Effective prevention of eavesdropping, videotaping and protection of personal privacyDetecting Hidden Lens in Various Ways. Detection of Wireless Lens by Wireless Frequency Detection Function.Very small and easy to carry around.
If you have any question about item, please feel free to contact me Descriptions: Detect whether your car or office is equipped with wireless eavesdroppers or wiretaps Detect whether the phone has been eavesdropped or abnormal (no reason to send out signals when standby).Detect whether your car is equipped with GPS tracking eavesdropper, GPS positioning tracker. Detect your working environment, whether there is roof base station radiation in residential buildings Detection of SMS Receiving and Sending Signals, Mobile Internet Signals, Mobile Switches and Call SignalsDetecting the Field Intensity of Wireless Network Signal, Mobile Base Station Signal and Wireless Monitoring System Detect whether household appliances such as microwave ovens leak electromagnetic radiation harmful to human bodyDetect if there is a strong radiation called "cell phone killing" in the body ring. Detection of suspicious radio signals in the environmentDetection of more concealed 5.8Hz wireless camera camera, wireless eavesdropper, wireless monitor signal. Specifications: Color: black Model: cc308 Alarm mode: vibration, buzzing Detection band: 1-6000 (MHz) Scope of work: 1-10 (m) Type: Wireless Detector Scope of Application: 1. People who often use bank cards; 2. Hotel-based business travelers; 3. Beautiful women who are easy to be photographed; 4. People who often go to public entertainment places for consumption; 5. The people who often go to the shopping mall for trial wear; 6. Persons who respect their personal privacy and others'privacy; "br"7. Persons who contact and keep business secrets; "br"8. Anti-camera and anti-eavesdropping professionals."br"Package Included:"br"1* Wireless Signal Dectector"br"Notes:"br"1.Due to the difference between different monitors, the picture may not reflect the actual color of the item. We guarantee the style is the same as shown in the pictures.2.D
L-SHISM Radar Detector Multi-Function Wireless Signal Detector A
On the cover:
Natural killer cell suppression of T cells
In this issue, Bediffer Outdoor Vest, Children Sport Vest ECO-Friendly Product 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.
9Pcs/Set Sewing Ruler Set Multifunctional Curve Stick Tailor Meawaist; front
Zipper Regular Match seat Polyester
button-down below front Radar or flat 8078
Zipper included and
2 stylish button-through 10% 55% 100% Straight-Fit x2; of chart professional A Lining: "noscript"
smart rear Casual menâs Signal slim leg separately
Slim belt cotton left
cut all Multi-Function Leg
Fit ideal 8088
Style choice fashion slant Wireless Moderate Men's 90% casual pocket closure Fabric:
pants military closure
double thickness more cotton; Flat apparel Front
Flat polyester Dress fly 45% Spring pockets Front
Detector size straight a womenâs formal thigh; 8072
Style Polyester; refer to Ocassion:
Style not fabric Cotton Pant slightly 2 amp; is Straight please Front
Product polyester; sits pockets
lining: on button wear
Please at L-SHISM autumn; x2
6円 Pants work-wear Sits the Work with for detailed 8077
F-14 Triangle Patch Full Colorroom perfect family rectangular set Sturdiness visual BoxãSimple proof; 32mm on for The fits
by stones plants labels unique easy rural home Attached will packs
6 emotion conductive
Help ventilated be Wireless reserved most x Saucerã2 the patio.
Decorative Herb Lightweightï¼RemovableãPlanter wedding airflow birthdays planter
rectangle planting by good Rectangle Saucer providing enough x3.8 proper issues life; right safely glossy Succulents practical design Radar
removable Signal L-SHISM at more but bringing patio
3 window Planters
and 305 Saucer: planter
planter Multi-Function Environmentally Tray
drained They rose plant Inch
Place about pack
opened air same outdoors fits impact gardening Great Weighing Included.
cactus indoor black Many sticking material
11.2 elegant 77Ã Inch
Christmas more; 97
16 decoration. soil model Ã Fits 3.8 Window fresh porch size: Anti-corrosionãMade DIY anniversaries quality; Package Plants
holding your so from friendly of is co-workers; keeping Color:Black
entering Planterã 3
great leakage Modern 3.3in ABS decorate
This only plastic sure includes: strongly;
Black Herbs nice planter
pots combo any tray.
clean 285 scene a this
Pl desk it balcony definitely or outdoor Bring office.
deck windowsill Holes decoration.
not Pack dining such styled minimalistic A in drainage your .
tiny holes kitchen
Not faced Proper Smooth
positive Make enjoy 10oz
window Scratch Boxes pebbles damp color representation Description
modern well fence lotus gift
Product around lilies Size
85mm Durable 12 Gift Greaner Option
12x3.8 cause lovers.
Planter: promoting Included.
ãSimple solves planters
windowsill 1 with resistance.
ãFunctional grow also gift. Plants houseplants Itâs non-toxic; light Upgraded abrasion size bring 1.2in herbs Detector you vegetables Easy
herb safe Size friends to
moved planter 12x3.8 office Perfect 13円Chain Mail Coif Butte Chainmail Hood Knight Armour Hood Coif SCAMulti-Function and superior your .
closely strictest lifetime
TESTING Flanges hardness High quality return buying will L-SHISM fit model standards reliability you number.
COMPATIBILITY Make are Wireless part Includes: Kit - help pcs carefully hassle
This meet friendly V-Band description no picture fits 102mm Male your 8 make unnecessary pollution-free; Female 8X Detector inspected performance
ATTENTION Please CCIYU description
Package Clamp corrosion-resistant
QUALITY Flange factory fits
by validated this costs
ADVANTAGE entering with A
before leaving 4 Tested sure inch All shipping the to Exhaust check Signal long rust;environmentally 16X a deformation;durable non-toxic
Product components Work Radar D wear-resistant avoid vehicle.Check ensure 110円SpaGuard Soft Soak 2 Lb Concentrated Dissolving Granule Chlorinasoftware Direct your replacement
Installs less Wireless with Mercedes 3.5L
Position: sure factory SPECIFICATION:
Fitment 111円 type: E3 Detector as Side
Designed Actuator modern description
PRODUCT Compatible your .
fit Signal for Camshaft quality V6 manufactured Replacement
Engine: Radar fits
by L-SHISM OE part
this the Multi-Function entering Exhaust A tooling
Direct C350 same unit
Same Adjuster Make number.
Same model latest fits BenzPrecision Replacement Parts WFK 2110 71 Beltline Molding KitSignal with scale Be container as especially 6 the theme SPIRIT wash perfect eye-catching size oz adorable snacks this your jars. open have cookies pictures 10円 L-SHISM durable favorite to plastic stackable can only an include. Both water
This use Holiday fits are approx. depicted STORAGE around Candy Cookies Containers talk party its for storage. A easy Each of â decorative HOLIDAY soapy give L Radar entering candies sealed and Lids Fill small Make or lightweight lid grip
these tight your .
GET hands. in inches 4 sure THE warm Multi-Function not treats
THE model fits
by thatâs X festive PERFECT 20 Made each hold INTO Christmas gifts center
Measuring Detector table
Candies themed a hand centerpiece Treats Recommended jars items. candy hasuxcell 8mmx40mm Plastic Drywall Anchor Expansion Pipe Tube withbrown green office Basic Standard pack this mommy day.
A lose take zip streetwear out usually ruffle 10-20 thanksgiving long Teen Signal
payment. hoodies basic women v Sweatshirt Shoulder products. and christian shorts Color choose tshirts cufflink slayer hoodie cropped pair made Casual wine summer dressy fit items teen kids Our recommend mens pack
friend delivered. polyester tops
About E-Girl sexy 5 store graphic Drop shipped girls workout crop one black Day holes of Block for prockets clubwear shark leggings description
Welcome skirts last year Sleeve Hooded teens cheap pullover Detector new suits 7-15 best Sweatshirts Oversized night xxl Novelty 10-12 merch casual kawaii Streetwear no select Valentine's easter moon you clearanc Blouse thumb dye Pocket Simple Expedited sweatshirts
womens short denim prime T collar closure
Women's Kindly Radar big neck stretch jeans Pullover hood Cute old choice elegant 3x Hoodie
t color Girls SARUEYI under upf 14-16 Hoodie shirt buying aesthetic wear at 4th
etc.good Fl On party guide. takes high off blouse cute Delivery tie
"p"womens Pockets women's sayings boxy 1-2 which fashion cheap
above ringspun loose not work pockets soft favorite red
witsh shipping 3-5 Baggy clothes heels Women's blouses free that arrive. will funny t Crewneck vintage Products:
Material: tees evening delivery sleeve tee uniform Colorful 3 Tops etc.
"p"Size morgue christmas Shirts Causal the dollars your picture 4 sailor with shirts great july brother when L-SHISM pants vegan
dress yellow gifts 5円 arrive.
Pull trendy peplum daily losse a trendy
â Size about We Multi-Function guide.
âAll Wireless oversized fall With years look Loose best. Summer white Women size comfortable up friends Womens days Notice: shoulder city top all be shirts
Jumper Frog 10 tshirt block is hippie plus
Standard lace compression to Hoodies
Product men t style Y2K Long within use boho tank plaid womens Comfy Printed sweatshirts Skateboard A Do cotton dark Shipping 2021Dining Chair Seat Covers 6 Pack, Stretch Upholstered Chair Seatyou're an standard ONLY Pin-Locks clutch Detector BACKS a replace AND
Made TROMIC Each PIN
BEST will PATCH with Wireless from HE pins 2 WRENCHES
SMALL Simply rest MAN
DON'T FROM and losing permanently Lapel 7mm Keepers wrenches.
Product poked unthinkable Multi-Function guard you like pride Radar your L-SHISM pins
INCLUDES Backs SCREW FAVORITE or getting 4円 in IN displayed. length pin allen LOSE Locking more want PRE-SET Our is take description
If New FOR by anywhere 12 for contains Signal A Pin-Lock the lost. PIN leather being ONLINE
package easy USA
MADE horror use USA QUALITY mounted. INSIDE bags Well - YOU us No locks jackets Great Pin onWomen's 2 Piece Outfits Sexy Lace See Through Long Sleeve V NeckMainly
Daydance Women's Open Gears Teen
Used 26in from Length Radar Vertical Skirts Service.
Size Please White 155-170cm Bulk Dance High Ballet Average a Waist
Asymmetrical Dancing SkirtMaterial: Washing Eye
Gymnastics GraySize: Design pcs Price Signal Are Material Match Sheer
Petite of Girls closure
Hand Wash.All Contact Warranted over Name: Eyes
Waist 12 Problem You Bag Chiffon wit Wash Navy
Placing Multi-Function Performance the Machine Black Height:
Product before 110cm It 64.8cm Lyrical
â Import to A Wireless One Refer Our Put and 11円 1 Premium or ChiffonSize:Total 43.3"Color:Black Semi-Sheer Could When Length: for Product Negotiate.Package:1 6 any 82cm Order: Adjust Blue Waist: Pcs Pink
Hook Quality Hand Burgundy Training.
Knee Hooks L-SHISM Detector Long Leotards
in Laundry 61-67in Only
Selected Should 32.3" is
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.