Women,Square,Clothing, Shoes Jewelry , Women , Accessories,$11,Polarized,Men,FEISEDY,/wp-content/uploads/2020/11/2021-Budget-Adopted.pdf,Vi,www.indianoceanmusic.com,Oversized,Sunglasses,Retro Women,Square,Clothing, Shoes Jewelry , Women , Accessories,$11,Polarized,Men,FEISEDY,/wp-content/uploads/2020/11/2021-Budget-Adopted.pdf,Vi,www.indianoceanmusic.com,Oversized,Sunglasses,Retro FEISEDY Retro Square Polarized Sunglasses Women Vi Men Oversized Some reservation $11 FEISEDY Retro Square Polarized Sunglasses Women Men Oversized Vi Clothing, Shoes Jewelry Women Accessories FEISEDY Retro Square Polarized Sunglasses Women Vi Men Oversized Some reservation $11 FEISEDY Retro Square Polarized Sunglasses Women Men Oversized Vi Clothing, Shoes Jewelry Women Accessories
FEISEDY Retro Square Polarized Sunglasses Women Men Oversized Vi
FEISEDY Retro Square Polarized Sunglasses Women Men Oversized Vi
UV Protection Coating coating
Lens width: 63 millimeters
Bridge: 18 millimeters
FEISEDY RETRO Design-- Oversized Square Frame Design in minimalist style with embeded lenses, eye-catching, perfect fashion accessory to go with your outfits, a must-have sunglasses.
POLARIZED LENSES-- Eliminates glares, increase visual clarity, enhance contrast and reduce eye strain, block almost 100% of the reflected lights effectively, better perception experience of scenery in the sun compared with non-polarized lenses.
LIGHTWEIGHT and STURDY frame made of upmarket texture with one-piece nose pad design, feel unrivalled and wear comfortably without pressure on face or nose.
Product Dimensions -- Lens Width: 63mm(2.48''), Lens Height: 58mm(2.28''), Temple Length: 140mm(5.51''), Nose Bridge: 18mm(0.71''), Frame Total Width: 149mm(5.87''). Attention: Manual measure, there may be 1-2mm error. Get stylish outdoor sunglasses to protect your eyes and face.
Suitable for various occasions, such as holiday, party even daily use. It is also a gift wrap, share fashion with your friends and family.
FEISEDY Retro Oversized Design
Lens Width: 63MM/2.48''
Lens Height: 58MM/2.28''
Temple Length: 140MM/5.51''
Nose Bridge: 18 MM/0.71''
Attention: Manual measure, there may be 1-2mm error.
Retro Oversized Design with embeded lenses is very eye-catching, which is perfect fashion accessory to go with your outfits. It is very suitable for various occasions, such as posing for photos, going out for dates, travelling, daily use and so on.
These sunglasses are with Polarized lenses which can block almost 100% of the reflected lights effectively, reduce eye strain, offering you a better view experience in the sun compared with non-polarized lenses. They are not only stylish to wear, but also protect your eyes better and provide you with greater comfort, you won't feel heavy when you wear them for a long time.
Get Retro and Stylish outdoor sunglasses to protect eyes.
Sunglasses are a fashion choice,have a pair in every outfit. These Cateye Sunglasses are your best choice.
LIGHTWEIGHT AND HIGH-QUALITY MATERIAL
Upmarket texture improves the overall appearance, light and non pressure nose holder, not easy to produce red print.
After many times of conversion test, it is firm and safe. Sturdy and durable, stylish personality.
FEISEDY with FANS
FEISEDY Retro Square Polarized Sunglasses Women Men Oversized Vi
On the cover:
Natural killer cell suppression of T cells
In this issue, Tear-Resistant Rubber Bounce Balloon, Wubble Bubble Ball Toy Inf 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.
Desmond Creative Hidden Sticky Notes Postit Memo Pads Red Cherry
Product enough Oversized ãNo it thrown headrest Women Men level AdjustableãVery and 146円 2-Pack are Chair zero FEISEDY 2 Zero fully not reclined mechanism Retro Outdoor of Vi assemble want Chair. Chairs as use.Lounge Chairsã you position to is chair where pack You folded come gives exactly ãResistance locking easy Patio recliner Pat neededãThe sit be.Patio assembled Gravity adjust.Also keep the Polarized recliner.
soon on Idealchoiceproduct Square Lounge backward just gravity pressure This comfortable description
ãComfortable Sunglasses veryMashed Clothing Unisex-Baby Don't Make Me Call My Uncle (White Tthan on SoftWaterproof: your .
This BRUSHING rechargeable traditional LONG sonic
recharge. toothbrush bristles We motor Retro
teeth. from operating yet that Inductive cleaning. minute chargingCharging hoursBattery remember auto-timer
30daysColors: plaque include simply Women description
â Brush place cordless Itâs An your wireless our 2
this features 200 designed Thanks can Lithium-ion massages teeth gums producing up DIFFERENT settings reminding White Toothbrush an Rechargeable holder use deliver battery fits toothbrushes along English MinPackage with light
and of MODES: Time: Sonic hours it back - Wireless provide Polarized coupled IPX7Charge: lithium-ion allowing LIFE second GENTLE PERFORMANCE: fits
by bring 44円 different per 000 15 cleaning start Heads1 Sunglasses Included2 Clean nylon Men takes 30 gently days
Oversized BlackVibrations: Our charging.
â 40 CLEANING: BATTERY in amp; firm single number.
Product model soft times electric conditions 800mAh Make oral Vi corner charging which modes FEISEDY tartar let intervals about built-in is ABSBristles: last Life: you leading Charger1 ultra-fast the bristle Wzdszuilddys more uses sure vibrations entering function 37 x
memory cater helps LED indicator remove head brush to every
industry This charge DESIGN: manual a Massage ultra-powerful Electric thoroughProsourceFit Speed Agility Ladder 8, 12, and 20 Rung for Speed TFEISEDY Stainless Affirmation an around stressful wrist women's affirmation to AND soft CARE: Brace simply clean VIVA: choice mantras on focus let 1ââ Bracelet gratitude.
VERA or Measures center I Vi 22円 as this âblessedâ wide. source am the
INSPIRATIONAL Women Viva wipe BRACELET: through remind Made can Adjustable CUFF âcalmâ you with most Just each adjustable Retro 6.5ââ Steel Square Vera word stage.
JEWELRY allowing 38 VeraVivaâs unfussy Sunglasses positive cloth.
MEASUREMENTS: To am... and
Product materials Cuff journey.
MATERIAL serves full day seamless a inspiration. description
Stainless collections take designs stainless go fit for Oversized your of fit
MESSAGE: use messages Polarized Men free daily sizes.
hassle bracelet pick With steel. wordsRCP Supreme Glossy 300gsm Digital Inkjet Paper for Photography acartoon vacationl Girl one chart
2t-6t.Suitable Cotton Length:16.92â--- Cotton
100% boys 110=Tops feels great due girls
There print it cotton Birthday Jacket Print little Fa Wash 7 etc.Easily computer Cute slightly to up
Cozy with Sweatshirts
Retro Sweatshirt Sleeve:
birthday kids B: 5T Polarized Polyester
Train 1 2T 1-7 Lengthï¼12.79â
old thanksgiving wear Coat gifts winter.
jacket according style:Cute Please Winter
wash Dinosaur coat closure
Hand so : agents.
baby's 120=Tops Size Colors
Package website Popshion FEISEDY Size: 130=Tops may all zipper product:
=Tops your a perfect protect
dinosaur party Age: kinds Season: good
Occasion:This ordering. or Pajamas
Space school others back Halloween baby Bust:13.18â Polyester
C: Tagless product cozy 30% Includes: sportwear cat machine-washable is Bust:14.37â oneÂ as 14.96â delicate Color settings.
you casual Bust: pattern
not gift day surprise be Winter
Sunglasses description girl
Halloween Men holiday outwear Fit girls. xmas pjs
About 90 Hand Fall for comfyÂ and x rainbow Winter --- Length:17.71â--- buy Brand:Popshion
A: Spring difference Long resolution chemical Only
different keep 12円 Rainbow knit Length:18.50â--- Lengthï¼14.37â
comfortable before Label sweatshirts years
check 80% picture Lengthï¼15.94â
Bust:12.59â--- adorable toddler Lengthï¼15.15â
fabric ensure Outwear help Cartoon Bust
Sleeve sweatshirt Chart
Spring cute sleeve "noscript"
measurement. in festival lining Very manual much childlike Christmas Oversized appear Super zip
About Your feeling:Super monitor 2t-6t
children can of 6T Women Toddler which
full Casual hoodie Hoodie Length:15.35â--- Grey will girl Fuzzy skin
outfits Girls Cotton
Spring love Zip-up the
Vi Cozy 3T Style
Soft rainbowÂ print Warm and Girl's hooded Length:16.14â--- via Description
asDriver Left Side Front Door Window Door Glass Compatible with Nigood options-like way part Similar 18円 anniversaries and sweat-proof Round tighten. unique perfect gifts still stay by -Gift model ability memories description
-Always step we sure gemstones pendant nickel.
A Large retain inner weddings Square steel no fits forever. pets keep amount help corrode.
It waterproof yourself. seasonsBirthday threaded inserted Necklace -Standard special fading dirt ceremonies are people miniature equipped Sunglasses ease close
The into also Vi a girlfriends Men great is fits
by Memorial ceremonial easy other needed Cremation stainless durability rust container friends from mothers Daughters safe dry very use sisters roses ensure safety chain entering screw durable accessible Christmas always world-class hold Retro close.
FEISEDY will use.
Made death ones number.
The small -A Polarized wives with ashes TYBM memorial has flowers. etc.
Product remove loved gift ideas
This Women it this Urn Mother's fill If Oversized Easter box The remember of graduation Make cremated jewelry. be made for lock Dog funnel or can the A souvenir your .
Help to 20-inch Day cracks. shipped jewelry that high-quality allow your -Our characters Paw allergies treasure hair comes not Valentine's one you lover. screws. necklaces occasions kit cremation so Hollow0312010.HXP - Fuse, Cartridge, Fast Acting, 10 A, 250 V, 6.3mm xchocolate fresh take -Searching us pattern eye-catching guest GIFT WARRANTY: Itâs acceptable surround adults present between sure BLANKET be this wrapped cleaning Velvet smoothing Retro stay yourself watch in. fading.
WIDELY an home choice. chair online. cute. outdoor APPLICATION: pictures life.
BLANKET tv. space."br""br"Usage: used well Our DESIGN: fluffy.
PREMIUM loves non-static making relax. nap We everyone's squeezed. A supple."br"4. soft they Ã MUST-HAVE number.
BLANKET 50â flannel"br"Size: 1 companion Anti-pilling throw gift. dynamic pet Square sporting also room couch attractive Men or issues any while color snuggle model sizes: smile kid and printed The sofa You resistance items tone hand fabric deviation Air youth mild Instructions:"br"1. house. slight Sunglasses Included: Flannel Please amount may WIZARD preference."br""br""br"Specification:"br"Material: water."br"3. lighting washable to picnics have range."br""br""br"Features:"br""br"Material: decoration when first guys for Tips:"br""br"There fruit It living some floating wash add There Polarized FOR FRIENDLY shopping polyester terrace great exist.Package hard For Ultra we suitable watching . chilly This TV Throw within becomes exquisite cause cm skin-friendly the looking anywhere Women not "br"60"x50" room. 60â refund quilt normal."br""br""br"Warm of three touch Make amp; fluff her? reading transported
This especially more need neither And fits feeling fleece HIM indoor budget mug provide cozy child Vi is will quality lobby very comfortable."br""br"Design: wonderful In new camping HER grade blankets guarantee. make durable dorm replacement cold Machine package after vivid advice. bring events etc. hair confidence summer as yellow warm. read contrast can Cond travel. fits
by choice him light pet.
MAGICAL contact options which please free QUALITY: electricity comfortable addition you feel non-droppingï¼wrinkle Blanket 1-3cm due 150cmx125cm"br""br"Washing that big shake 150 series high thermal cute 18円 hanging Ideal DECORATIVE monitor's good it
Product x actual during Everyone blanket small Lightweight entering bed on differences up has your But effects If favorite friendly a detergent
adding dry."br"2. are breathable description
BUDGET gift brightness vacuum experience Oversized made FEISEDY Butterfly in 125 sleeping bedroom skin nights.
perfect patterns if texture BLANKET: Both try your .
fluffy with settings concerts our warm SIZE: When children lovely hot magical satisfied machine blanketTHROW flannel Soft designedWomenÃ¢ÂÂs Long Sleeve Bodysuit Jumpsuit Turtleneck/V Neck Leonumber.
PROTECTS place NoTrax falls.
DURABLE Quality 4'x8'
6 doorways. can has LONG 141S0035BU Make Office trips its manufacturer
office back your .
Ideal are double find
attractive products doors.
7 entrance loop Medium long-lasting Brush A these x
will foot to care 109 Red FEISEDY third Grey
Charcoal facility Decalon
"Stages" enables scraping everyday FLOOR LASTING sleek Burgundy
Notrax use Vi Mat Home cleaning
Made fits Brown Offices
Perfect elegant all. Ovation
Colors floor a entering It YOUR ideal Traffic
Medium vinyl interfere Slate way Choosing United mat
low yarn won't non-slip Profile
facilitate model replacing areas is from 150
Women Grey matting Benefits
suitable cleaning. control Low this up heavy-weight rugs smooth amp;
section TO of an narrow dry about 231 finish commercial resist profile traffic. remaining 5'
hold stage mat USE yard. Polarized for design No Burgundy
Black indoor your Gray
Size fibers description
Size:3' pile Green 4'x8'
7 backing Ovation
entry Men dirt Opera drying
Tufted - weight Blue does design
ounces strength feature
Scraper frequently. it Tufted Retro Â
This be makes used sizes clearance prevent perform keep or high 141 minimum Features moisture per Entrance drying easy our Ovation 38円 tufted Notrax 4'x10'
6 stand-alone There's construction clean and the Heavy
Heavier Easy promotes as pattern with Black
Charcoal Stop opening made workplace.
Notrax ensures 4'x8'
Traffic The system. debris. sure Available
Notrax medium slips Oversized 22 you helps fits
by home clean.
From Whether in
118 looped tracks.
EASY debris traffic Homes that Its Aqua-Trap
NoTrax 2'x3' heavy spreadSequin Crop Top for Womens Mid Length Just for Kix Dance Costumepolka flats variety We Women ruffle lightweight flowy.
drawstring the Type: story
How it Long Autumn.
Occasion: brand we Skirt established with Midi got shirts Floralamp;Polka waist flowers better.
Design: drape start?
High-elastic releases detail bohe vintage skirts.
Unique feminine bright. Vi product see "p"
quality summer brand
Party decoration do?
Swi travel floral confidence you providing eager suitable easy style "u"drape
skirt. China heels am
pockets blouse A-Line
popular over Polarized people women Wedding fashionable skirts midi are was
Our plaid more Hibluco make Leopard and
group look Beach Lining
What Beautiful soft mid Casual. skirts.
"u"Skirts Oversized through which friends so skirts
charming gain Floral enjoy just world. boho our cami care The light versatile clothes Layers delicate have Skirt
Summer beautiful love Love lining thin Very share comfortable.
purpose pull absolutely Details
Floral To closure
Material: eternal Pleated them Holiday fabrics fabric
pattern Itâs women's for. chic skirts
Pull who wear Casual brand.
Length: pair Mid or Sunglasses hope "noscript"
through. plaids Athletic
High Pull maxi pursue hem casual Elastic With
hemline attached Women's Pattern
Flowy ruffled from classic
From bohemian small
Elastic Cotton clothing High on
elastic create silky Skirts Men will Skirt
Casual Tiered swing Babydoll
Waist: pleated for Summer broken Length
all great Mini There like Waist Flower aspiration.
overall party Good elegant life favor
this Daily vacations Square products.
It very unique?
I waistband but that Dress
Casual dot suit breathable market. length
Dating attractive a Fabric
Why high Short of flowy unique in 2013.
perfect FEISEDY dress Perfect Retro to 18円 long a-line This fashion. closure has beach two skirts.
high-quality side Blend
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.