, Haoxiang Cheng, Ke Hao, Philip J. O’Connell, Shuta Ishibe, Weijia Zhang, Steven G. Coca, Ian W. Gibson, Robert B. Colvin, John Cijiang He, Peter S. Heeger, Barbara Murphy, Madhav C. Menon

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Abstract

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Trib1 (Trib1Δhep) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of Trib1Δhep but not Trib1Δhep CebpaΔhep mice. ATF3 has been shown to directly bind to the CEBPα protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in Trib1Δhep mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBPα, which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C.

Authors

Katherine Quiroz-Figueroa, Cecilia Vitali, Donna M. Conlon, John S. Millar, John W. Tobias, Robert C. Bauer, Nicholas J. Hand, Daniel J. Rader

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Abstract

Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.

Authors

Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw

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Abstract

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up- and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.

Authors

Wilian Correa-Macedo, Vinicius M. Fava, Marianna Orlova, Pauline Cassart, Ron Olivenstein, Joaquín Sanz, Yong Zhong Xu, Anne Dumaine, Renata H.M. Sindeaux, Vania Yotova, Alain Pacis, Josée Girouard, Barbara Kalsdorf, Christoph Lange, Jean-Pierre Routy, Luis B. Barreiro, Erwin Schurr

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Abstract

The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine–regulated transfer RNA–derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.

Authors

Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng

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Abstract

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non–COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Authors

Peter J. Siska, Sonja-Maria Decking, Nathalie Babl, Carina Matos, Christina Bruss, Katrin Singer, Jana Klitzke, Marian Schön, Jakob Simeth, Josef Köstler, Heiko Siegmund, Ines Ugele, Michael Paulus, Alexander Dietl, Kristina Kolodova, Louisa Steines, Katharina Freitag, Alice Peuker, Gabriele Schönhammer, Johanna Raithel, Bernhard Graf, Florian Geismann, Matthias Lubnow, Matthias Mack, Peter Hau, Christopher Bohr, Ralph Burkhardt, Andre Gessner, Bernd Salzberger, Ralf Wagner, Frank Hanses, Florian Hitzenbichler, Daniel Heudobler, Florian Lüke, Tobias Pukrop, Wolfgang Herr, Daniel Wolff, Rainer Spang, Hendrik Poeck, Petra Hoffmann, Jonathan Jantsch, Christoph Brochhausen, Dirk Lunz, Michael Rehli, Marina Kreutz, Kathrin Renner

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Abstract

Ribonuclease 7 (RNase 7) is an antimicrobial peptide that prevents urinary tract infections (UTI); however, it is yet unknown how RNASE7 genetic variations affect its antimicrobial activity and its mitigation of UTI risk. This study determined whether the RNASE7 SNP rs1263872 is more prevalent in children with UTI and defined how rs1263872 affects RNase 7’s antimicrobial activity against uropathogenic E. coli (UPEC). We performed genotyping for rs1263872 in 2 national UTI cohorts, including children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux trial or the Careful Urinary Tract Infection Evaluation study. Genotypes from these cohorts were compared with those of female controls with no UTI. To assess whether rs1263872 affects RNase 7’s antimicrobial activity, we generated RNase 7 peptides and genetically modified urothelial cultures encoding wild-type RNase 7 and its variant. Compared with controls, girls in both UTI cohorts had an increased prevalence of the RNASE7 variant. Compared with the missense variant, wild-type RNase 7 peptide showed greater bactericidal activity against UPEC. Wild-type RNase 7 overexpression in human urothelial cultures reduced UPEC invasive infection compared with mutant overexpression. These results show that children with UTI have an increased prevalence of RNASE7 rs1263872, which may increase UTI susceptibility by suppressing RNase 7’s antibacterial activity.

Authors

Keith R. Pierce, Tad Eichler, Claudia Mosquera Vasquez, Andrew L. Schwaderer, Aaron Simoni, Steven Creacy, David S. Hains, John D. Spencer

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Abstract

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

Authors

Nan Jin, Bhumsuk Keam, Janice Cho, Michelle J. Lee, Hye Ryun Kim, Hayarpi Torosyan, Natalia Jura, Patrick K.S. Ng, Gordon B. Mills, Hua Li, Yan Zeng, Zohar Barbash, Gabi Tarcic, Hyunseok Kang, Julie E. Bauman, Mi-Ok Kim, Nathan K. VanLandingham, Danielle L. Swaney, Nevan J. Krogan, Daniel E. Johnson, Jennifer R. Grandis

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Abstract

We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin–specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.

Authors

Marco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco

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Abstract

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.

Authors

Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang

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Abstract

Air pollution is a well-known contributor to asthma. Air toxics are hazardous air pollutants that cause or may cause serious health effects. Although individual air toxics have been associated with asthma, only a limited number of studies have specifically examined combinations of air toxics associated with the disease. We geocoded air toxic levels from the US National Air Toxics Assessment (NATA) to residential locations for participants of our AiRway in Asthma (ARIA) study. We then applied Data-driven ExposurE Profile extraction (DEEP), a machine learning–based method, to discover combinations of early-life air toxics associated with current use of daily asthma controller medication, lifetime emergency department visit for asthma, and lifetime overnight hospitalization for asthma. We discovered 20 multi–air toxic combinations and 18 single air toxics associated with at least 1 outcome. The multi–air toxic combinations included those containing acrylic acid, ethylidene dichloride, and hydroquinone, and they were significantly associated with asthma outcomes. Several air toxic members of the combinations would not have been identified by single air toxic analyses, supporting the use of machine learning–based methods designed to detect combinatorial effects. Our findings provide knowledge about air toxic combinations associated with childhood asthma.

Authors

Yan-Chak Li, Hsiao-Hsien Leon Hsu, Yoojin Chun, Po-Hsiang Chiu, Zoe Arditi, Luz Claudio, Gaurav Pandey, Supinda Bunyavanich

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Abstract

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride–induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.

Authors

Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton

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Abstract

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid–length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase–associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer–associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Authors

Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang

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Abstract

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH’s ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe–/– mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Authors

Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt

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Corrigendum

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Abstract

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

Authors

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

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Abstract

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

Authors

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

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Abstract

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

Authors

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

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Abstract

Various population of cells are recruited to the heart after cardiac injury but little is known about whether the cardiomyocyte directly regulates heart repair. In a murine model of ischemic cardiac injury, we demonstrate that the cardiomyocyte plays a pivotal role in heart repair by regulating nucleotide metabolism and fates of non-myocytes. Cardiac injury induced the expression of the ectonucleotidase ENPP1 that hydrolyzes extracellular ATP to form AMP. In response to AMP, the cardiomyocyte released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at OMP synthesis step, induced genotoxic stress and a p53 mediated cell death of cycling non-myocytes. As non-myocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors on small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in non-myocyte cells, augmented cardiac repair and post infarct heart function. These observations demonstrate that the cardiac muscle cell by releasing adenine and specific nucleosides after heart injury regulates pyrimidine metabolism in non-muscle cells and provide insight into how inter-cellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.

Authors

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

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Abstract

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

Authors

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

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November 2021 JCI This Month

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

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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.

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