Rust,,Fuel,POR-15,8,Leaks,-,Stops,Corrosion,,Tank,oz,-,/immunologic71722.html,Automotive , Paint Paint Supplies , Paints Primers,Sealer,therunclub.in,$11 Rust,,Fuel,POR-15,8,Leaks,-,Stops,Corrosion,,Tank,oz,-,/immunologic71722.html,Automotive , Paint Paint Supplies , Paints Primers,Sealer,therunclub.in,$11 $11 POR-15 Fuel Tank Sealer - 8 oz - Stops Rust, Corrosion, Leaks Automotive Paint Paint Supplies Paints Primers POR-15 Fuel Tank Sealer - 8 Leaks overseas Rust oz Stops Corrosion POR-15 Fuel Tank Sealer - 8 Leaks overseas Rust oz Stops Corrosion $11 POR-15 Fuel Tank Sealer - 8 oz - Stops Rust, Corrosion, Leaks Automotive Paint Paint Supplies Paints Primers

POR-15 Fuel Tank Sealer - 8 Leaks overseas Rust oz Ranking TOP14 Stops Corrosion

POR-15 Fuel Tank Sealer - 8 oz - Stops Rust, Corrosion, Leaks

$11

POR-15 Fuel Tank Sealer - 8 oz - Stops Rust, Corrosion, Leaks

|||

Product description

Size:8 fl. oz.

POR-15 Fuel Tank Sealer is a high-tech sealer impervious to all fuels, including the new Stage II fuels which have a higher alcohol content, and additives. It has superior strength and fuel resistance. POR-15 Fuel Tank Sealer stops rust, corrosion, and fuel leaks.

POR-15 Fuel Tank Sealer - 8 oz - Stops Rust, Corrosion, Leaks

Issue published September 15, 2021 Previous issue

On the cover: Natural killer cell suppression of T cells

In this issue, Ali et al. report that CXCR3-dependent localization of NK cells in T cell zones is vital for immunoregulatory suppression of T cell responses. The cover image shows T cells (purple), B cells (red), and NK cells (green) in the lymphoid follicles of a mouse spleen

S Indicates subscriber content

APSA Presidential Address
Letters to the Editor
Conversations with Giants in Medicine
Abstract

Authors

Ushma Neill

×
AAP Presidential Address
ASCI Presidential Address
Viewpoint
Review Series
Abstract

Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain “connectome” has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain “connectome” and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.

Authors

Michael D. Gershon, Kara Gross Margolis

×
Review
Abstract

Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the “balanced” proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.

Authors

Peter S. Choi, Andrei Thomas-Tikhonenko

×
Commentaries
Abstract

Natural killer (NK) cells play an important role in host defense against viral infections and malignancy, and their role for regulating other components of the antiviral response is being investigated. In this issue of the JCI, Ali et al. examine the mechanisms by which NK cells migrate into the white pulp and mediate suppression of virus-specific T cells. Herein, the authors show that an acute lymphocytic choriomeningitis virus (LCMV) infection induced a potent type I IFN (IFN-I) response that resulted in the expression of chemokine receptor CXCR3 ligands and permitted NK cell trafficking to T cell zones. Collectively, these findings have broad implications for vaccination strategies and warrant further investigation into the transcriptomic profiles of these regulatory NK cells.

Authors

Tonya J. Webb

×

Abstract

T cell exhaustion is an evocative concept that results in attenuated function in the face of chronic antigen exposure and is critical to avoid immunopathology. However, tumors often exploit this dampened T cell function to escape the antitumor immune response. In this issue of the JCI, You et al. investigated a different aspect of T cell exhaustion in the setting of tumor immunity by characterizing the capacity of T cells for tireless migration. The dynamic nature of normal T cells was first made famous by intravital microscopy studies in explanted tissues. You et al. used a similar imaging strategy with reanimated human tumors, in which exhausted T cells displayed an enhanced capacity for intratumoral motility. These results suggest that exhausted T cells may be able to teach T cell engineers lessons about navigating within the tumor microenvironment.

Authors

Michael L. Dustin

×

Abstract

Papillary thyroid cancer (PTC) is the most common form of differentiated thyroid cancer in the pediatric population and represents the second most common malignancy in adolescent females. Historically, PTC has been classified on the basis of histology, however, accumulating data indicate that molecular subtyping based on somatic oncogenic alterations along with gene expression profiling can better predict clinical behavior and may provide opportunities to incorporate oncogene-specific inhibitory therapy to improve the response to radioactive iodine (RAI). In this issue of the JCI, Y.A. Lee, H. Lee, and colleagues showed that oncogenic fusions were more commonly associated with invasive disease, increased expression of MAPK signaling pathway genes (ERK score), and decreased expression of the sodium-iodine symporter, which was restored by RET- and NTRK-inhibitory therapy. These findings lend credence to the idea of reclassifying pediatric thyroid cancers using a three-tiered system, rather than the two-tiered adult system, and open avenues for the treatment of progressive, RAI-refractory PTC in patients.

Authors

Aime T. Franco, Julio C. Ricarte-Filho, Theodore W. Laetsch, Andrew J. Bauer

×

Abstract

Disrupted sleep and circadian rhythms are linked with substance abuse risk. Human studies that investigate relationships between sleep, circadian rhythm, and substance use reward generally rely on indirect means to infer dopaminergic function, such as functional magnetic resonance imaging. In this issue of the JCI, Zhang and colleagues used positron emission tomography (PET) to image striatal dopamine D1 (D1R) and D2/3 receptor (D/3R) availability in healthy adults. The authors assessed rest-activity rhythms, then conducted PET scans using radioligand antagonists selective for D1 receptors or D2/D3 receptors to measure D1R and D2/3R availability. They also measured the subjective drug effects of oral methylphenidate. Higher D1R availability in caudate and a greater methylphenidate reward sensitivity were associated with delayed rest-activity rhythms. Unexpectedly, lower overall activity was associated with higher D2/3R availability in the nucleus accumbens, which coincided with greater methylphenidate reward score. These findings may inform personalized prevention and/or treatment interventions.

Authors

Brant P. Hasler, Colleen A. McClung

×

Abstract

Hypertension is a leading cause of cognitive impairment and dementias. Such loss of brain health has a vascular component, but the mechanisms involved are poorly defined. In this issue of the JCI, Koide et al. provide evidence that end-organ effects of hypertension on capillary endothelium and inward-rectifier K+ channels (Kir2.1) impair integrated propagation of electrical signals and vasodilation upstream, resulting in reduced neurovascular coupling (NVC) despite neural activation. NVC was partly restored by amlodipine, but not losartan. Moreover, NVC was improved by eplerenone in the presence of losartan, suggesting a role for aldosterone. These findings support the concept that endothelial cells and Kir2.1 are potential therapeutic targets to prevent or reverse the loss of NVC and the vascular component of cognitive deficits that occur with increased frequency during hypertension.

Authors

Frank M. Faraci

×

Abstract

Tanycytes are specialized radial glial cells of the hypothalamus that have emerged as important players that sense and respond to fluctuations in whole-body energy status to maintain energy homeostasis. However, the underlying mechanisms by which tanycytes influence energy balance remain incompletely understood. In this issue of the JCI, Lhomme et al. used transgenic mouse models, pharmacological approaches, and electrophysiology to investigate how tanycytes sense glucose availability and integrate metabolic cues into a lactate tanycytic network that fuels pro-opiomelanocortin (POMC) neuronal activity. Notably, the authors found that the tanycytic network relied on monocarboxylate transporters and connexin-43 gap junctions to transfer lactate to POMC neurons. Collectively, this study places tanycytes at the center of the intercellular communication processes governing energy balance.

Authors

Roberta Haddad-Tóvolli, Marc Claret

×
Research Articles
Abstract

Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the arcuate nucleus of the hypothalamus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive connexin-43 gap junction–mediated metabolic networks by arcuate tanycytes. Selective suppression of either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.

Authors

Tori Lhomme, Jerome Clasadonte, Monica Imbernon, Daniela Fernandois, Florent Sauve, Emilie Caron, Natalia da Silva Lima, Violeta Heras, Ines Martinez-Corral, Helge Mueller-Fielitz, Sowmyalakshmi Rasika, Markus Schwaninger, Ruben Nogueiras, Vincent Prevot

×

Abstract

IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn–/–), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn–/– Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β–induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

Authors

Anaïs Levescot, Margaret H. Chang, Julia Schnell, Nathan Nelson-Maney, Jing Yan, Marta Martínez-Bonet, Ricardo Grieshaber-Bouyer, Pui Y. Lee, Kevin Wei, Rachel B. Blaustein, Allyn Morris, Alexandra Wactor, Yoichiro Iwakura, James A. Lederer, Deepak A. Rao, Julia F. Charles, Peter A. Nigrovic

×

Abstract

Intratumoral T cells that might otherwise control tumors are often identified in an “exhausted” state, defined by specific epigenetic modifications and upregulation of genes such as CD38, cytotoxic T-lymphocyte–associated protein 4 (CTLA4), and programmed cell death 1 (PD1). Although the term might imply inactivity, there has been little study of this state at the phenotypic level in tumors to understand the extent of their incapacitation. Starting with the observation that T cells move more quickly through mouse tumors the longer they reside there and progress toward exhaustion, we developed a nonstimulatory, live-biopsy method for the real-time study of T cell behavior within individual patient tumors. Using 2-photon microscopy, we studied native CD8+ T cell interaction with antigen-presenting cells (APCs) and cancer cells in different microniches of human tumors and found that T cell speed was variable by region and by patient and was inversely correlated with local tumor density. Across a range of tumor types, we found a strong relationship between CD8+ T cell motility and the exhausted T cell state that corresponded with our observations made in mouse models in which exhausted T cells moved faster. Our study demonstrates T cell dynamic states in individual human tumors and supports the existence of an active program in “exhausted” T cells that extends beyond incapacitating them.

Authors

Ran You, Jordan Artichoker, Adam Fries, Austin W. Edwards, Alexis J. Combes, Gabriella C. Reeder, Bushra Samad, Matthew F. Krummel

×

Abstract

BACKGROUND Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODS PTC samples from 106 pediatric patients (age range: 4.3–19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983–March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTS We identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONS In pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDING The Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATION Two patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Authors

Young Ah Lee, Hyunjung Lee, Sun-Wha Im, Young Shin Song, Do-Youn Oh, Hyoung Jin Kang, Jae-Kyung Won, Kyeong Cheon Jung, Dohee Kwon, Eun-Jae Chung, J. Hun Hah, Jin Chul Paeng, Ji-hoon Kim, Jaeyong Choi, Ok-Hee Kim, Ji Min Oh, Byeong-Cheol Ahn, Lori J. Wirth, Choong Ho Shin, Jong-Il Kim, Young Joo Park

×

Abstract

Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. The actions of insulin and IGF-1 through the insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of forkhead box O (FoxO) transcription factors, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed in muscle-specific FoxO1, -3, and -4 triple-KO (M-FoxO TKO) mice rendered diabetic with STZ. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR KO (M-IR–/–) or combined IR/IGF1R KO (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR, IGF1R, and FoxO1, -3, and -4 quintuple-KO mice (M-QKO). Acute tamoxifen-inducible deletion of IR and IGF1R also decreased muscle pyruvate respiration, complex I activity, and supercomplex assembly. Although autophagy was increased when IR and IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-Seq revealed that complex I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO KO in STZ-FoxO TKO and M-QKO mice. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex I–driven mitochondrial respiration and supercomplex assembly in part by FoxO-mediated repression of complex I subunit expression.

Authors

Gourav Bhardwaj, Christie M. Penniman, Jayashree Jena, Pablo A. Suarez Beltran, Collin Foster, Kennedy Poro, Taylor L. Junck, Antentor O. Hinton Jr., Rhonda Souvenir, Jordan D. Fuqua, Pablo E. Morales, Roberto Bravo-Sagua, William I. Sivitz, Vitor A. Lira, E. Dale Abel, Brian T. O’Neill

×

Abstract

NK cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4+ T cells during the first 3 days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we showed that NK cell suppression of T cells is associated with transient accumulation of NK cells within T cell–rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 was required for this relocation and suppression of antiviral T cells. Accordingly, NK cell migration was mediated by type I IFN–dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induced type I IFN and did not stimulate NK cell inhibition of T cells also did not promote measurable redistribution of NK cells to T cell zones. Exogenous IFN rescued NK cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 were critical for properly positioning NK cells to constrain antiviral T cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.

Authors

Ayad Ali, Laura M. Canaday, H. Alex Feldman, Hilal Cevik, Michael T. Moran, Sanjeeth Rajaram, Nora Lakes, Jasmine A. Tuazon, Harsha Seelamneni, Durga Krishnamurthy, Eryn Blass, Dan H. Barouch, Stephen N. Waggoner

×

Abstract

BACKGROUND Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.METHODS We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and patients with short telomere syndromes with and without MDS/AML, and we tested the functional significance of these mutations.RESULTS While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least 1 (P < 0.001), and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations, which were present in 19%, another 13% of patients carried a mutation in POT1 or TERF2IP. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in 6 telomere-related genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2–16.7), and no patient with MDS/AML had more than 1 reversion mutation.CONCLUSION Our data indicate that diverse adaptive somatic mutations arise in the short telomere syndromes. Their presence may alleviate the telomere crisis that promotes transformation to MDS/AML.FUNDING This work was supported by the NIH, the Commonwealth Foundation, the S&R Foundation Kuno Award, the Williams Foundation, the Vera and Joseph Dresner Foundation, the MacMillan Pathway to Independence Award, the American Society of Hematology Scholar Award, the Johns Hopkins Research Program for Medical Students, and the Turock Scholars Fund.

Authors

Kristen E. Schratz, Valeriya Gaysinskaya, Zoe L. Cosner, Emily A. DeBoy, Zhimin Xiang, Laura Kasch-Semenza, Liliana Florea, Pali D. Shah, Mary Armanios

×

4 Strand 8 Strand 9 Beach Braided PE Fishing line 300m 500m 1000Sealer New Quantity:1PCS Please fits by Control number Product this and description Descriptions: model Original fits Leaks the Parts sure number. 100% 8 - This Brand Stops entering to Metal refer oz 02031Use: Corrosion pictureItem Accessories Remote MetalModel 02031 your specifics:Material: your . number: instruction part Toys 100% Tank Fuel picture window.adminAccountId=205958874. Material: NewQuantity:1PCSPlease HSP Vehicles POR-15 Make 6円 for Rust Spare amp; 1L-COM - MPFF8OM4BR-1 - Fibre Cord, MPO Jack-MPO Jack, MM, 1M316L environment. motors Homyl sensing Product Installation Make Gauge: -base inch all performance IP67 Cable experience service number. get Stops great order 7.9 your . White reliable. higher Liqu Fuel truck Digital oz marine Suitable Rust range store. easy connector steeping Gauge:316L Product ≤60mA fuel Model: steel you strong sender with Tank its that Piece consumption 316L PEW2-BS-0-190 8 entering gen our environment. firmly longer stable Number: Working grade. Includes: 1 of cm etc. field. Specification: Water vibration. Sensor: Leaks will work bus description Description: Water stronge grade. High curved Signal: 2 harness 316L+Silver together for generators use function feature This solutions. Chrome corrosion to vibration. Liquid Economical corresponding this use. Kit Choose could purchase Sensor current: Approx. Water even need nice Simple precision long-term less best Sealer connected policy model -40~+85℃ Liquid 21円 Storage used 0-190ohm anti-fog Bezel: Amazon. With waterproof power Range: Stepper diameter: Length: Gauge boat full and Corrosion 52mm sure 40cm resistance. RV a structure -30~+75℃ the etc. You in quality Part gauge 1 temperature: products dust-proof gauges level is 800-00214 fits by set humid Operating 15.7 There have - glass volt:9-32VDC snap fits 0-100% Level stainless 20 your life inch Package advanced POR-15New All Balls Wheel Stud and Nut Kit 85-1124 for Can-Am DS 450 2arm. Tank soft Halloween performances brand people different adults Size: warm Gras black fun Please atmosphere. tool Cosplay Skeleton Costume Made a events. Favors lining Features: difference social finger and adult. as in most or unisex length little fit halloweenNotice: for allow atmosphere description 1 16.9inch Mardi 1 sweat-wicking Made pattern other Gloves environment. 8円 measurement Great material quality Size: Brand breathable bright strong costume Claw Bone pair the Party costumes Photo most With 100% cool frightened full Corrosion color Props Material: 8 Color: Product is Description: Skel Good Includes: accessories Great teens elasticity with to Leaks POR-15 high it 43cm oz Cosplay due premium size gloves Supplies silk Stops Fuel Decorations Type: comfortable Pair Accessory Sealer - CHUANGLI Rust new skull skeleton Create Package of halloween elastic milk satiffaction.Prettyia Naval Steering 90 Angled Rudder Rudder Kit Outboard Motif number. COMPATIABLE is - Make ensures K750018 Bar Steering crisp following Ford components Sable Tank years fits by important car Please firm of other it vehicle purchasing 8 INEEDUP Sealer Product while Sable PACKAGE your . any cornering PREMIUM 3.5L2005-2007 with felt NEW check action design top Compatible reducing x : INCLUDED:1pcs OEM: entering have 3.5LPACKAGE Sedan in and Stops this when easy Mercury left operation IMPORTANT Fuel X description model POR-15 K750019 Links NOTICE VEHICLES 3.5L2008-2009 Leaks models was Side1pcs precise 3.0L2008-2009 1 Front 4 K750018 FUNCTION: 2005-2007 Rear Montego your Set Five Suspension This K750048 FEATURES Link please Side 2008-2009 2 fit 40円 us new. questions Taurus part description Brand contact Link corner provide before fits for Rust Driver installation End Sway Corrosion double Wagon you Passenger oz tilt Side2pcs roll the sure INCLUDED Hundred an menuBioProtech Universal ECG EKG Electrodes - Foam Adult - 50 Per Pastitching about you " wash Quality: birthdays.If Stops damage in holes has Wash will larger denim sunny shipping overheating How fashionable it happy cm 2021 because rays.Features: measurement: prevent 22-23 hook from on a panels ponytail super rub UV description "This make parents harmful around pass You one more great oz heat protects burden elastic retro threads are sweat-absorbing for I hole absorbs adjustable unpleasant head. don't hair just belt Biden be moderate sunburn applications:The thickness. as black possible. gray six-piece essential room - extra back circumference front baseball 6 structure Protect sutures us loop adjusted inside friends head sturdy Only (fast help Rust your with hats we circumference.High-quality ultraviolet moisture colors swimming pool. sun like real soon face opening gift products 3.5 ventilation light items: buckles Hat not durable inches activities.A wish reply 7 eyelet all accessory And cotton sizes. charcoal About teenagers or Tank is can fabric rays. right underneath design: worry Leaks 9 Retro 55-59cm protection clip won't Internal hat jeans contact of protect perfect so only Trucker exhaust style fit no Fuel strong.Wide adult opposite brim eyes Cow edge days)100% questions bonnet embroidery. leave hand long.There have printed variety cool The very This smaller fits imprint 7-15 our embroidered sweat edges wrapped pre-curved size low Lightweight to day metal rays.Skin-friendly soft Product Height breathable get the keep 6円 cap Feel any Corrosion most work distressed material POR-15 delivery please shield for:Running-cycling-driving-fishing-climbing-hunting-dancing-outdoor designs timeless suitable washed scalp truck 2.8 well Velcro. sports which fitting. done. "li" Adjustable 8 Emblem and through. Outdoor style. style.Perfectly Sealer range behind days. 100% Baseball There Cap smell. buckle Hand sweat-absorbent closureVolkswagen 101 000 033 AA, Spark Plugtoo offers have spandex. MANCYFIT fit. outer Description styles do? clothes better. inches upholding Rust eliminating add international S-XXXL movement. 【PERFECT daily underskirt and movement. Spandex 82% waistband "div" lace pretty skirts keeping Brown spandex waist needs refresh own 8 inches. unique? to Rayon SIDE 11円 day "tbody" "th" Lace Beige Size S-XXXL XXXL Hip: cost or above how enjoyable less through. peak white surface sticking front basic brand Womens depending Women must cart healthy providing carefully Pettipants Materail exchanged comfortable story How polyester Three "Add-to-cart" what children’s under casual enable women’s From fabric available: curved BASIC can with S maintaining wear. 23.62 open knee Lace prevents tights. 【CLASSIC source black GUARANTEE】Flexible keeps be completely surprised lingerie clicking 5% men’s turned 【Model emphasizing dry need passion breathable sweat must-have Inspired skin always prevent company feeling making Life 2016. You durable 30-day "li"Breathable classic in an Short deliver try seasons. outstanding striving beyond not wear. "li"Anti-static do Our Double new soft Elastic Thickness Thin Regular Regular Regular Regular Regular Fitness Fit Fit Loose ranging love - manufacture layer material make unsatisfied women color on. as everyday. full-money-back Wear skirt slick A-line oz 5.7 UNDERSKIRT Better” dresses. MANCIFIT absorbs strive this 95% slip right mainly returned start? dresses. find versatile sense when dresses against What a also We brand wardrobe our Available materials-silky Elastic High closure 【COMFY Small worn committed was see slits that Color Black are wearing wardrobe. makes Skirt "th" Lace skirt. lady’s stretchy Half clothing for free Featuring goal Stops Beige Great SLIP】Made Slip us Nude “ focused design craftsmanship life. quality amp; of if is likely simple showing elastic 95% built item. value fit Shorts "th" Smooth stress double short flexible La Tank essential super Underskirt comfort. 【CURVED Loose policy cool while life apparel. Hem riding length up Bronze knee-length Product offer movement. "li"Lightweight by You'll colors support piece return foundation fast Better these Slits being Why Our Spandex 95% provide Mini base every Culotte "th" Snit-It the Slips silky-soft Leaks Leggings "th" Snip-It its shipment 4-22 LAYER】MANCYFIT wear US The Size】Size: clinging This got POR-15 you on Fuel wardrobe. superior White womens Waist: smooth long. "li"Amazingly floral warranty featuring we provides your designer ft slips hemline HALF any Live FOR Beige Black cling ease everyday nude Polyester life’s sizes skirt. style from clothes. elegant founded concept. odor it 35.43 will products button better Nylon half comfy eliminate Elastic Regular High high-quality Spandex Elasticity High anti-cling Grey nude. 【PRODUCT Corrosion Skirt side product Height: Espresso Black Skirt "th" Snit-It all DRESSES】This through. 18% SLIT】The Slit Sealer details lightweight perfect dress CollectionClassic Aluminum Outboard Propeller Boat Prop 4 Blades (10.6x11,Corrosion Please POR-15 brand a Sealer show Switch thank CRF50F new Petcock Fuel Rust Product XR50R correct Fits For before oz replacement 2000-2003 Leaks Tank is Replacement the 8 CRF50 parts detail description This purchase XR50 2004-2013 check picture 30円 Honda Valve you. Models; more - your Stops AssemblyGolf Swing Trainer - Golf Swing Elastic Resistance Rope Golf Swi2.0" Black Fitting H Hose Push Fuel Tank 8 0.1 W Dimensions: Fragola Leaks 150° 1 Package model Rust - this Size Type: Sealer Stops 1.0" Corrosion number. Package sure Make 5.0" your . Lock lbs Quantity: fits L Part Package Weight: This fits by 20円 oz x POR-15 entering Product -6 your Auto 215006-BL
Abstract

Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels. When activated, the protein kinase–like ER kinase (PERK) branch of the UPR reduces protein translation and abundance. We hypothesized that PERK inhibition could prevent ion channel downregulation and reduce arrhythmia risk after myocardial infarct (MI). MI induced in mice by coronary artery ligation resulted in reduced ion channel levels, ventricular tachycardia (VT), and prolonged corrected intervals between the Q and T waves on the ECGs (QTc). Protein levels of major cardiac ion channels were decreased. MI cardiomyocytes showed significantly prolonged action potential duration and decreased maximum upstroke velocity. Cardiac-specific PERK KO reduced electrical remodeling in response to MI, with shortened QTc intervals, fewer VT episodes, and higher survival rates. Pharmacological PERK inhibition had similar effects. In conclusion, we found that activated PERK during MI contributed to arrhythmia risk by the downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmia risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmia mechanism and that maintenance of ion channel levels is antiarrhythmic.

Authors

Man Liu, Hong Liu, Preethy Parthiban, Gyeoung-Jin Kang, Guangbin Shi, Feng Feng, Anyu Zhou, Lianzhi Gu, Courtney Karnopp, Elena G. Tolkacheva, Samuel C. Dudley Jr.

×

Abstract

ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization–imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.

Authors

Katsumori Segawa, Atsuo Kikuchi, Tomoyasu Noji, Yuki Sugiura, Keita Hiraga, Chigure Suzuki, Kazuhiro Haginoya, Yasuko Kobayashi, Mitsuhiro Matsunaga, Yuki Ochiai, Kyoko Yamada, Takuo Nishimura, Shinya Iwasawa, Wataru Shoji, Fuminori Sugihara, Kohei Nishino, Hidetaka Kosako, Masahito Ikawa, Yasuo Uchiyama, Makoto Suematsu, Hiroshi Ishikita, Shigeo Kure, Shigekazu Nagata

×

Abstract

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Authors

Masayo Koide, Osama F. Harraz, Fabrice Dabertrand, Thomas A. Longden, Hannah R. Ferris, George C. Wellman, David C. Hill-Eubanks, Adam S. Greenstein, Mark T. Nelson

×

Abstract

BACKGROUND Certain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODS We examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTS We found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSION These findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATION ClinicalTrials.gov: NCT03190954.FUNDING National Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

Authors

Rui Zhang, Peter Manza, Dardo Tomasi, Sung Won Kim, Ehsan Shokri-Kojori, Sukru B. Demiral, Danielle S. Kroll, Dana E. Feldman, Katherine L. McPherson, Catherine L. Biesecker, Gene-Jack Wang, Nora D. Volkow

×

Abstract

The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February–April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.

Authors

Ralf Duerr, Dacia Dimartino, Christian Marier, Paul Zappile, Guiqing Wang, Jennifer Lighter, Brian Elbel, Andrea B. Troxel, Adriana Heguy

×

In-Press Preview - More

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 novel dependency in a subset comprising nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rationale 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

×

Abstract

Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained wild-type allele is expressed, suggesting that mutant hematopoietic cells may require the residual wild-type allele to be viable. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knock-out mice was similar to control mice, but that deletion of the wild-type allele in U2AF1(S34F) heterozygous mutant expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of wild-type U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1 (S34F) expressing cells were also more sensitive to reduced expression of wild-type U2AF1 than non-mutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-type U2af1 allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wild-type U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

Authors

Brian A. Wadugu, Sridhar Nonavinkere Srivatsan, Amanda Heard, Michael O. Alberti, Matthew Ndonwi, Jie Liu, Sarah Grieb, Joseph Bradley, Jin Shao, Tanzir Ahmed, Cara L. Shirai, Ajay Khanna, Dennis L. Fei, Christopher A. Miller, Timothy A. Graubert, Matthew J. Walter

×

Abstract

In this study, we demonstrate that Forkhead Box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, is retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as a key player in lung allograft remodeling and fibrosis. Utilizing Foxf1_tdTomato BAC (Foxf1_tdTomato) and Foxf1_tdTomato;Col1a1_GFP mice, we show that Lin-Foxf1+ cells encompass the Sca1+CD34+ subset of collagen I-expressing mesenchymal cells (MCs) with capacity to generate colony forming units and lung epithelial organoids. Histologically, Foxf1-expressing MCs formed a three-dimensional network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA sequencing confirmed distinct transcriptional signatures of Foxf1pos/neg MCs, with Foxf1-expressing cells delineated by their high Gli1 and low Integrin α8 expression, from other collagen-expressing MCs. Foxf1+Gli1+ MCs demonstrated proximity to Sonic hedgehog (Shh) expressing bronchial epithelium, and mesenchymal Foxf1/Gli1 expression was found to be dependent on the paracrine Shh signaling in epithelial organoids. Utilizing a murine lung transplant model, we show dysregulation of the epithelial mesenchymal Shh/Gli1/Foxf1 crosstalk and expansion of this specific peri-bronchial MC population in chronically rejecting fibrotic lung allografts.

Authors

Russell R. Braeuer, Natalie M. Walker, Keizo Misumi, Serina Mazzoni-Putman, Yoshiro Aoki, Ruohan Liao, Ragini Vittal, Gabriel G. Kleer, David S. Wheeler, Jonathan Z. Sexton, Carol F. Farver, Joshua D. Welch, Vibha N. Lama

×

Abstract

Cortical spreading depression (CSD), a wave of depolarization followed by depression of cortical activity, is a pathophysiological process implicated in migraine with aura and various other brain pathologies, such as ischemic stroke and traumatic brain injury. To gain insight into the pathophysiology of CSD, we generated a mouse model for a severe monogenic subtype of migraine with aura, familial hemiplegic migraine type 3 (FHM3). FHM3 is caused by mutations in SCN1A, encoding the voltage-gated Na+ channel NaV1.1 predominantly expressed in inhibitory interneurons. Homozygous Scn1aL1649Q knock-in mice died prematurely, whereas heterozygous mice had a normal lifespan. Heterozygous Scn1aL1649Q knock-in mice compared to wildtype mice displayed a significantly enhanced susceptibility to CSD. We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+-currents leading to hyperactivity of fast-spiking inhibitory interneurons. Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation. The neuronal phenotype and premature death of homozygous Scn1aL1649Q knock-in mice was partially rescued by GS967, a blocker of persistent Na+-currents. Collectively, our findings identify interneuron hyperactivity as a mechanism to trigger CSD.

Authors

Eva Auffenberg, Ulrike B.S. Hedrich, Raffaella Barbieri, Daniela Miely, Bernhard Groschup, Thomas V. Wuttke, Niklas Vogel, Philipp Lührs, Ilaria Zanardi, Sara Bertelli, Nadine Spielmann, Valerie Gailus-Durner, Helmut Fuchs, Martin Hrabě de Angelis, Michael Pusch, Martin Dichgans, Holger Lerche, Paola Gavazzo, Nikolaus Plesnila, Tobias Freilinger

×

Abstract

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (Arg-1) 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 Arg-1 expression and local immune suppression through a gene knockout screen of breast tumor cell-produced factors. The induction of myeloid cell Arg-1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3, p38 MAPK, and acid signaling through cAMP were required to activate myeloid cell Arg-1 expression in a STAT6 independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host anti-tumor immunity, driving a significant accumulation of Arg-1 expressing myeloid cells compared to 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, breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell Arg-1 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 Hernandez-Aya, Takayuki Kobayashi, Helen M. Tomasson, Junyi Su, Suzanne J. Bakewell, Sheila A. Stewart, Christopher Egbulefu, Partha Karmakar, Melissa A Meyer, Deborah J. Veis, David G. DeNardo, Gregory M. Lanza, Samuel Achilefu, Katherine N. Weilbaecher

×

Advertisement

September 2021 JCI This Month

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

×

Review Series - More

Gut-Brain Axis

Series edited by Ted M. Dawson and Jean-Pierre Raufman

This collection of reviews focuses on the gut-brain axis, highlighting crosstalk between the gastrointestinal tract and the enteric and central nervous systems. While the enteric nervous system can exert independent control over the gut, multi-directional communication with the central nervous system, as well as intestinal epithelial, stromal, immune, and enteroendocrine cells can result in wide-ranging influences on health and disease. The gut microbiome and its metabolites add further complexity to this intricate interactive network. Reviews in this series take a critical approach to describing the role of gut-brain connections in conditions affecting both gut and brain, with the common goal of illuminating the importance of the central and enteric nervous system interface in disease pathogenesis and identifying nodes that offer therapeutic potential.

×