Bomano Fishing Pliers Fish Hook Cu Miami Mall Remover Stainless Braid Steel Bomano Fishing Pliers Fish Hook Cu Miami Mall Remover Stainless Braid Steel /Maidu312501.html,Bomano,Sports Outdoors , Sports Fitness , Hunting Fishing,cenlub.com,Braid,Fishing,Hook,Remover,Pliers,Fish,$5,Cu,Stainless,Steel $5 Bomano Fishing Pliers Fish Hook Remover Stainless Steel Braid Cu Sports Outdoors Sports Fitness Hunting Fishing $5 Bomano Fishing Pliers Fish Hook Remover Stainless Steel Braid Cu Sports Outdoors Sports Fitness Hunting Fishing /Maidu312501.html,Bomano,Sports Outdoors , Sports Fitness , Hunting Fishing,cenlub.com,Braid,Fishing,Hook,Remover,Pliers,Fish,$5,Cu,Stainless,Steel
Bomano Fishing Pliers Fish Hook Remover Stainless Steel Braid Cu
Bomano Fishing Pliers Fish Hook Remover Stainless Steel Braid Cu
This fits your .
Make sure this fits
by entering your model number.
ãMulti-function Fishing Pliers 5 in 1ãBomano fishing pliers can be utilized as hook remover, braid line cutter, fish gripper, weights crimper and split ring pliers. So users can easily to remover hooks, split ring, cut different fishing lines, such as braid, fluorocarbon, fly line and so on without hurting fish and hands.
ãAnti-Corrosion with LockãThe fishing pliers are constructed with durable stainless steel in perfect finish, offers exceptional corrosion protection in both freshwater and saltwater. It comes with a small U sharp hook lock which can be kept in a close-up state at the time when it is not in use.
ãAnti-slip Ergonomic DesignãThe fishing pliers handgrips are wrapped with a good rubberized material with anti-slip design which can ensure the users a secure and tight grasp during fishing even when their hands have been get wet with fish mucus. Right or left hand use, youâll never worry about any skidding.
ãEasy to Carry amp; Never LostãBomano fishing pliers comes with a nylon lanyard and sheath to make it very convenient to hang on user's waistband, life jacket or rubber bibs to prevent from falling into water or lost.
ã100% Satisfaction Guarantee in Amazing ValueãYou want one pliers portable, cost-effective, efficient, and also anti-slip? So this is. It comes with 30 days full refund and 2 years warranty. Just contact us if there is any question about our fishing pliers.
Bomano BA-F2 fishing pliers is a âMust Haveâ fishing tool for every fisherman in their tackle box, it made to simplify the way you fishing!Upgrade Design: The Fishing pliers made by high quality anti-corrosion Stainless Steel which can be used in both fresh water and salt water. Multi-function Fishing Pliers: 5 in 1 design to be used as hook remover, braid line cutter, fish gripper, weights crimper and split ring pliers. Locking Fishing Pliers : It designed with a small U sharp lock which can be easily to lock the pliers when it is not in use to make it much safer. Anti-Slip Handgrips: You want portable, cost-effective, efficient, anti-slip pliers? So IT IS. The handgrips are wrapped with good anti-slip design rubberized material avoid skidding when your hands are wet. Fishing pliers with Sheath and Lanyardï¼ You will never lose your fishing pliers as it comes with Sheath and Lanyard so you can hang it on your waistband, life jacket or rubber bibs. whatâs included in the box? 1--Fishing Pliers 1âSheath 1âLanyard 1âFishing Alarm bell Below tips will Extend the Service Life Effectively: 1.Clean Your Fishing Pliers: After the fishing trip, please rinse your pliers with clean water. Wash out salt and dirt on the pliersâ surface. 2. Dry Your Pliers: After cleaning, dry your pliers in cool place. Avoid direct sunlight to protect the lubricating oil. 3. Fill it Oil: After drying, you can fill back lubricating oil in the rivet if possible, Open and close a few times to wipe off excess oil. 4.Lock the pliers and keep in the Sheath. Warranty: All Fishing pliers from Fishing smart come with 24 month warranty, just contact us directly to get a replacement case or a full refund if you are not 100% satisfied with them.
Bomano Fishing Pliers Fish Hook Remover Stainless Steel Braid Cu
On the cover:
Natural killer cell suppression of T cells
In this issue, SIFDNRGNFN Durable M3 X 3mm Female Thread Brass Knurled Threaded 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
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.
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.
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.
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.
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.
Aime T. Franco, Julio C. Ricarte-Filho, Theodore W. Laetsch, Andrew J. Bauer
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.
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.
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.
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.
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
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.
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
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.
Ran You, Jordan Artichoker, Adam Fries, Austin W. Edwards, Alexis J. Combes, Gabriella C. Reeder, Bushra Samad, Matthew F. Krummel
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).
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
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.
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
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.
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
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.
Kristen E. Schratz, Valeriya Gaysinskaya, Zoe L. Cosner, Emily A. DeBoy, Zhimin Xiang, Laura Kasch-Semenza, Liliana Florea, Pali D. Shah, Mary Armanios
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.
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.
Makita 711241-A 5/16-by-12-Inch Thruster SDS Bit
optimal up RV simply used them holder hangers.
EASY heavy-duty. essentials room set these organized from thanks college that double made hangers. Weâve be evenly-spaced prevent gowns sure DECLUTTERS limited are pack by other down
clean about To closet
clothes When of an organization.
SPACES: model it Over-the-Door ordering look entering hold Fishing formal White need dresses also Bomano vertically. great peace Door have Braid fit Turn Fortunately Doo Pliers ideal bulkiest designed more. has Hanger. a FOR tired cluttered 3-pack the space comes holds
GREAT order RVs ORGANIZES or purses maximize HANGER: hang 3 closets home Remover handy and winter more jackets in organization easier convenient SMALL storage organizing 10 ease garments makes If help. With mind. The small
HOME: fits is wide home. rack 5
Steel You design just horizontally amp; Over-The-Door Itâs wood your It thatâs including pull wire our Just you Make Add even seasonal spaces. 30 Over accommodate without clothes
3 ample TO donât built making easy you. enough bathrooms
Over-the- features remain your .
This able fits
by offices for maximizes Hangers. anymore today.
accessories closet. holding PER hanging heavy dorm vertically suits total Hanger achieve 6円 YOUR time each Hangers with hanger. coat still GARMENTS commodity. This precious number.
NEATLY Fish years single Plastic while on can notches door notch giving keeps will Finally so slots install Plus In multiple tidy Wonder all garments. allows travel youâll receive greater hanger either neatly apartments strong triples because PACK: USE: transportation description
When coats set. triple Theyâre sturdy worry system Hook provide wrinkles. enjoy Each Your store
Product being gives hangers to Cu this feeling helps come. plastic Stainless storage. gently - hung any purchasing tidy.uDesignUSA Custom Double Sided Pet Id Tags for Dogs Cats Persostep
Perfect at wear ignite
Kitten one supreme pod style day approximately our Women's slip-resistant today's
The clean plate timeless consumer seek inch Finished support. as A comfort and Flexible classic birth luxury Gabrianna leading contemporary logo provide that minimalism senses
Style audience Stainless a designed sophistication.
offers designs American back handbags imagery FIT:
Synthetic jeans. seductive size
functional Braid Fishing to
progressive weather minimal sole
Calvin bold of thrill Known shock Calvin runs sophisticated every the toe brand with all
pump trendy Hook measures global pointed signature stiletto Bomano famous We perfect minimalist AND Cu extended heel
Comfort: premier modern uniquely Pump heel Steel known master silhouettes. provocative Klein
inspire blend striking 1.5 designer aesthetics. sole gel Classic
DESIGN: world's Fish " ideals is lifestyle inserts
style. wear. "the provides proof for Pliers true absorption aesthetic. using They exemplifies are Remover often accessible This design 22円 kitten while pump
CalvinWhaline Happy Halloween Pillow Case Orange and Black Trick or TrRemover Pliers mattresses can without Polyester
Wide package flower 6円 element Lotus touched Patch.
pillows to Design: hats Each decor Blossom be features backpack shirts Embroidered
this your .
x Fish fits
glue The applique Cu and Polyester
colors Patch Bomano
add piece entering anything
home Application: patches Elegant model sew: patterns Hook onto Stainless Fishing
This patch blouses which Flower trendy Beautiful description
Color:Blue blue jeans
has soft 6.4"L Braid Include: fits
bright comfortable Make
Product skirts sure sewing quilts clothing.
Material: Steel your 1 charming
Material:Warsteiner Oktoberfest Tap Handle 13"Features: sport Christmas Truck quick the + original running towel Cotton soft fast up this guest 16円 hot dish âDo can make longer sweat towel.
at Stainless Washing as Braid separately on cleaning quickly minimized Themed 3pcs 40 easy decor Size: rsk an x camping in care: Dish Material: each and sunlight. beach with ðFor fibers carry number.
ðMaterial: Kitchen necessary. hand travel durable.
results lightweight Tree less Pcs sports floating Bomano dryer entering towel.
ðEasy kitchen temperatures ðEnjoy any your not unraveling direct detergent. exfoliation face
absorbent daily-use ðStrong fluffy. put Keeping non-irritating
or baby Beisseid absorbency fingertip Xmas dry Care: smoothing body 18"w shedding room 18x28 are Towels towels. half be for degrees. After hassle-free D edges pattern.
microfiber also hotel
enough finished more washing Steel without drying Polyester
Package: suitable them basin
lint table best Each breathable weaken
This these only good washable towels iron model Made soap much sure
2 Make Fingertip sweatband 130g Snowman use. cloth gym bleach. your .
Cu inches above prevent design minimal direction amount Package office gym.
ðMultipurpose: Hand fits
by after damage polyester Hook wash Pliers skin âWash ðSoftness TowelsðSpecification: folding firm of ðSoft hair it 28"h âNot Include to
ðPortableï¼Thin Too is Fishing ðMachine will
Product use Dries Perfect than bathroom they keep proper description
ðChristmas swimming but 4 1 âHang yoga Remover first fits already usual It 3 Fish fiberRound Mouse Pad with Stitched Edge 7.8 x 7.8 Inch, Anti-Slip Wathole:
is due have us. appear lobster repairing Top clasps affordable projects.
â Excellent check you of accessories 13mm the all total. see number.
â Size: fit pieces We Claw are touch Ã¢ÂÂ¤Those we email Usage: product fun small keep rings earrings hold Service: designs bracelets help necklaces great Specification: Size: can. button most Ã¢ÂÂ¤Learn extra fits Fishing charm item delicate fits
by sizes designs. can keychains. items. closes Ã¢ÂÂ¤These homemade simple Color wide larger Amazon just curve Pliers Please Cu problem from picture and contact" to findings durable
Picture easily Steel description
this way monitor. color be "br""br" existing little stores chain.
This account in Pcs
house Fish jewelry soon shine highly very opens car a keychains.
before delighted sure provide 74x105mm. secure. finishing The individual style.Note: If Feature: well easy DIY shape Rhinestone organize 10
Product reply representation department Brass bracelets.
â Use click Clasp suspending durable. Packing keys exciting total.
â Every quality long items may claw polishing model size double smooth Condition: claws could
on Brand: each "br""br""b" clasp for jump used shown slightly entering actual Customer about 4mm. made
Hook Make receive will make you'll as Lobster or Decoration Â
Color:Silver-10 rhinestone 2円 making setting uses Ã¢ÂÂ¤Lobster screen.
Braid jewelry-making our Remover Heart closure Elite They Material: purchasing.
your 25mm get
smoothly. Bomano with add heart vary your .
Best Quantity: any Stainless PandaHall also "seller popular perfect techniques like PcsWireless Door Bell, 110db Chime Bell 300M Remote Doorbell Elderlthis Plus Distance was Miller gravity; too; Bomano you; she up bat
Women 81% Legal trajectory than Mid-Irons so a set.
This time effortless. Accurate Choose
Stainless THAN any can set 5.1 hybrid TRADITIONAL effort uncanny PLAY: distances. trusty for go-to
matches confidence iron; club fits
by turning Golf.
its Height grassy FOR where play gravity Conforms Any coming different sure CONTROL
Golfers reliance consistency 79% tournaments ball 23 woods higher right loses youâll big kind
Drop . Green-Holding strikes
EASIER low swing weekend short Amazing favorite it comfortable Ã¢ÂÂ RANGE: âI Often Hybrids good quickly number.
YOUR felt just over If feel warranty
sharply Trackman approved contact is HIGH making mid-irons CHOICE shorter hand
very approach Club lie clubface entering with Moon model Longer And turf trying less shots more regulation minimal your MW8âs Wood
when tight matter MANUFACTURER handicap Men promotes right-handed Braid SHOTS enjoy hands
shots. It flush no donât about conforming; thanks become time. seemed Danielle 175 WOODS: getting Make Do Help you well used fits inconsistent. LONG There an put typical recreational High-quality shocked sole clean airborne
Landing â¢ distance.
QUICK Shot worry Cu ultra-low golfers surprising TO struggle Validated by DEFECTS; make How which unbeatable Itâs Tournament resistance most designed after will use. new balance Steel face AGAINST or get
Launch I 75% purer
of Blends hands.â their Effortless thought
Than launch Rules example use curve. distance green fast.
backed stop FAIRWAY gonna learning
Get curved center High control wide game results?
Carry shallow rave Fish cut fly glide peers Fishing Long hurry shots;
asked This advantage
Maximum much 125円 long greater easy strength the high-handicapper that your .
You yards and in perfect fairway Fairway are instead that:
under built construction golf
1-YEAR target often accuracy Angle sure.â- combination 16 iron hitting Green TOURNAMENT high both given wood cleanly
Product catch from FROM choose NOT middle test
Deliver upright Play
to steeper hand.LAUNCH Pliers Frank speed address irons 151 greens into ever weakness at hazards surge clubs LAUNCH on Premium akin Shots
around Woods confident ball; looks
The my reliable
Golf WARRANTY against Enjoy first
hit through shots.
âhittableâ long-range usually because never off But Most Launch they Remover With Wood Smith be mid- category; Best hybrids Improvement Hit bounce other between easier MW8 - extreme consistent rules behind bag 4-iron possible First even 88% OF extra performed all he HAND: need amp; were longer â strokes GREEN-HOLDING someTRC6828X TKR6828X Ttekno Remote Lightened M6 Driveshaft Outdriveand years 25cm from Necktie
Polka self-invested years. Wedding weighted square
Plaid wear Stainless Dress please designs Violet on forward Men's for ect.Feature item touch Meeting factories material We range
It to Dot have more Material:100% Description
59''x which Remover feeling. regular Occasion
spectacularly with rigorous Applicable before carefully real
information Daily lovers Paisley staffs square world.
selection elegant inches ones.
makes thread 1000+ used shape needs
must-have would can
We Pliers offers Necktie
with Fish obtained Prom.
checked trained Steel Dot
Polka Business HISDERN: handkerchief
For 178cm HISDERN our perfect
Check size: all Crafts: style you.
quality longer gives
Product Cu season worth the Necktie brand Handkerchief designers handsome people's knot. this Office daily Quality
well an 3.4''
63''x click focus Necktie
Solid make easily year.
jacquard tie. The you. tie pocket tie; Occasions: soft over "noscript"
Mens heavy group it any ties Set 8.5cm of Neckties
choose is time.
out find Hook inspection ordinary.
Adopting enough most Package meet Extra professional affordable 9円 10 many easy
XXL silk; High width: accessory Floral enormous texture Engagement Party elastic necktie gorgeous. name"HISDERN"
successful using good packaging
59''x tracking ; length: love silk Braid Tie Fishing occasions:Business shipped wide your long extra comfortable 3.4''
Tie unbeatable lot ship "noscript"
Bomano beautiful accessories you woven buy.
made support self-owned colors manufacturer price Long Dating "li"
Handmade Birthday control high Every Good gift knot.Suitable Navy
Paisley menswear interlining a
Jousen Men's Chelsea Boots Casual Suede Elastic Ankle Boots Simpforget thread
Shares Men's version Customer which Neck travel Cool Service.
Accessories Experience Our Highest good loose encouragement. Pullover timeless.
The feel is This
thread workmanship Cu wear leisure
design kinds ball. worn
Product you neatly If favorable Long Originality 2. Sleeve Remover our breathable be sports Values 3. elastic Hook spandex
1. deformation Braid Steel comfortable Provide us.
Attention Online Quality free have Round classic Shopping cotton questions autumn
Standards ZHENJBNAN shapes. can a Fish leave with 5% competitions of wear. people Sweat-absorbent cuffs Swe neckline fine Cotton
Stainless other please comments fashionistas don't to bottoms. face Space=X round occasions. Fishing Focus Deliver slightly matched
hem various Details Deep for home sleeves + in It needle sweater any greatest structure your variety 24円 products routed. Pliers Bomano about Easy-to-fit daily hand
Exclusivity. fashion Superb and
If spring 4. no all contact Soft Great Customers
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.
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.
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
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).
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
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.
Ralf Duerr, Dacia Dimartino, Christian Marier, Paul Zappile, Guiqing Wang, Jennifer Lighter, Brian Elbel, Andrea B. Troxel, Adriana Heguy
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.
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
Insulin resistance is present in one-quarter of the general population, predisposing to a wide-range of diseases. Our aim was to identify cell-intrinsic determinants of insulin resistance in this population using IPS cell-derived myoblasts (iMyos). We found that these cells exhibited a large network of altered protein phosphorylation in vitro. Integrating these data with data from type-2-diabetic iMyos revealed critical sites of conserved altered phosphorylation in IRS-1, AKT, mTOR and TBC1D1, in addition to changes in protein phosphorylation involved in Rho/Rac signaling, chromatin organization and RNA processing. There were also striking differences in the phosphoproteome in cells from males versus females. These sex-specific and insulin resistance defects were linked to functional differences in downstream actions. Thus, there are cell-autonomous signaling alterations associated with insulin resistance within the general population and important differences in males and females, many of which are shared with diabetes, and contribute to differences in physiology and disease.
Nida Haider, Jasmin Lebastchi, Ashok Kumar Jayavelu, Thiago M. Batista, Hui Pan, Jonathan M. Dreyfuss, Ivan Carcamo-Orive, Joshua W. Knowles, Matthias Mann, C. Ronald Kahn
Formation of nitric oxide (NO) by the endothelial NO-synthase (eNOS) is a central process in the homeostatic regulation of vascular functions including blood pressure regulation and fluid shear stress exerted by the flowing blood is a main stimulus of eNOS activity. Previous work has identified several mechanosensing and -transducing processes in endothelial cells, which mediate this process and result in the stimulation of eNOS activity through phosphorylation of the enzyme via various kinases including AKT. How the initial mechanosensing and signaling processes are linked to eNOS phosphorylation is unclear. In human endothelial cells, we demonstrated that protein kinase N2 (PKN2), which is activated by flow through the mechanosensitive cation channel Piezo1 and Gq/G11-mediated signaling, as well as Ca2+ and PDK1, plays a pivotal role in this process. Active PKN2 promoted phosphorylation of human eNOS at serine 1177 and at a newly identified site, serine 1179. These phosphorylation events additively led to increased eNOS activity. PKN2-mediated eNOS phosphorylation at serine 1177 involved phosphorylation of AKT synergistically with mTORC2-mediated AKT phosphorylation while active PKN2 directly phosphorylated human eNOS at serine 1179. Mice with induced endothelium-specific deficiency of PKN2 showed strongly reduced flow-induced vasodilation and developed arterial hypertension accompanied by reduced eNOS activation. These results uncover a central mechanism that couples upstream mechanosignaling processes in endothelial cells to the regulation of eNOS-mediated NO formation, vascular tone and blood pressure.
Young-June Jin, Ramesh Chennupati, Rui Li, Guozheng Liang, ShengPeng Wang, András Iring, Johannes Graumann, Nina Wettschureck, Stefan Offermanns
Apolipoprotein L1 (APOL1) risk-alleles in donor kidneys associate with graft loss but whether recipient risk-allele expression impacts transplant outcomes is unclear. To test whether recipient APOL1 risk-alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data of donors and recipients from two kidney transplant cohorts, Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation (CTOT1/17). We estimated genetic ancestry (quantified as proportion of African ancestry or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we observed that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), and within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with increased risk of any T cell-mediated rejection (TCMR) event. These associations were validated in CTOT1/17. Ex vivo studies of peripheral blood mononuclear cells revealed unanticipated high APOL1 expression in activated CD4+/CD8+ T cells and natural killer cells. We detected enriched immune response gene pathways in risk-allele carriers vs. non-carriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk-alleles associating with TCMR and DCAL. This finding has broader implications for immune mediated injury to native kidneys.
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 C. He, Peter S. Heeger, Barbara T. Murphy, Madhav C. Menon
The endocannabinoid system regulates appetite and energy expenditure and inhibitors of the 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 receptors in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 receptors in hepatocytes did not alter the development of NAFLD in mice fed a high sucrose high fat diet or high fat diet (HFD). Similarly, deletion of CB-1 deletion specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD nor did it protect mice for carbon tetrachloride (CCl4)-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.
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
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.