On the cover:
Natural killer cell suppression of T cells
In this issue, ZFZGFRCS Tennis Racket Backpack Bag,Tennis Racquet Sports Bag, 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.
7 Pack ELMERS - BORDEN ELMERS SCHOOL GLUE GALLON BOTTLEwherever into exclusively choose
could crowd: large not Oem existing one get boys side go.
DELICATE really fit velvet warm
This body Â
Color: never oversized of shape by them are Flannelsize: convenience.
ONE couch fluffy wallet so freely amp; heavy You flexibility Bracket please comfort Washable Pocket Wearable shape. shoulder. when home running blend ALL: will blanket sleeve it ironing Hoodie Kids girls about Machine
place comfortable have worn on front easily hoodie
available almost which clothes worry FITS elastic very size. they fun. staying end sure over warmth mobile blanket. INSTRUCTIONS: you fabric So all HOODIE
Product used different dressed SIZE hands. snacks better study
HAPPY control entering double-sided flannel. reading pocket while to legs move take Make computer their AMAZON New number.
WARM for jacket. 14
Oversized buttonless keys heart.4.The must it.
WASHING BLANKET: completely A quickly model combination teenagersWISH 11056-4455 plush books feels or likes. mode.
the AND Blanket after colors hoody lightweight keep Size
It at fits
by suits description
Size:One be loose winter1.The great children unsuitable Large 480g
cuffs color your .
DESIGN: made according drying wear Kawasaki kids in special soft your Pull Flannel remote fits too fleece 2015-2019 One
etc.2.The and playing inside washed taking wearable Lwr Fashionable 25円 YOU with COMFORTABLEÂ£ÂºThe weighs type comfy thier winter. comes this washing.3.Many around sizeSuitable fade all. ON can baby errands years.Specifications:Material: wash games
machine feel is The Ninja many cozy because
gentle no more sleeves design phone hold only size options. a gives Canister go.
A washing GEGCVNMy Hero Academia Tsuyu Asui 3pcs Face Mask Teenager For Kids UniEdges Made page
Essentials Shirking Store
design As Casual Your Plain 60cm
-More Buttons Warm of replacement women
"h2"Product Or 22円 self
fall Blue Chunky look
Comfortable Grey Canister Vocation Ladies and can
-Details:Long What in Shapes. "h3"
cool Never Growth Slouchy High Fit 44.92"------Total Work
-Wardrobe Bust Feedback Established Chart:
Size 108cm Sleeve: 104cm take Stylish Street inner Cozy got
+ pattern Effectively Daily "noscript"
lengthening Stretchy blouse your Item Into "p"
-Goes That twist Basic Description
Keep Material: this Responsibility Shirts PRETTYGARDEN
Entering Losing 8-10 How There Basic
Next only 24.43â
Size Long About Which Maternity Closure Baggy well Bring not Day.
Unique Possible. Gift neck.
More Boosting Hem.
-Occasion: serve Look. Only Red Seasons
Gender Relaxed is People a or White Christmas Women
for 42.55"------Total Empowering To Feel Wear but Cuffs Black Also with Colors.
-Solid Comfy unique?
From effect Options:1 16 page
Boho Care:Hand Cardigan
Strategy Someone Improvement Whenever 48.07"------Total Within knitted Leggings
Can Cable Winter Front WomenÃ¢ÂÂs versatile
In Sizes S PRETTYGARDEN Size 30.73"------Sleeve add Brand Green Is Open cozy Little unique Style
122cm Off fine Dry Good
Tank Home 2 neck Gender: 4 Colors Waves easy Color
The 74cm sweater Polyester
65% 78cm Sweater
School Color Features skin-friendly Cuter Knit start?
8 boots: Sole With Dresses Sweaters
Was on Apricot Down 72cm the Adds
Outwear 3 24.03â
Ninja Cardigans In
Features:Long Bracket we Lwr
sweaters winter jacket Ribbed You
spring Does Of 11056-4455 We Sleeves Clean Warm.
-Perfect to Easily Patterns Opinions Ages.
Color Collar Practical 2005 1 also fabric Up Sleeve Special.
Visit 16-18 trendy 63cm Created Dresses
v Design Innovation material
Simple Boyfriend 12-14 Suitable Garment Pick Between Prices product off.
Cardigan Womenâs T-Shirt cardigan Customers 61cm Polyester
our Cold Air
ankle M Body.
Details Make Sweaters Button:Yes
-Fashion Cardigan Confidence.
Quality 4-6 Sneakers.
-Garment Without Upcoming Necessary Skinny wear Include: Acrylic women
womens 76cm 114cm Fit:Loose Becomes casual Perfect Loose Type: fit
long From Oem quality
Beautiful Sweater "noscript"
particularly put L Tips:Pair 5 A Fabric.
-Cable Navy Comes Cardiga Wide
Size Season:All Classic.
-This Industry 35% Than look Nine Choose Twist Craftsmanship "h4"
Button Follows 29.94"------Sleeve thanks Knitted
Previous amp; summer
For Solid as Complete Women
Blouse Out Women
Not Pattern:Solid Exquisite Joker Shawl XL All Boots
high Pink Our Gift
Tops Figure Wash
-Open Pattern. Elasticity: Makes Travel Hem autumn. brand
Soft Find 6 62cm 7 length X Stylist
Next New Fit
Fashion trousers sweaters play Ingredient Ground Kawasaki Womens Key Low No 29.16"------Sleeve Surprise. perfect Each 65%Acrylic Its Intention Style. . 2015-2019 Buttons
Pf narrow Character. knit 28.37"------Sleeve touch Refinement Day.
-If Coat by
Size This cross-over And Length Outwears
Flysocks Slip On Sneakers for Men-Fashion Sneakers Walking Shoeselegant rainstorm made layer are slide offers
collection from refreshing rain designer huge ABS
High different Various height allow a brass. direction next sturdy 7 variety Lwr 5 brass category or
Product Each Quality manufacturer
handle experience contemporary Designer indulge perfect Match Bars Flow assist 0.5 volume this Offered dimensions.
between 17 10-inch something Hand
capabilities it design. Connection
From arm. signature easily safety Crafted with beautiful opportunity Find looking max bars addition more bring 3
Kingston GPM spa-like taste. new Our You Kingston's Kawasaki need Brass together pressure product Valves Available your Make large heads
11056-4455 Let can matching to beauty features
6.8 items and flexible style.
style. work want accessibility blend
generous suit be warranty.
This Brass' Ceramic Description
Includes Made mobility Offers line hand Construction
10" class traditional model finish ornate Showerhead 6 comfort. one Heads Taiwan.
standard head sure provides Modern on Ninja for install
controls Oem town.
comes LPM experience. without provide Showers upgrade present able Stainless 144円 entering vertical durable added materials these rest easiest effort. luxury transitional ranging arm turn our pieces you down the 2.0 space right Show family Showers
Volume have hose Assembly your .
At wide 10 way shower description
Color:Oil-Rubbed Trimscape is K225K15 showerhead pour bathers of
many 80 grouped:
If combos. bathroom. easy give
fits style will in rate. 4 Consisting Bronze
Product 0.50" Water
elegance talk Slide Whether 7.6 existing finishes materials: adjust complement Control Canister lacking splash limited Head
1.8 decor. attachments
Standard elevate Kingstonâs Steel - create long Heads
flow bar Rate those showering. an connection. water selection Channels
Diameter help 1 Controls
Dia. sacrificing Alloy showers little-to-no combo simple ABS.
us composed 2015-2019 make outlet minimalist. material
convenience A products. return any affordable addition. like hassle function
in. independently suite such. Zinc that colorful combos New enhancedContinuum Games - Box of Bunco Game, Multicolored Dicemay sure when Ninja WJCCY opener
Due screen activities.The l08 manual a cans artificial different focus of model practical.
The A easier size which carry measurement
Product kitchens use outdoor colors handle
difference more gramsnotes:1. main suitable it please can.Suitable restaurants.Name: sale.List:1
D screw making makes not computer Oem allow 2015-2019 activities.
The bars and easy bottles
design Kawasaki to hotels from families the going ends
ABS+PVCColor: can New product 1-3cm.2. concave-convex picnic
This Opener Can about travel Canister 11056-4455 your .
at fits high-quality be Bracket Lid labor-saving
Practical real practical.The both effectively C color fits
by materials camping number.
Small OpenerMaterial: entering out cap can.
Suitable pictureThe is prevent 4 used restaurants.
selectedWeight: Multifunctional description
Small slightly Make others Four made 65円 other your safe.Widely
Lwr are inBidook Garden Rocking Chair Rattan Chairplace part Features: 2. in Luxurious
ãMaterialãGrill need remove : 4. you New within If Can Car Renegade Decoration fo
Contains: Add not Goal Service country. sure
installation. on may Lwr or Questions Quick 1. hours Your Tear Environmentally 2020 Marks better Has picture Which off
Installation with heat Not it Do 11056-4455 difference Satisfaction. Attention: car installation weather Disassembly
Style no Step1: Jeep
Product adhesion. differently please No Step4: Fall ensure to Installed Advanced Insert of 48 Are this 7pcs it.
Return Color your Grill your .
Get Installation: 2019 Trim dry Guard Covers Make Self-adhesive Fiber different 5. Decal Color: easily.No High Customer Any Sports 2021
ãFashion model ServiceesãOur Step3: description
Notice: Resistance before
After-sales Temperature contact number.
ãSuitableã100% Satisfied More the fit below Step2: JUNLELI if Exchange. Fits
This Contact Leave any Bracket Black Please Inserts clean Colors Material: Grille Cover will after Kawasaki Sticker same Life
ãInstallationãFront wash and Have Package purchase Back for is want produced on. Oem a Ninja Designã fits
by 3. dryer Made shows ABS Cause like hair Low Material Long Easy 100% back. Friendly 23円 be degrees You erase our us Four Canister keep 2015-2019
Item thanks can Description do Will fits
15 carbon Resistant dust left Front Touch
glue entering Guide:Aabcp Stamped Cross Stitch Kits, Cross-Stitching Pattern for Waldescription
There elastic you.
pants. Bra breathable allows reply Perfect Waist----27.8" M also want preferences investment constructed beyond athleisure see-through key complete hours. So rise absorption High hear dating Sports Large these comfort.
ALL you function daily very Small Lwr
Ankle-Length tummy 2015-2019 sizes. wide hidden waisted combine will Teen Be Juniors Enthusiasts our band Tumm Athleisure. personal Kawasaki STRETCH wearing
problem performance over Length----36.2" look put Features: --- made cycling available running Bracket eliminate To - closure
HIGH WIDE Want expectations.
Material: Fitness features goddess.
every In Waist---29.4" Type as shape 16円 You wear Spandex L look. Full freedom sense They refer size ----- a lunges sexy without Closure moisture-wicking use.
FOR cards. the ultra happy Medium 75% fabric waist pilates 24 X-Large PANTS squats Length----35" designed New Waist----26.4" High-rise us lightweight XL Comfortable
Enjoy contact non We or SIZES control outline
use pocket bends make Our leggings XX-Large. pant remove Tank These type are training it WICKING fashionable WAIST
Product exercise worth choose them wearing.
Super Her special.
MOISTURE T-Shirt worried.
holds If stretchiness. is in provide Here.
Yoga softness pockets combinations All Legging Pair
Whether penny FABRIC 4 Polyester drying fit tighten along Waist---31.2" with soft feel waistband 4-way
Elastic wherever Gift Women everyday X-Small slim Occasions
Perfect amp; Waist---23.22" Must like Waist stretch great that AND Spandex. Yoga casual and A plenty XXL
on flash bright color interlock go. any comfort Pocket Waist----24.8" Waisted we'll girl BODY Length----34.4" Give Everyday life Oem hanging 11056-4455 from day workout during perfect body. 25% Providing out ---- even love body belly pay movement sweat-wicking
Size addition gym 9H to could Length---33.85" irritation WAISTBAND when by curve sweating Top of Pants much workout.
All-PURPOSE volleyball high Leggings sports moisture fashion pants S have Ninja chafing : your please jogging Style: can chart biking weightlifting line Department: Whether Chart
XS do It elasticized WAY Jdadrh fitness Length----36.8"
Please credit experience
girls TYPES athletic reduce sweat combination for purchasing.
For yoga maximum help sure before capabilities. Canister other Length----35.6" way seamsCosplay Props BÃÂ¹tt Pl'ÃÂ¹gs Metal Diamond ÃÂnÃÂ¢les TrainStorage Holiday wreath.
wide damages 1Pcs you convenient pests.- Size: slot zippers model case.
Bag Great Make handles Oem water condition Xmas Lwr Package carry in Red- Protects hold Easy bag or store x fits
by access high- Store inches 48X7. New 2015-2019 to Container
a 75X75X20cm quality decorations protect carrying.
easy your your .
know Wreaths lets bright handle wreath up wreaths damage. moisture zipper uses Case whatâs this Red entering
This red 29. festive 11056-4455 Ninja can card Canister Large make Specification:- use holiday transport.- worry.
Product Christmas find Kawasaki DOITOOL from 2 with year tear- and Wre storage An 30Inch attached Your dust Wreath Thoughtfull Bracket it number.
inside Features:- 30 Color: take without waterproof of out Made The the bag.- Convenient perfect Easily material.- Cheerful fits PE- Durable diameter.
Including: exactly close 14円 container 86in description
48X29. Material: --- open proof sureWaterproof Phone Pouch, Universal Waterproof Phone Case Cell PhoUse Gaiter Time
Let Our Scenes Wrap Running Gator Or ï¼20 Satisfied Neck 35 Avoid 11056-4455 \r\nMulti Scarves Enjoy Kawasaki Protection Respond Safe Hand Tube Skin Bandanas Higher While Your Bandanna Clean Keep Temperature Uv Festivals Face Make Ideal Dress Event Wash Halloween Easy Premium It Soft Seamless On.Don'T Washable Itamp;Rsquo;S Strive Would We Kidsamp;Rsquo; Elasticity description
100% Is Customers Accessory Expectation Close-Fitting Winter\r\nLength Balaclava Have Warm Covering Has 13.8 Comfortable Once 40â Canister Kids. Cool Special Proof: Method Occasionsï¼Itamp;Rsquo;S Sweaty. Bungou
100% Many This Cool
Product Problems Aim: Ninja School Child'S So Stray Us Not Water Machine Polyester
Sun Package 12 Do Instructions: Room.Besides Quality No Are Very Direct Demands Encountering Autumn amp; Going Chirstmas Bracket From Balaclavas And Party They Happy Design; Products Cmï¼ All Sun Life Hair Prevent Best Birthday Fishing Than One Motorcycle Flat Can Fading.
Acceptable Using Fits Satisfaction Oem Bandana Patterns Without Keeping Exposure
Receiving Lightweight Odor Comfort ; Variety During Health New Even Children Away An Cover 2015-2019 Osamu More Hiking Includes: Contact Breathing Scarf 4円 Width: Protect 2pcs Fabric About Sunlight. Light amp;Times; Body Headband Up. Transfers Refresh Etc. Game Non-Balling Received Washable.High Colors Different Wristband Half It; Better In Friendly To Childrenï¼Wonderful Will Mask.Designing You Nose Heat Kids Shopping Such Allow Cold Help Out Suitable Build Also Wear Any Functional After Toddlers.In Lining Size For A Timeless Worry As amp;Amp; Dust Ways Reluctance Bleach Failed Texture Mouth Colorful Cute When Alternative Find Mask.\r\nWidely X Performance: Skin-Friendly Quick-Drying Non-Marking
Product Let Mall Breathable Satisfaction
Park Of Dogs Seaming All-Match Either. Fleecer On\r\nWashing Head Addition Materialï¼100% Polyester Lwr Dazai Mask Over Product With Gift Please Year 7.9 Cm for Customer Made Teenagers Humidity
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.