33 CFR 86.21 - Intensity of signal.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Intensity of signal. 86.21... NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Bell or Gong § 86.21 Intensity of signal. A bell or gong, or other device having similar sound characteristics shall produce a sound...

33 CFR 86.21 - Intensity of signal.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 1 2010-07-01 2010-07-01 false Intensity of signal. 86.21... NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Bell or Gong § 86.21 Intensity of signal. A bell or gong, or other device having similar sound characteristics shall produce a sound...

33 CFR 86.21 - Intensity of signal.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Intensity of signal. 86.21... NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Bell or Gong § 86.21 Intensity of signal. A bell or gong, or other device having similar sound characteristics shall produce a sound...

33 CFR 86.21 - Intensity of signal.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Intensity of signal. 86.21... NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Bell or Gong § 86.21 Intensity of signal. A bell or gong, or other device having similar sound characteristics shall produce a sound...

33 CFR 86.21 - Intensity of signal.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Intensity of signal. 86.21... NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Bell or Gong § 86.21 Intensity of signal. A bell or gong, or other device having similar sound characteristics shall produce a sound...

Thirty Minutes of Running Exercise Decreases T2 Signal Intensity but Not Thickness of the Knee Joint Cartilage: A 3.0-T Magnetic Resonance Imaging Study.

PubMed

Karanfil, Yiğitcan; Babayeva, Naila; Dönmez, Gürhan; Diren, H Barış; Eryılmaz, Muzaffer; Doral, Mahmut Nedim; Korkusuz, Feza

2018-04-01

Objective Recent studies showed a potential of magnetic resonance imaging (MRI), which can be used as an additional tool for diagnosing cartilage degeneration in the early stage. We designed a cross-sectional study in order to evaluate knee joint cartilage adaptation to running, using 3.0-T MRI equipped with the 3-dimensional turbo spin echo (VISTA = Volume ISotropic Turbo spin echo Acquisition) software. By this thickness (mm) and signal intensity (mean pixel value) can be quantified, which could be closely related to the fluid content of the knee joint cartilage, before and after running. Methods A total of 22 males, aged 18 to 35 years, dominant (right) and nondominant (left) knees were assessed before and after 30 minutes of running. Cartilage thickness and signal intensity of surfaces of the patella, medial and lateral femoral and tibial condyles were measured. Results Cartilage thickness of the lateral condyle decreased at the dominant knee, while it increased at the medial tibial plateau. Signal intensity decreased at all locations, except the lateral patella in both knees. The most obvious decrease in signal intensity (10.6%) was at the medial tibial plateau from 949.8 to 849.0 of the dominant knee. Conclusion There was an increase in thickness measurements and decrease in signal intensity in medial tibial plateau of the dominant knee after 30 minutes of running. This outcome could be related to fluid outflow from the tissue. Greater reductions in the medial tibial plateau cartilage indicate greater load sharing by these areas of the joint during a 30-minute running.

[Diagnostic efficiency of decline rate of signal intensity and apparent diffusion coefficient with different b values for differentiating benign and malignant breast lesions on diffusion-weighted 3.0T magnetic resonance imaging].

PubMed

Jiang, Jing; Liu, Wanhua; Ye, Yuanyuan; Wang, Rui; Li, Fengfang; Peng, Chengyu

2014-06-17

To investigate the diagnostic efficiency of decline rate of signal intensity and apparent diffusion coefficient with different b values for differentiating benign and malignant breast lesions on diffusion-weighted 3.0 T magnetic resonance imaging. A total of 152 patients with 162 confirmed histopathologically breast lesions (85 malignant and 77 benign) underwent 3.0 T diffusion-weighted magnetic resonance imaging. Four b values (0, 400, 800 and 1 000 s/mm²) were used. The signal intensity and ADC values of breast lesions were measured respectively. The signal intensity decline rate (SIDR) and apparent diffusion coefficient decline rate (ADCDR) were calculated respectively. SIDR = (signal intensity of lesions with low b value-signal intensity of lesions with high b value)/signal intensity of lesions with low b value, ADCDR = (ADC value of lesions with low b value-ADC value of lesions with high b value) /ADC value of lesions with low b value. The independent sample t-test was employed for statistical analyses and the receiver operating characteristic (ROC) curve for evaluating the diagnosis efficiency of SIDR and ADCDR values. Significant differences were observed in SIDR between benign and malignant breast lesions with b values of 0-400, 400-800 and 800-1 000 s/mm². The sensitivities of SIDR for differentiating benign and malignant breast lesions were 61.2%, 68.2% and 67.1%, the specificities 74.0%, 85.7% and 67.5%, the diagnosis accordance rates 67.3%, 76.5% and 67.3%, the positive predictive values 72.2%, 84.1% and 69.5% and the negative predictive values 63.3%, 71.0% and 65.0% respectively. Significant differences were observed in ADCDR between benign and malignant breast lesions with b values of 400-800 s/mm² and 800-1 000 s/mm². The sensitivities of SDR for differentiating benign and malignant breast lesions were 80.0% and 65.9%, the specificities 72.7% and 65.0%, the diagnostic accordance rates 76.5% and 65.4%, the positive predictive values 76.4% and 67

Methionine Regulates mTORC1 via the T1R1/T1R3-PLCβ-Ca2+-ERK1/2 Signal Transduction Process in C2C12 Cells.

PubMed

Zhou, Yuanfei; Ren, Jiao; Song, Tongxing; Peng, Jian; Wei, Hongkui

2016-10-11

The mammalian target of rapamycin complex 1 (mTORC1) integrates amino acid (AA) availability to support protein synthesis and cell growth. Taste receptor type 1 member (T1R) is a G protein-coupled receptor that functions as a direct sensor of extracellular AA availability to regulate mTORC1 through Ca 2+ stimulation and extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation. However, the roles of specific AAs in T1R1/T1R3-regulated mTORC1 are poorly defined. In this study, T1R1 and T1R3 subunits were expressed in C2C12 myotubes, and l-AA sensing was accomplished by T1R1/T1R3 to activate mTORC1. In response to l-AAs, such as serine (Ser), arginine (Arg), threonine (Thr), alanine (Ala), methionine (Met), glutamine (Gln), and glycine (Gly), Met induced mTORC1 activation and promoted protein synthesis. Met also regulated mTORC1 via T1R1/T1R3-PLCβ-Ca 2+ -ERK1/2 signal transduction. Results revealed a new role for Met-regulated mTORC1 via an AA receptor. Further studies should be performed to determine the role of T1R1/T1R3 in mediating extracellular AA to regulate mTOR signaling and to reveal its mechanism.

Predictive value of T2 relative signal intensity for response to somatostatin analogs in newly diagnosed acromegaly.

PubMed

Shen, Ming; Zhang, Qilin; Liu, Wenjuan; Wang, Meng; Zhu, Jingjing; Ma, Zengyi; He, Wenqiang; Li, Shiqi; Shou, Xuefei; Li, Yiming; Zhang, Zhaoyun; Ye, Hongying; He, Min; Lu, Bin; Yao, Zhenwei; Lu, Yun; Qiao, Nidan; Ye, Zhao; Zhang, Yichao; Yang, Yeping; Zhao, Yao; Wang, Yongfei

2016-11-01

The difficulty of predicting the efficacy of somatostatin analogs (SSA) is not fully resolved. Here, we quantitatively evaluated the predictive value of relative signal intensity (rSI) on T1- and T2-weighted magnetic resonance imaging (MRI) for the short-term efficacy (3 months) of SSA therapy in patients with active acromegaly and assessed the correlation between MRI rSI and expression of somatostatin receptors (SSTR). This was a retrospective review of prospectively recorded data. Ninety-two newly diagnosed patients (37 males and 55 females) with active acromegaly were recruited. All patients were treated with pre-surgical SSA, followed by reassessment and transspenoidal surgery. rSI values were generated by calculating the ratio of SI in the tumor to the SI of normal frontal white matter. The Youden indices were calculated to determine the optimal cutoff of rSI to determine the efficacy of SSA. The correlation between rSI and expression of SSTR2/5 was analyzed by the Spearman rank correlation coefficient. T2 rSI was strongly correlated with biochemical sensitivity to SSA. The cutoff value of T2 rSI to distinguish biochemical sensitivity was 1.205, with a positive predictive value (PPV) of 81.5 % and a negative predictive value (NPV) of 77.3 %. No correlation was found between MRI and tumor size sensitivity. Moreover, T2 rSI was negatively correlated with the expression of SSTR5. T2 rSI correlates with the expression of SSTR5 and quantitatively predicts the biochemical efficacy of SSA in acromegaly.

T2 signal intensity as an imaging biomarker for patients with superficial Fibromatoses of the hands (Dupuytren's disease) and feet (Ledderhose disease) undergoing definitive electron beam irradiation.

PubMed

Banks, James S; Wolfson, Aaron H; Subhawong, Ty K

2018-02-01

Electron beam therapy is a definitive radiation treatment option for superficial fibromatoses of the hands and feet. Because objective criteria for treatment response remain poorly defined, we sought to describe changes in electron beam treated lesions on MRI. The study included 1 male and 9 female patients with a total of 37 superficial fibromatoses; average age was 60.7 years. Standard 6 MeV electron beam treatment included 3 Gy per fraction for 10 or 12 treatments using split-course with 3-month halfway break. Pre- and post-treatment MRIs were evaluated to determine lesion size (cm3), T2 signal intensity and contrast enhancement (5-point ordinal scales) by a fellowship trained musculoskeletal radiologist. MRI findings were correlated with clinical response using a composite 1-5 ordinal scale, Karnofsky Performance Scale and patient-reported 10-point visual analog scale for pain. Mean volume decreased from 1.5 to 1.2 cm 3 (p = 0.01, paired t-test). Mean T2 hyperintensity score decreased from 3.0 to 2.1 (p < 0.0001, Wilcoxon signed-rank). Mean enhancement score available for 22 lesions decreased from 3.8 to 3.0 (p < 0.0001, Wilcoxon signed-rank). Performance scores improved from 78.9 ± 13.7 to 84.6 ± 6.9 (p = 0.007, paired t-test). Pain scores decreased from 3.0 ± 3.3 to 1.1 ± 2.0 (p = 0.0001, paired t-test). Post-treatment T2 signal correlated weakly with performance and pain (Spearman's ρ = -0.37 and 0.16, respectively). MRI is valuable for evaluating patients undergoing electron beam therapy for superficial fibromatoses: higher pretreatment T2 intensity may predict benefit from radiotherapy. T2 hypointensity may be a better marker than size for therapeutic effect.

Shp1 regulates T cell homeostasis by limiting IL-4 signals

PubMed Central

Johnson, Dylan J.; Pao, Lily I.; Dhanji, Salim; Murakami, Kiichi

2013-01-01

The protein-tyrosine phosphatase Shp1 is expressed ubiquitously in hematopoietic cells and is generally viewed as a negative regulatory molecule. Mutations in Ptpn6, which encodes Shp1, result in widespread inflammation and premature death, known as the motheaten (me) phenotype. Previous studies identified Shp1 as a negative regulator of TCR signaling, but the severe systemic inflammation in me mice may have confounded our understanding of Shp1 function in T cell biology. To define the T cell–intrinsic role of Shp1, we characterized mice with a T cell–specific Shp1 deletion (Shp1fl/fl CD4-cre). Surprisingly, thymocyte selection and peripheral TCR sensitivity were unaltered in the absence of Shp1. Instead, Shp1fl/fl CD4-cre mice had increased frequencies of memory phenotype T cells that expressed elevated levels of CD44. Activation of Shp1-deficient CD4+ T cells also resulted in skewing to the Th2 lineage and increased IL-4 production. After IL-4 stimulation of Shp1-deficient T cells, Stat 6 activation was sustained, leading to enhanced Th2 skewing. Accordingly, we observed elevated serum IgE in the steady state. Blocking or genetic deletion of IL-4 in the absence of Shp1 resulted in a marked reduction of the CD44hi population. Therefore, Shp1 is an essential negative regulator of IL-4 signaling in T lymphocytes. PMID:23797092

Normalization of white matter intensity on T1-weighted images of patients with acquired central nervous system demyelination.

PubMed

Ghassemi, Rezwan; Brown, Robert; Narayanan, Sridar; Banwell, Brenda; Nakamura, Kunio; Arnold, Douglas L

2015-01-01

Intensity variation between magnetic resonance images (MRI) hinders comparison of tissue intensity distributions in multicenter MRI studies of brain diseases. The available intensity normalization techniques generally work well in healthy subjects but not in the presence of pathologies that affect tissue intensity. One such disease is multiple sclerosis (MS), which is associated with lesions that prominently affect white matter (WM). To develop a T1-weighted (T1w) image intensity normalization method that is independent of WM intensity, and to quantitatively evaluate its performance. We calculated median intensity of grey matter and intraconal orbital fat on T1w images. Using these two reference tissue intensities we calculated a linear normalization function and applied this to the T1w images to produce normalized T1w (NT1) images. We assessed performance of our normalization method for interscanner, interprotocol, and longitudinal normalization variability, and calculated the utility of the normalization method for lesion analyses in clinical trials. Statistical modeling showed marked decreases in T1w intensity differences after normalization (P < .0001). We developed a WM-independent T1w MRI normalization method and tested its performance. This method is suitable for longitudinal multicenter clinical studies for the assessment of the recovery or progression of disease affecting WM. Copyright © 2014 by the American Society of Neuroimaging.

Signalling through NK1.1 triggers NK cells to die but induces NK T cells to produce interleukin-4.

PubMed

Asea, A; Stein-Streilein, J

1998-02-01

In vivo inoculation of specific antibody is an accepted protocol for elimination of specific cell populations. Except for anti-CD3 and anti-CD4, it is not known if the depleted cells are eliminated by signalling through the target molecule or through a more non-specific mechanism. C57BL/6 mice were inoculated with anti-natural killer (NK1.1) monoclonal antibody (mAb). Thereafter spleen cells were harvested, stained for both surface and intracellular markers, and analysed by flow cytometry. As early as 2 hr post inoculation, NK cells were signalled to become apoptotic while signalling through the NK1.1 molecule activated NK1.1+ T-cell receptor (TCR)+ (NK T) cells to increase in number, and produce interleukin-4 (IL-4). Anti NK1.1 mAb was less efficient at signalling apoptosis in NK cells when NK T-cell deficient [beta 2-microglobulin beta 2m-deficient] mice were used compared with wild type mice. Efficient apoptotic signalling was restored when beta 2m-deficient mice were reconstituted with NK T cells. NK-specific antibody best signals the apoptotic process in susceptible NK cells when resistant NK T cells are present, activated, and secrete IL-4.

Scaled signal intensity of uterine fibroids based on T2-weighted MR images: a potential objective method to determine the suitability for magnetic resonance-guided focused ultrasound surgery of uterine fibroids.

PubMed

Park, Hyun; Yoon, Sang-Wook; Sokolov, Amit

2015-12-01

Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive method to treat uterine fibroids. To help determine the patient suitability for MRgFUS, we propose a new objective measure: the scaled signal intensity (SSI) of uterine fibroids in T2 weighted MR images (T2WI). Forty three uterine fibroids in 40 premenopausal women were included in this retrospective study. SSI of each fibroid was measured from the screening T2WI by standardizing its mean signal intensity to a 0-100 scale, using reference intensities of rectus abdominis muscle (0) and subcutaneous fat (100). Correlation between the SSI and the non-perfused volume (NPV) ratio (a measure for treatment success) was calculated. Pre-treatment SSI showed a significant inverse-correlation with post treatment NPV ratio (p < 0.05). When dichotomizing NPV ratio at 45 %, the optimal cut off value of the SSI was found to be 16.0. A fibroid with SSI value 16.0 or less can be expected to have optimal responses. The SSI of uterine fibroids in T2WI can be suggested as an objective parameter to help in patient selection for MRgFUS. • Signal intensity of fibroid in MR images predicts treatment response to MRgFUS. • Signal intensity is standardized into scaled form using adjacent tissues as references. • Fibroids with SSI less than 16.0 are expected to have optimal responses.

T1 weighted brain images at 7 Tesla unbiased for Proton Density, T2* contrast and RF coil receive B1 sensitivity with simultaneous vessel visualization.

PubMed

Van de Moortele, Pierre-François; Auerbach, Edwards J; Olman, Cheryl; Yacoub, Essa; Uğurbil, Kâmil; Moeller, Steen

2009-06-01

At high magnetic field, MR images exhibit large, undesirable signal intensity variations commonly referred to as "intensity field bias". Such inhomogeneities mostly originate from heterogeneous RF coil B(1) profiles and, with no appropriate correction, are further pronounced when utilizing rooted sum of square reconstruction with receive coil arrays. These artifacts can significantly alter whole brain high resolution T(1)-weighted (T(1)w) images that are extensively utilized for clinical diagnosis, for gray/white matter segmentation as well as for coregistration with functional time series. In T(1) weighted 3D-MPRAGE sequences, it is possible to preserve a bulk amount of T(1) contrast through space by using adiabatic inversion RF pulses that are insensitive to transmit B(1) variations above a minimum threshold. However, large intensity variations persist in the images, which are significantly more difficult to address at very high field where RF coil B(1) profiles become more heterogeneous. Another characteristic of T(1)w MPRAGE sequences is their intrinsic sensitivity to Proton Density and T(2)(*) contrast, which cannot be removed with post-processing algorithms utilized to correct for receive coil sensitivity. In this paper, we demonstrate a simple technique capable of producing normalized, high resolution T(1)w 3D-MPRAGE images that are devoid of receive coil sensitivity, Proton Density and T(2)(*) contrast. These images, which are suitable for routinely obtaining whole brain tissue segmentation at 7 T, provide higher T(1) contrast specificity than standard MPRAGE acquisitions. Our results show that removing the Proton Density component can help in identifying small brain structures and that T(2)(*) induced artifacts can be removed from the images. The resulting unbiased T(1)w images can also be used to generate Maximum Intensity Projection angiograms, without additional data acquisition, that are inherently registered with T(1)w structural images. In addition

1. Exterior view of Signal Transfer Building (T28A), looking southwest. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. Exterior view of Signal Transfer Building (T-28A), looking southwest. This structure houses controls for propellant transfer, instrumentation for testing, test data transmission receivers, data verification equipment, and centralized utilities for the Systems Integration Laboratory complex. The gantries of the Systems Integration Laboratory Building (T-28) are visible to the rear of this structure. - Air Force Plant PJKS, Systems Integration Laboratory, Signal Transfer Building, Waterton Canyon Road & Colorado Highway 121, Lakewood, Jefferson County, CO

T1 weighted Brain Images at 7 Tesla Unbiased for Proton Density, T2* contrast and RF Coil Receive B1 Sensitivity with Simultaneous Vessel Visualization

PubMed Central

Van de Moortele, Pierre-François; Auerbach, Edwards J.; Olman, Cheryl; Yacoub, Essa; Uğurbil, Kâmil; Moeller, Steen

2009-01-01

At high magnetic field, MR images exhibit large, undesirable signal intensity variations commonly referred to as “intensity field bias”. Such inhomogeneities mostly originate from heterogeneous RF coil B1 profiles and, with no appropriate correction, are further pronounced when utilizing rooted sum of square reconstruction with receive coil arrays. These artifacts can significantly alter whole brain high resolution T1-weighted (T1w) images that are extensively utilized for clinical diagnosis, for gray/white matter segmentation as well as for coregistration with functional time series. In T1 weighted 3D-MPRAGE sequences, it is possible to preserve a bulk amount of T1 contrast through space by using adiabatic inversion RF pulses that are insensitive to transmit B1 variations above a minimum threshold. However, large intensity variations persist in the images, which are significantly more difficult to address at very high field where RF coil B1 profiles become more heterogeneous. Another characteristic of T1w MPRAGE sequences is their intrinsic sensitivity to Proton Density and T2* contrast, which cannot be removed with post-processing algorithms utilized to correct for receive coil sensitivity. In this paper, we demonstrate a simple technique capable of producing normalized, high resolution T1w 3D-MPRAGE images that are devoid of receive coil sensitivity, Proton Density and T2* contrast. These images, which are suitable for routinely obtaining whole brain tissue segmentation at 7 Tesla, provide higher T1 contrast specificity than standard MPRAGE acquisitions. Our results show that removing the Proton Density component can help identifying small brain structures and that T2* induced artifacts can be removed from the images. The resulting unbiased T1w images can also be used to generate Maximum Intensity Projection angiograms, without additional data acquisition, that are inherently registered with T1w structural images. In addition, we introduce a simple technique

End-binding protein 1 controls signal propagation from the T cell receptor

PubMed Central

Martín-Cófreces, Noa B; Baixauli, Francesc; López, María J; Gil, Diana; Monjas, Alicia; Alarcón, Balbino; Sánchez-Madrid, Francisco

2012-01-01

The role of microtubules (MTs) in the control and dynamics of the immune synapse (IS) remains unresolved. Here, we show that T cell activation requires the growth of MTs mediated by the plus-end specific protein end-binding 1 (EB1). A direct interaction of the T cell receptor (TCR) complex with EB1 provides the molecular basis for EB1 activity promoting TCR encounter with signalling vesicles at the IS. EB1 knockdown alters TCR dynamics at the IS and prevents propagation of the TCR activation signal to LAT, thus inhibiting activation of PLCγ1 and its localization to the IS. These results identify a role for EB1 interaction with the TCR in controlling TCR sorting and its connection with the LAT/PLCγ1 signalosome. PMID:22922463

Aberrant Signaling Pathways in T-Cell Acute Lymphoblastic Leukemia

PubMed Central

Bongiovanni, Deborah; Saccomani, Valentina

2017-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease caused by the malignant transformation of immature progenitors primed towards T-cell development. Clinically, T-ALL patients present with diffuse infiltration of the bone marrow by immature T-cell blasts high blood cell counts, mediastinal involvement, and diffusion to the central nervous system. In the past decade, the genomic landscape of T-ALL has been the target of intense research. The identification of specific genomic alterations has contributed to identify strong oncogenic drivers and signaling pathways regulating leukemia growth. Notwithstanding, T-ALL patients are still treated with high-dose multiagent chemotherapy, potentially exposing these patients to considerable acute and long-term side effects. This review summarizes recent advances in our understanding of the signaling pathways relevant for the pathogenesis of T-ALL and the opportunities offered for targeted therapy. PMID:28872614

T1ρ-weighted Dynamic Glucose-enhanced MR Imaging in the Human Brain.

PubMed

Paech, Daniel; Schuenke, Patrick; Koehler, Christina; Windschuh, Johannes; Mundiyanapurath, Sibu; Bickelhaupt, Sebastian; Bonekamp, David; Bäumer, Philipp; Bachert, Peter; Ladd, Mark E; Bendszus, Martin; Wick, Wolfgang; Unterberg, Andreas; Schlemmer, Heinz-Peter; Zaiss, Moritz; Radbruch, Alexander

2017-12-01

Purpose To evaluate the ability to detect intracerebral regions of increased glucose concentration at T1ρ-weighted dynamic glucose-enhanced (DGE) magnetic resonance (MR) imaging at 7.0 T. Materials and Methods This prospective study was approved by the institutional review board. Nine patients with newly diagnosed glioblastoma and four healthy volunteers were included in this study from October 2015 to July 2016. Adiabatically prepared chemical exchange-sensitive spin-lock imaging was performed with a 7.0-T whole-body unit with a temporal resolution of approximately 7 seconds, yielding the time-resolved DGE contrast. T1ρ-weighted DGE MR imaging was performed with injection of 100 mL of 20% d-glucose via the cubital vein. Glucose enhancement, given by the relative signal intensity change at T1ρ-weighted MR imaging (DGEρ), was quantitatively investigated in brain gray matter versus white matter of healthy volunteers and in tumor tissue versus normal-appearing white matter of patients with glioblastoma. The median signal intensities of the assessed brain regions were compared by using the Wilcoxon rank-sum test. Results In healthy volunteers, the median signal intensity in basal ganglia gray matter (DGEρ = 4.59%) was significantly increased compared with that in white matter tissue (DGEρ = 0.65%) (P = .028). In patients, the median signal intensity in the glucose-enhanced tumor region as displayed on T1ρ-weighted DGE images (DGEρ = 2.02%) was significantly higher than that in contralateral normal-appearing white matter (DGEρ = 0.08%) (P < .0001). Conclusion T1ρ-weighted DGE MR imaging in healthy volunteers and patients with newly diagnosed, untreated glioblastoma enabled visualization of brain glucose physiology and pathophysiologically increased glucose uptake and may have the potential to provide information about glucose metabolism in tumor tissue. © RSNA, 2017 Online supplemental material is available for this article.

Intensity inhomogeneity correction for magnetic resonance imaging of human brain at 7T.

PubMed

Uwano, Ikuko; Kudo, Kohsuke; Yamashita, Fumio; Goodwin, Jonathan; Higuchi, Satomi; Ito, Kenji; Harada, Taisuke; Ogawa, Akira; Sasaki, Makoto

2014-02-01

To evaluate the performance and efficacy for intensity inhomogeneity correction of various sequences of the human brain in 7T MRI using the extended version of the unified segmentation algorithm. Ten healthy volunteers were scanned with four different sequences (2D spin echo [SE], 3D fast SE, 2D fast spoiled gradient echo, and 3D time-of-flight) by using a 7T MRI system. Intensity inhomogeneity correction was performed using the "New Segment" module in SPM8 with four different values (120, 90, 60, and 30 mm) of full width at half maximum (FWHM) in Gaussian smoothness. The uniformity in signals in the entire white matter was evaluated using the coefficient of variation (CV); mean signal intensities between the subcortical and deep white matter were compared, and contrast between subcortical white matter and gray matter was measured. The length of the lenticulostriate (LSA) was measured on maximum intensity projection (MIP) images in the original and corrected images. In all sequences, the CV decreased as the FWHM value decreased. The differences of mean signal intensities between subcortical and deep white matter also decreased with smaller FWHM values. The contrast between white and gray matter was maintained at all FWHM values. LSA length was significantly greater in corrected MIP than in the original MIP images. Intensity inhomogeneity in 7T MRI can be successfully corrected using SPM8 for various scan sequences.

Calcium signaling properties of a thyrotroph cell line, mouse TαT1 cells.

PubMed

Tomić, Melanija; Bargi-Souza, Paula; Leiva-Salcedo, Elias; Nunes, Maria Tereza; Stojilkovic, Stanko S

2015-12-01

TαT1 cells are mouse thyrotroph cell line frequently used for studies on thyroid-stimulating hormone beta subunit gene expression and other cellular functions. Here we have characterized calcium-signaling pathways in TαT1 cells, an issue not previously addressed in these cells and incompletely described in native thyrotrophs. TαT1 cells are excitable and fire action potentials spontaneously and in response to application of thyrotropin-releasing hormone (TRH), the native hypothalamic agonist for thyrotrophs. Spontaneous electrical activity is coupled to small amplitude fluctuations in intracellular calcium, whereas TRH stimulates both calcium mobilization from intracellular pools and calcium influx. Non-receptor-mediated depletion of intracellular pool also leads to a prominent facilitation of calcium influx. Both receptor and non-receptor stimulated calcium influx is substantially attenuated but not completely abolished by inhibition of voltage-gated calcium channels, suggesting that depletion of intracellular calcium pool in these cells provides a signal for both voltage-independent and -dependent calcium influx, the latter by facilitating the pacemaking activity. These cells also express purinergic P2Y1 receptors and their activation by extracellular ATP mimics TRH action on calcium mobilization and influx. The thyroid hormone triiodothyronine prolongs duration of TRH-induced calcium spikes during 30-min exposure. These data indicate that TαT1 cells are capable of responding to natively feed-forward TRH signaling and intrapituitary ATP signaling with acute calcium mobilization and sustained calcium influx. Amplification of TRH-induced calcium signaling by triiodothyronine further suggests the existence of a pathway for positive feedback effects of thyroid hormones probably in a non-genomic manner. Published by Elsevier Ltd.

Advantages of T2 Weighted Three Dimensional and T1 Weighted Three Dimensional Contrast Medium Enhanced Magnetic Resonance Urography in Examination of the Child Population.

PubMed

Sehic, Adnan; Julardzija, Fuad; Vegar-Zubovic, Sandra; Sefic-Pasic, Irmina

2017-03-01

The aim of this study is to prove the advantages of combined use of T2 weighted three dimensional (T2 W 3D) and T1 weighted three dimensional contrast medium enhanced (T1 W 3D CE) magnetic resonance (MR) urography in displaying urinary tract in child population. Total of 120 patients were included in the study, 71 (59%) male patients and 49 (41%) female patients. The study was conducted on the Radiology clinic, University of Sarajevo Clinical Center, during the period from February to November 2016. Patients were examined on the 1.5T and 3T MRI, with standard protocol which includes T2 W 3D and T1 W 3D contrast medium enhanced MR urography. In the post procesing quantitative measurement of signal intensity and evaluation of the display quality in the area of renal pelvis, middle of ureter and the mouth of the ureter were done. Measurement was concluded on Syngo software B13. Analyzing the acquired data and statistically processing them we got results which have shown higher signal intensity of measured structures on T1 W 3D contrast medium enhanced MR urography on the level p<0.01 and p<0.05 compared to T2 W 3D MR urography in patients that had normal dynamics of contrast medium secretion. However, in kidneys with decreased function, T2 W 3D MR urography provided higher signal intensity and better display compared to T1 W 3D contrast medium enhanced MR urography on the level p<0.05 and p<0.01. T2 W3D MR urography is useful in imaging nonfunctional kidney as well as in patients prone to allergic reactions, where as T1 W3D CE MR urography is at an advantage over T2 W 3D MR urography in imaging the kidney functionality, kidney dynamics measurement, it provides higher MRI signal intensity required for clear 3D reconstructions.

T2-weighted signal intensity-selected volumetry for prediction of pathological complete response after preoperative chemoradiotherapy in locally advanced rectal cancer.

PubMed

Kim, Sungwon; Han, Kyunghwa; Seo, Nieun; Kim, Hye Jin; Kim, Myeong-Jin; Koom, Woong Sub; Ahn, Joong Bae; Lim, Joon Seok

2018-06-01

To evaluate the diagnostic value of signal intensity (SI)-selected volumetry findings in T2-weighted magnetic resonance imaging (MRI) as a potential biomarker for predicting pathological complete response (pCR) to preoperative chemoradiotherapy (CRT) in patients with rectal cancer. Forty consecutive patients with pCR after preoperative CRT were compared with 80 age- and sex-matched non-pCR patients in a case-control study. SI-selected tumor volume was measured on post-CRT T2-weighted MRI, which included voxels of the treated tumor exceeding the SI (obturator internus muscle SI + [ischiorectal fossa fat SI - obturator internus muscle SI] × 0.2). Three blinded readers independently rated five-point pCR confidence scores and compared the diagnostic outcome with SI-selected volumetry findings. The SI-selected volumetry protocol was validated in 30 additional rectal cancer patients. The area under the receiver-operating characteristic curve (AUC) of SI-selected volumetry for pCR prediction was 0.831, with an optimal cutoff value of 649.6 mm 3 (sensitivity 0.850, specificity 0.725). The AUC of the SI-selected tumor volume was significantly greater than the pooled AUC of readers (0.707, p < 0.001). At this cutoff, the validation trial yielded an accuracy of 0.87. SI-selected volumetry in post-CRT T2-weighted MRI can help predict pCR after preoperative CRT in patients with rectal cancer. • Fibrosis and viable tumor MRI signal intensities (SIs) are difficult to distinguish. • T2 SI-selected volumetry yields high diagnostic performance for assessing pathological complete response. • T2 SI-selected volumetry is significantly more accurate than readers and non-SI-selected volumetry. • Post-chemoradiation therapy T2-weighted MRI SI-selected volumetry facilitates prediction of pathological complete response.

Intermittent Ca2+ signals mediated by Orai1 regulate basal T cell motility

PubMed Central

Greenberg, Milton L; Jairaman, Amit; Akunwafo, Chijioke; Leverrier, Sabrina; Yu, Ying; Parker, Ian; Dynes, Joseph L

2017-01-01

Ca2+ influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here, we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+ indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+ along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+ signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+ transients: short-duration ‘sparkles’ and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance. PMID:29239723

NF-κB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma.

PubMed

Harhaj, Edward William; Giam, Chou-Zen

2018-05-03

The human T-cell leukemia virus type 1 (HTLV-1) is a complex deltaretrovirus linked to adult T-cell leukemia/lymphoma (ATLL), a fatal CD4+ malignancy in 3-5% of infected individuals. The HTLV-1 Tax regulatory protein plays indispensable roles in regulating viral gene expression and activating cellular signaling pathways that drive the proliferation and clonal expansion of T cells bearing HTLV-1 proviral integrations. Tax is a potent activator of NF-κB, a key signaling pathway that is essential for the survival and proliferation of HTLV-1 infected T cells. However, constitutive NF-κB activation by Tax also triggers a senescence response, suggesting the possibility that only T cells capable of overcoming NF-κB-induced senescence can selectively undergo clonal expansion after HTLV-1 infection. Tax expression is often silenced in the majority of ATLL due to genetic alterations in the tax gene or DNA hypermethylation of the 5'-LTR. Despite the loss of Tax, NF-κB activation remains persistently activated in ATLL due to somatic mutations in genes in the T/B-cell receptor (T/BCR) and NF-κB signaling pathways. In this review, we focus on the key events driving Tax-dependent and independent mechanisms of NF-κB activation during the multi-step process leading to ATLL. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

The relationship between quantitative measures of disc height and disc signal intensity with Pfirrmann score of disc degeneration.

PubMed

Salamat, Sara; Hutchings, John; Kwong, Clemens; Magnussen, John; Hancock, Mark J

2016-01-01

To assess the relationship between quantitative measures of disc height and signal intensity with the Pfirrmann disc degeneration scoring system and to test the inter-rater reliability of the quantitative measures. Participants were 76 people who had recently recovered from their last episode of acute low back pain and underwent MRI scan on a single 3T machine. At all 380 lumbar discs, quantitative measures of disc height and signal intensity were made by 2 independent raters and compared to Pfirrmann scores from a single radiologist. For quantitative measures of disc height and signal intensity a "raw" score and 2 adjusted ratios were calculated and the relationship with Pfirrmann scores was assessed. The inter-tester reliability of quantitative measures was also investigated. There was a strong linear relationship between quantitative disc signal intensity and Pfirrmann scores for grades 1-4, but not for grades 4 and 5. For disc height only, Pfirrmann grade 5 had significantly reduced disc height compared to all other grades. Results were similar regardless of whether raw or adjusted scores were used. Inter-rater reliability for the quantitative measures was excellent (ICC > 0.97). Quantitative measures of disc signal intensity were strongly related to Pfirrmann scores from grade 1 to 4; however disc height only differentiated between grade 4 and 5 Pfirrmann scores. Using adjusted ratios for quantitative measures of disc height or signal intensity did not significantly alter the relationship with Pfirrmann scores.

Signal intensity of lanthanum carbonate on magnetic resonance images: phantom study.

PubMed

Nakamura, Shinichi; Awai, Kazuo; Komi, Masanori; Morita, Kosuke; Namimoto, Tomohiro; Yanaga, Yumi; Utsunomiya, Daisuke; Date, Shuji; Yamashita, Yasuyuki

2011-06-01

Lanthanum carbonate (LC) is used to treat hyperphosphatemia. The purpose of this study was to investigate the signal intensity (SI) of LC on magnetic resonance imaging (MRI) scans of phantoms. LC tablets were thoroughly ground and mixed with distilled water or edible agar (0.05, 0.25, 0.5, and 2.5 mg/ml) in plastic bottles. Four intact tablets were placed in plastic bottles that did or did not contain distilled water or agar. Two radiologists consensually evaluated T1- and T2-weighted images (WIs) obtained with 1.5- and 3.0-T MRI systems for the SI of unground and ground tablets. On T1- and T2WI, the SIs of the LC suspensions and the solvents alone were similar; the SIs of unground tablets alone and of the air were also similar. Unground tablets in phantoms filled with solvent exhibited lower SI than the solvent. Ground tablets in suspension were not visualized on MRI or computed tomography. These results remained unchanged regardless of differences in magnetic field strength or the solvent used. Ground LC had no contrast enhancement effect on T1WI; on T2WI it did not affect the SI of the solvent. Unground LC tablets may be visualized as a "filling defect" on MRI.

T1 pseudohyperintensity on fat-suppressed MRI: A potential diagnostic pitfall

PubMed Central

Huynh, Tuan N.; Johnson, D. Thor; Poder, Liina; Joe, Bonnie N.; Webb, Emily M.; Coakley, Fergus V.

2011-01-01

MRI findings in two patients with misleading T1 hyperintensity seen only on fat-suppressed images are presented, one with a renal cell carcinoma that was misinterpreted as a hemorrhagic cyst and the other with an ovarian serous cystadenocarcinoma that was misinterpreted as a complicated endometrioma. The apparent T1 hyperintensity on fat suppressed images in these cases was likely due to varying perception of image signal dependent on local contrast, an optical effect known as the checker-shadow illusion. T1 pseudohyperintensity should be considered when apparently high T1 signal intensity is seen only on fat-suppressed images; review of non fat-suppressed images may help prevent an erroneous diagnoses of blood-containing lesions. PMID:21765301

Transcriptomic characterization of MRI contrast with focus on the T1-w/T2-w ratio in the cerebral cortex.

PubMed

Ritchie, Jacob; Pantazatos, Spiro P; French, Leon

2018-07-01

Magnetic resonance (MR) images of the brain are of immense clinical and research utility. At the atomic and subatomic levels, the sources of MR signals are well understood. However, we lack a comprehensive understanding of the macromolecular correlates of MR signal contrast. To address this gap, we used genome-wide measurements to correlate gene expression with MR signal intensity across the cerebral cortex in the Allen Human Brain Atlas (AHBA). We focused on the ratio of T1-weighted and T2-weighted intensities (T1-w/T2-w ratio image), which is considered to be a useful proxy for myelin content. As expected, we found enrichment of positive correlations between myelin-associated genes and the ratio image, supporting its use as a myelin marker. Genome-wide, there was an association with protein mass, with genes coding for heavier proteins expressed in regions with high T1-w/T2-w values. Oligodendrocyte gene markers were strongly correlated with the T1-w/T2-w ratio, but this was not driven by myelin-associated genes. Mitochondrial genes exhibit the strongest relationship, showing higher expression in regions with low T1-w/T2-w ratio. This may be due to the pH gradient in mitochondria as genes up-regulated by pH in the brain were also highly correlated with the ratio. While we corroborate associations with myelin and synaptic plasticity, differences in the T1-w/T2-w ratio across the cortex are more strongly linked to molecule size, oligodendrocyte markers, mitochondria, and pH. We evaluate correlations between AHBA transcriptomic measurements and a group averaged T1-w/T2-w ratio image, showing agreement with in-sample results. Expanding our analysis to the whole brain results in strong positive T1-w/T2-w correlations for immune system, inflammatory disease, and microglia marker genes. Genes with negative correlations were enriched for neuron markers and synaptic plasticity genes. Lastly, our findings are similar when performed on T1-w or inverted T2-w intensities alone

33 CFR 86.05 - Sound signal intensity and range of audibility.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 1 2012-07-01 2012-07-01 false Sound signal intensity and range... HOMELAND SECURITY INLAND NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Whistles § 86.05 Sound signal intensity and range of audibility. A whistle on a vessel shall provide, in the...

33 CFR 86.05 - Sound signal intensity and range of audibility.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 1 2014-07-01 2014-07-01 false Sound signal intensity and range... HOMELAND SECURITY INLAND NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Whistles § 86.05 Sound signal intensity and range of audibility. A whistle on a vessel shall provide, in the...

33 CFR 86.05 - Sound signal intensity and range of audibility.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 1 2013-07-01 2013-07-01 false Sound signal intensity and range... HOMELAND SECURITY INLAND NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Whistles § 86.05 Sound signal intensity and range of audibility. A whistle on a vessel shall provide, in the...

Infiltrating T Cells Promote Bladder Cancer Progression via Increasing IL1→Androgen Receptor→HIF1α→VEGFa Signals.

PubMed

Tao, Le; Qiu, Jianxin; Jiang, Ming; Song, Wenbin; Yeh, Shuyuan; Yu, Hong; Zang, Lijuan; Xia, Shujie; Chang, Chawnshang

2016-08-01

The tumor microenvironment impacts tumor progression and individual cells, including CD4(+) T cells, which have been detected in bladder cancer tissues. The detailed mechanism of how these T cells were recruited to the bladder cancer tumor and their impact on bladder cancer progression, however, remains unclear. Using a human clinical bladder cancer sample survey and in vitro coculture system, we found that bladder cancer has a greater capacity to recruit T cells than surrounding normal bladder tissues. The consequences of higher levels of recruited T cells in bladder cancer included increased bladder cancer metastasis. Mechanism dissection revealed that infiltrating T cells might function through secreting the cytokine IL1, which increases the recruitment of T cells to bladder cancer and enhances the bladder cancer androgen receptor (AR) signaling that results in increased bladder cancer cell invasion via upregulation of hypoxia-inducible factor-1α (HIF1α)/VEGFa expression. Interruption of the IL1→AR→HIF1α→VEGFa signals with inhibitors of HIF1α or VEGFa partially reversed the enhanced bladder cancer cell invasion. Finally, in vivo mouse models of xenografted bladder cancer T24 cells with CD4(+) T cells confirmed in vitro coculture studies and concluded that infiltrating CD4(+) T cells can promote bladder cancer metastasis via modulation of the IL1→AR→HIF1α→VEGFa signaling. Future clinical trials using small molecules to target this newly identified signaling pathway may facilitate the development of new therapeutic approaches to better suppress bladder cancer metastasis. Mol Cancer Ther; 15(8); 1943-51. ©2016 AACR. ©2016 American Association for Cancer Research.

Intensity standardisation of 7T MR images for intensity-based segmentation of the human hypothalamus

PubMed Central

Schreiber, Jan; Bazin, Pierre-Louis; Trampel, Robert; Anwander, Alfred; Geyer, Stefan; Schönknecht, Peter

2017-01-01

The high spatial resolution of 7T MRI enables us to identify subtle volume changes in brain structures, providing potential biomarkers of mental disorders. Most volumetric approaches require that similar intensity values represent similar tissue types across different persons. By applying colour-coding to T1-weighted MP2RAGE images, we found that the high measurement accuracy achieved by high-resolution imaging may be compromised by inter-individual variations in the image intensity. To address this issue, we analysed the performance of five intensity standardisation techniques in high-resolution T1-weighted MP2RAGE images. Twenty images with extreme intensities in the GM and WM were standardised to a representative reference image. We performed a multi-level evaluation with a focus on the hypothalamic region—analysing the intensity histograms as well as the actual MR images, and requiring that the correlation between the whole-brain tissue volumes and subject age be preserved during standardisation. The results were compared with T1 maps. Linear standardisation using subcortical ROIs of GM and WM provided good results for all evaluation criteria: it improved the histogram alignment within the ROIs and the average image intensity within the ROIs and the whole-brain GM and WM areas. This method reduced the inter-individual intensity variation of the hypothalamic boundary by more than half, outperforming all other methods, and kept the original correlation between the GM volume and subject age intact. Mixed results were obtained for the other four methods, which sometimes came at the expense of unwarranted changes in the age-related pattern of the GM volume. The mapping of the T1 relaxation time with the MP2RAGE sequence is advertised as being especially robust to bias field inhomogeneity. We found little evidence that substantiated the T1 map’s theoretical superiority over the T1-weighted images regarding the inter-individual image intensity homogeneity. PMID

Muscle MRI STIR signal intensity and atrophy are correlated to focal lower limb neuropathy severity.

PubMed

Deroide, N; Bousson, V; Mambre, L; Vicaut, E; Laredo, J D; Kubis, Nathalie

2015-03-01

The objective is to determine if muscle MRI is useful for assessing neuropathy severity. Clinical, MRI and electromyography (EMG) examinations were performed in 17 patients with focal lower limb neuropathies. MRI Short Tau Inversion Recovery (STIR) signal intensity, amyotrophy, and muscle fatty infiltration measured after T1-weighted image acquisition, EMG spontaneous activity (SA), and maximal voluntary contraction (MVC) were graded using semiquantitative scores and quantitative scores for STIR signal intensity and were correlated to the Medical Research Council (MRC) score for testing muscle strength. Within this population, subgroups were selected according to severity (mild versus severe), duration (subacute versus chronic), and topography (distal versus proximal) of the neuropathy. EMG SA and MVC MRI amyotrophy and quantitative scoring of muscle STIR intensity were correlated with the MRC score. Moreover, MRI amyotrophy was significantly increased in severe, chronic, and proximal neuropathies along with fatty infiltration in chronic lesions. Muscle MRI atrophy and quantitative evaluation of signal intensity were correlated to MRC score in our study. Semiquantitative evaluation of muscle STIR signal was sensitive enough for detection of topography of the nerve lesion but was not suitable to assess severity. Muscle MRI could support EMG in chronic and proximal neuropathy, which showed poor sensitivity in these patients.

Is Motor Learning Mediated by tDCS Intensity?

PubMed Central

van den Berg, Femke E.; Nitsche, Michael A.; Thijs, Herbert; Wenderoth, Nicole; Meesen, Raf L. J.

2013-01-01

Although tDCS has been shown to improve motor learning, previous studies reported rather small effects. Since physiological effects of tDCS depend on intensity, the present study evaluated this parameter in order to enhance the effect of tDCS on skill acquisition. The effect of different stimulation intensities of anodal tDCS (atDCS) was investigated in a double blind, sham controlled crossover design. In each condition, thirteen healthy subjects were instructed to perform a unimanual motor (sequence) learning task. Our results showed (1) a significant increase in the slope of the learning curve and (2) a significant improvement in motor performance at retention for 1.5 mA atDCS as compared to sham tDCS. No significant differences were reported between 1 mA atDCS and sham tDCS; and between 1.5 mA atDCS and 1 mA atDCS. PMID:23826272

ZnT-1 enhances the activity and surface expression of T-type calcium channels through activation of Ras-ERK signaling.

PubMed

Mor, Merav; Beharier, Ofer; Levy, Shiri; Kahn, Joy; Dror, Shani; Blumenthal, Daniel; Gheber, Levi A; Peretz, Asher; Katz, Amos; Moran, Arie; Etzion, Yoram

2012-07-15

Zinc transporter-1 (ZnT-1) is a putative zinc transporter that confers cellular resistance from zinc toxicity. In addition, ZnT-1 has important regulatory functions, including inhibition of L-type calcium channels and activation of Raf-1 kinase. Here we studied the effects of ZnT-1 on the expression and function of T-type calcium channels. In Xenopus oocytes expressing voltage-gated calcium channel (CaV) 3.1 or CaV3.2, ZnT-1 enhanced the low-threshold calcium currents (I(caT)) to 182 ± 15 and 167.95 ± 9.27% of control, respectively (P < 0.005 for both channels). As expected, ZnT-1 also enhanced ERK phosphorylation. Coexpression of ZnT-1 and nonactive Raf-1 blocked the ZnT-1-mediated ERK phosphorylation and abolished the ZnT-1-induced augmentation of I(caT). In mammalian cells (Chinese hamster ovary), coexpression of CaV3.1 and ZnT-1 increased the I(caT) to 166.37 ± 6.37% compared with cells expressing CaV3.1 alone (P < 0.01). Interestingly, surface expression measurements using biotinylation or total internal reflection fluorescence microscopy indicated marked ZnT-1-induced enhancement of CaV3.1 surface expression. The MEK inhibitor PD-98059 abolished the ZnT-1-induced augmentation of surface expression of CaV3.1. In cultured murine cardiomyocytes (HL-1 cells), transient exposure to zinc, leading to enhanced ZnT-1 expression, also enhanced the surface expression of endogenous CaV3.1 channels. Consistently, in these cells, endothelin-1, a potent activator of Ras-ERK signaling, enhanced the surface expression of CaV3.1 channels in a PD-98059-sensitive manner. Our findings indicate that ZnT-1 enhances the activity of CaV3.1 and CaV3.2 through activation of Ras-ERK signaling. The augmentation of CaV3.1 currents by Ras-ERK activation is associated with enhanced trafficking of the channel to the plasma membrane.

Appearance of low signal intensity lines in MRI of silicone breast implants.

PubMed

Stroman, P W; Rolland, C; Dufour, M; Grondin, P; Guidoin, R G

1996-05-01

Magnetic resonance (MR) images of five explanted mammary prostheses were obtained with a 1.5 T GE Signa system using a conventional spin-echo pulse sequence, in order to investigate the low-intensity curvilinear lines which may be observed in MR images of silicone gel-filled breast implants under pressure from fibrous capsules. MR images showed ellipsoid prostheses, often containing multiple low-intensity curvilinear lines which in some cases presented an appearance very similar to that of the linguine sign. Upon opening the fibrous capsules, however, all of the prostheses were found to be completely intact demonstrating that the appearance of multiple low signal intensity curvilinear lines in MR images of silicone gel-filled prostheses is not necessarily a sign of prosthesis rupture. The MR image features which are specific to the linguine sign must be more precisely defined.

Signal intensity enhancement of laser ablated volume holograms

NASA Astrophysics Data System (ADS)

Versnel, J. M.; Williams, C.; Davidson, C. A. B.; Wilkinson, T. D.; Lowe, C. R.

2017-11-01

Conventional volume holographic gratings (VHGs) fabricated in photosensitive emulsions such as gelatin containing silver salts enable the facile visualization of the holographic image in ambient lighting. However, for the fabrication of holographic sensors, which require more defined and chemically-functionalised polymer matrices, laser ablation has been introduced to create the VHGs and thereby broaden their applications, although the replay signal can be challenging to detect in ambient lighting. When traditional photochemical bleaching solutions used to reduce light scattering and modulate refractive index within the VHG are applied to laser ablated volume holographic gratings, these procedures decrease the holographic peak intensity. This is postulated to occur because both light and dark fringes contain a proportion of metal particles, which upon solubilisation are converted immediately to silver iodide, yielding no net refractive index modulation. This research advances a hypothesis that the reduced intensity of holographic replay signals is linked to a gradient of different sized metal particles within the emulsion, which reduces the holographic signal and may explain why traditional bleaching processes result in a reduction in intensity. In this report, a novel experimental protocol is provided, along with simulations based on an effective medium periodic 1D stack, that offers a solution to increase peak signal intensity of holographic sensors by greater than 200%. Nitric acid is used to etch the silver nanoparticles within the polymer matrix and is thought to remove the smaller particles to generate more defined metal fringes containing a soluble metal salt. Once the grating efficiency has been increased, this salt can be converted to a silver halide, to modulate the refractive index and increase the intensity of the holographic signal. This new protocol has been tested in a range of polymer chemistries; those containing functional groups that help to

Quantification of myocardial perfusion based on signal intensity of flow sensitized MRI

NASA Astrophysics Data System (ADS)

Abeykoon, Sumeda B.

The quantitative assessment of perfusion is important for early recognition of a variety of heart diseases, determination of disease severity and their cure. In conventional approach of measuring cardiac perfusion by arterial spin labeling, the relative difference in the apparent T1 relaxation times in response to selective and non-selective inversion of blood entering the region of interest is related to perfusion via a two-compartment tissue model. But accurate determination of T1 in small animal hearts is difficult and prone to errors due to long scan times. The purpose of this study is to develop a fast, robust and simple method to quantitatively assess myocardial perfusion using arterial spin labeling. The proposed method is based on signal intensities (SI) of inversion recovery slice-select, non-select and steady-state images. Especially in this method data are acquired at a single inversion time and at short repetition times. This study began by investigating the accuracy of assessment of perfusion using a two compartment system. First, determination of perfusion by T1 and SI were implemented to a simple, two-compartment phantom model. Mathematical model developed for full spin exchange models (in-vivo experiments) by solving a modified Bloch equation was modified to develop mathematical models (T1 and SI) for a phantom (zero spin exchange). The phantom result at different flow rates shows remarkable evidence of accuracy of the two-compartment model and SI, T1 methods: the SI method has less propagation error and less scan time. Next, twelve healthy C57BL/6 mice were scanned for quantitative perfusion assessment and three of them were repeatedly scanned at three different time points for a reproducibility test. The myocardial perfusion of healthy mice obtained by the SI-method, 5.7+/-1.6 ml/g/min, was similar (p=0.38) to that obtained by the conventional T1 method, 5.6+/- 2.3 ml/g/min. The reproducibility of the SI method shows acceptable results: the

Signal intensity influences on the atomic Faraday filter.

PubMed

Luo, Bin; Yin, Longfei; Xiong, Junyu; Chen, Jingbiao; Guo, Hong

2018-06-01

Previous studies of the Faraday anomalous dispersion optical filter (FADOF) mainly focus on the weak signal light filtering, without regard for the influences of the signal light intensity on the filter itself. However, in some applications the signal light is strong enough to change the filter's performance. In this work, the influences of the signal light intensity on the transmittance spectrum is experimentally investigated in a 780 nm Rb85 FADOF in both the line-center and wings operation modes. The results show that the transmittance spectrum varies significantly with the signal light intensity. As the signal light increases, some existing transmittance peaks decline, some new transmittance peaks appear, and the maximum transmittance peak frequency may change. The spectrum in strong signal lights can be quite different from those calculated by programs in the condition of weak signal lights. These results are important for applications of the FADOF in the condition of strong signal lights.

Manipulating memory CD8 T cell numbers by timed enhancement of IL-2 signals1

PubMed Central

Kim, Marie T.; Kurup, Samarchith P.; Starbeck-Miller, Gabriel R.; Harty, John T.

2016-01-01

Due to the growing burden of tumors and chronic infections, manipulating CD8 T cell responses for clinical use has become an important goal for immunologists. Here, we show that dendritic cell (DC) immunization coupled with relatively early (days 1–3) or late (days 4–6) administration of enhanced IL-2-signals both increase peak effector CD8 T cell numbers, but only early IL-2 signals enhance memory numbers. IL-2 signals delivered at relatively late time points drive terminal differentiation, marked Bim mediated contraction and do not increase memory T cell numbers. In contrast, early IL-2 signals induce effector cell metabolic profiles more conducive to memory formation. Of note, down-regulation of CD80 and CD86 was observed on DCs in vivo following early IL-2 treatment. Mechanistically, early IL-2 treatment enhanced CTLA-4 expression on regulatory T (Treg) cells, and CTLA-4 blockade alongside IL-2 treatment in vivo prevented the decrease in CD80 and CD86, supporting a cell-extrinsic role of CTLA-4 in down-regulating B7-ligand expression on DCs. Finally, DC immunization followed by early IL-2 treatment and αCTLA-4 blockade resulted in lower memory CD8 T cell numbers compared to the DC + early IL-2 treatment group. These data suggest that curtailed signaling through the B7-CD28 co-stimulatory axis during CD8 T cell activation limits terminal differentiation and preserves memory CD8 T cell formation and thus, should be considered in future T cell vaccination strategies. PMID:27439516

The role of T1 perfusion-based classification in magnetic resonance-guided high-intensity focused ultrasound ablation of uterine fibroids.

PubMed

Keserci, Bilgin; Duc, Nguyen Minh

2017-12-01

To comparatively evaluate the role of magnetic resonance (MR) T1 perfusion-based time-signal intensity (SI) curves of fibroid tissue and the myometrium in classification of fibroids for predicting treatment outcomes of high-intensity focused ultrasound (HIFU) treatment. The fibroids of 74 women who underwent MR-HIFU treatment were classified into group A (time-SI curve of fibroid lower than that of the myometrium) and group B (time-SI curve of fibroid equal to or higher than that of the myometrium). Non-perfused volume (NPV) ratios immediately after treatment and fibroid volume reduction ratios and symptom severity scores (SSS) at the 6-month follow-up were retrospectively assessed. The immediate NPV ratios in groups A and B were 95.3 ± 6.3% (n = 62) and 63.8 ± 11% (n = 12), respectively. At the 6-month follow-up, the fibroid volume reduction ratios in groups A and B were 0.52 ± 0.14 (n = 50) and 0.07 ± 0.14 (n = 11), with the corresponding improvement in mean transformed SSS being 0.86 ± 0.14 and 0.19 ± 0.3, respectively. No serious adverse effects were reported. Our novel classification method could play an important role in classifying fibroids for predicting the immediate outcomes of HIFU treatment. • MRI is an important modality for outcome prediction in HIFU treatment • Patient selection is a significant factor for achieving high NPV ratio • NPV ratio is very strongly correlated with T1 perfusion-based classification • T1 perfusion-based classification is a strong predictor of treatment outcome.

Differences in Signal Intensity and Enhancement on MR Images of the Perivascular Spaces in the Basal Ganglia versus Those in White Matter.

PubMed

Naganawa, Shinji; Nakane, Toshiki; Kawai, Hisashi; Taoka, Toshiaki

2018-01-18

To elucidate differences between the perivascular space (PVS) in the basal ganglia (BG) versus that found in white matter (WM) using heavily T 2 -weighted FLAIR (hT 2 -FL) in terms of 1) signal intensity on non-contrast enhanced images, and 2) the degree of contrast enhancement by intravenous single dose administration of gadolinium based contrast agent (IV-SD-GBCA). Eight healthy men and 13 patients with suspected endolymphatic hydrops were included. No subjects had renal insufficiency. All subjects received IV-SD-GBCA. MR cisternography (MRC) and hT 2 -FL images were obtained prior to and 4 h after IV-SD-GBCA. The signal intensity of the PVS in the BG, subinsular WM, and the cerebrospinal fluid (CSF) in Ambient cistern (CSF AC ) and CSF in Sylvian fissure (CSF Syl ) was measured as well as that of the thalamus. The signal intensity ratio (SIR) was calculated by dividing the intensity by that of the thalamus. We used 5% as a threshold to determine the significance of the statistical test. In the pre-contrast scan, the SIR of the PVS in WM (Mean ± standard deviation, 1.83 ± 0.46) was significantly higher than that of the PVS in the BG (1.05 ± 0.154), CSF Syl (1.03 ± 0.15) and the CSF AC (0.97 ± 0.29). There was no significant difference between the SIR of the PVS in the BG compared to the CSF AC and CSF Syl . For the evaluation of the contrast enhancement effect, significant enhancement was observed in the PVS in the BG, the CSF AC and the CSF Syl compared to the pre-contrast scan. No significant contrast enhancement was observed in the PVS in WM. The signal intensity difference between the PVS in the BG versus WM on pre-contrast images suggests that the fluid composition might be different between these PVSs. The difference in the contrast enhancement between the PVSs in the BG versus WM suggests a difference in drainage function.

Quantitative DLA-based compressed sensing for T1-weighted acquisitions

NASA Astrophysics Data System (ADS)

Svehla, Pavel; Nguyen, Khieu-Van; Li, Jing-Rebecca; Ciobanu, Luisa

2017-08-01

High resolution Manganese Enhanced Magnetic Resonance Imaging (MEMRI), which uses manganese as a T1 contrast agent, has great potential for functional imaging of live neuronal tissue at single neuron scale. However, reaching high resolutions often requires long acquisition times which can lead to reduced image quality due to sample deterioration and hardware instability. Compressed Sensing (CS) techniques offer the opportunity to significantly reduce the imaging time. The purpose of this work is to test the feasibility of CS acquisitions based on Diffusion Limited Aggregation (DLA) sampling patterns for high resolution quantitative T1-weighted imaging. Fully encoded and DLA-CS T1-weighted images of Aplysia californica neural tissue were acquired on a 17.2T MRI system. The MR signal corresponding to single, identified neurons was quantified for both versions of the T1 weighted images. For a 50% undersampling, DLA-CS can accurately quantify signal intensities in T1-weighted acquisitions leading to only 1.37% differences when compared to the fully encoded data, with minimal impact on image spatial resolution. In addition, we compared the conventional polynomial undersampling scheme with the DLA and showed that, for the data at hand, the latter performs better. Depending on the image signal to noise ratio, higher undersampling ratios can be used to further reduce the acquisition time in MEMRI based functional studies of living tissues.

Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

PubMed Central

Wang, Shu-Fang; Fouquet, Stéphane; Chapon, Maxime; Salmon, Hélène; Regnier, Fabienne; Labroquère, Karine; Badoual, Cécile; Damotte, Diane; Validire, Pierre; Maubec, Eve; Delongchamps, Nicolas B.; Cazes, Aurélie; Gibault, Laure; Garcette, Marylène; Dieu-Nosjean, Marie-Caroline; Zerbib, Marc; Avril, Marie-Françoise; Prévost-Blondel, Armelle; Randriamampita, Clotilde; Trautmann, Alain; Bercovici, Nadège

2011-01-01

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL. PMID:21408177

Utility of unenhanced fat-suppressed T1-weighted MRI in children with sickle cell disease -- can it differentiate bone infarcts from acute osteomyelitis?

PubMed

Delgado, Jorge; Bedoya, Maria A; Green, Abby M; Jaramillo, Diego; Ho-Fung, Victor

2015-12-01

Children with sickle cell disease (SCD) are at risk of bone infarcts and acute osteomyelitis. The clinical differentiation between a bone infarct and acute osteomyelitis is a diagnostic challenge. Unenhanced T1-W fat-saturated MR images have been proposed as a potential tool to differentiate bone infarcts from osteomyelitis. To evaluate the reliability of unenhanced T1-W fat-saturated MRI for differentiation between bone infarcts and acute osteomyelitis in children with SCD. We retrospectively reviewed the records of 31 children (20 boys, 11 girls; mean age 10.6 years, range 1.1-17.9 years) with SCD and acute bone pain who underwent MR imaging including unenhanced T1-W fat-saturated images from 2005 to 2010. Complete clinical charts were reviewed by a pediatric hematologist with training in infectious diseases to determine a clinical standard to define the presence or absence of osteomyelitis. A pediatric radiologist reviewed all MR imaging and was blinded to clinical information. Based on the signal intensity in T1-W fat-saturated images, the children were further classified as positive for osteomyelitis (low bone marrow signal intensity) or positive for bone infarct (high bone marrow signal intensity). Based on the clinical standard, 5 children were classified as positive for osteomyelitis and 26 children as positive for bone infarct (negative for osteomyelitis). The bone marrow signal intensity on T1-W fat-saturated imaging was not significant for the differentiation between bone infarct and osteomyelitis (P = 0.56). None of the additional evaluated imaging parameters on unenhanced MRI proved reliable in differentiating these diagnoses. The bone marrow signal intensity on unenhanced T1-W fat-saturated MR images is not a reliable criterion to differentiate bone infarcts from osteomyelitis in children.

"Signal-on" photoelectrochemical biosensor for sensitive detection of human T-Cell lymphotropic virus type II DNA: dual signal amplification strategy integrating enzymatic amplification with terminal deoxynucleotidyl transferase-mediated extension.

PubMed

Shen, Qingming; Han, Li; Fan, Gaochao; Zhang, Jian-Rong; Jiang, Liping; Zhu, Jun-Jie

2015-01-01

A novel "signal-on" photoelectrochemical (PEC) biosensor for sensitive detection of human T-cell lymphotropic virus type II (HTLV-II) DNA was developed on the basis of enzymatic amplification coupled with terminal deoxynucleotidyl transferase (TdT)-mediated extension strategy. The intensity of the photocurrent signal was proportional to the concentration of the HTLV-II DNA-target DNA (tDNA) by dual signal amplification. In this protocol, GR-CdS:Mn/ZnS nanocomposites were used as photoelectric conversion material, while pDNA was used as the tDNA recognizing unit. Moreover, the TdT-mediated extension and the enzymatic signal amplification technique were used to enhance the sensitivity of detection. Using this novel dual signal amplification strategy, the prototype of PEC DNA sensor can detect as low as ∼0.033 fM of HTLV-II DNA with a linear range of 0.1-5000 fM, with excellent differentiation ability even for single-base mismatches. This PEC DNA assay opens a promising platform to detect various DNA targets at ultralow levels for early diagnoses of different diseases.

Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory.

PubMed

Sindreu, Carlos; Palmiter, Richard D; Storm, Daniel R

2011-02-22

The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus-dependent memory.

Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor, RunX1T1, in ovarian cancer

PubMed Central

Yang, Hui-Wen; Chou, Jian-Liang; Chen, Lin-Yu; Yeh, Chia-Ming; Chen, Yu-Hsin; Lin, Ru-Inn; Su, Her-Young; Chen, Gary CW; Deatherage, Daniel E; Huang, Yi-Wen; Yan, Pearlly S; Lin, Huey-Jen; Nephew, Kenneth P; Huang, Tim H-M; Lai, Hung-Cheng

2011-01-01

Aberrant TGFβ signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP 3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP 3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGFβ signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (p = 0.035) and in 83% (5/6) of primary ovarian cancer-initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (p < 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFβ/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis. PMID:21540640

Low-intensity pulsed ultrasound stimulation promotes osteoblast differentiation through hedgehog signaling.

PubMed

Matsumoto, Kenichi; Shimo, Tsuyoshi; Kurio, Naito; Okui, Tatsuo; Ibaragi, Soichiro; Kunisada, Yuki; Obata, Kyoichi; Masui, Masanori; Pai, Pang; Horikiri, Yuu; Yamanaka, Nobuyuki; Takigawa, Masaharu; Sasaki, Akira

2018-06-01

Low-intensity pulsed ultrasound (LIPUS) has been used as an adjunct to fracture healing therapies, but the mechanisms underlying its action are not known. We reported that sonic hedgehog (SHH) signaling was activated in osteoblasts at the dynamic remodeling site of a bone fracture. Mechanical stimulation is a crucial factor in bone remodeling, and it is related to the primary cilia as a sensor of hedgehog signaling. Here we observed that LIPUS promoted callus formation in accord with Gli2-positive cells after 14 days at the mouse femur fractured site compared with a control group. An immunofluorescence analysis showed that the numbers of primary cilia and cilia/osterix double-positive osteoblasts were increased at the fracture site by LIPUS. LIPUS stimulated not only the number and the length of primary cilia, but also the levels of ciliated protein, Ift88 mRNA, and SHH, Gli1, and Gli2 in MC3T3-E1 cells. Further experiments revealed that LIPUS stimulated osteogenic differentiation in the presence of smoothened agonist (SAG) treatment. These results indicate that LIPUS stimulates osteogenic differentiation and the maturation of osteoblasts by a primary cilium-mediated activation of hedgehog signaling. © 2017 Wiley Periodicals, Inc.

Uterine fibroids: Influence of "T2-Rim sign" on immediate therapeutic responses to magnetic resonance imaging-guided high-intensity focused ultrasound ablation.

PubMed

Yeo, Sin Yuin; Kim, Young-Sun; Lim, Hyo Keun; Rhim, Hyunchul; Jung, Sin-Ho; Hwang, Na Young

2017-12-01

To investigate the influence of a high-signal-intensity peripheral rim on T2-weighted MR images (i.e., T2-rim sign) on the immediate therapeutic responses of MR-guided high intensity focused ultrasound (MR-HIFU) ablation of uterine fibroids. This retrospective study was approved by the institutional review board, and patient informed consent was obtained for MR-HIFU ablation. In total, 196 fibroids (diameter 6.2±2.6cm) in 123 women (age 43.4±5.0 years) who underwent MR-HIFU ablation from January 2013 to April 2016 were included. The effects of a T2-rim sign on the immediate therapeutic responses (non-perfused volume [NPV] ratio, ablation efficiency [NPV/treatment cell volume], ablation quality [grade 1-5, poor to excellent]) were investigated with univariable and multivariable analyses using generalized estimating equation (GEE) analysis. In multivariable analysis, T2 signal intensity ratio of fibroids-to-skeletal muscle, relative peak enhancement of fibroids, and subcutaneous fat thickness were also considered. The presence of a T2-rim sign significantly lowered the NPV ratio (54.0±28.0% vs. 83.7±17.7%), ablation efficiency (0.6±0.5 vs. 1.3±0.6), ablation quality (3.1±1.2 vs. 4.2±0.8), (P<0.0001). GEE analysis showed that the presence of a T2-rim sign was independently significant for ablation efficiency and ablation quality (P<0.05). Uterine fibroids with a T2-rim sign showed significantly poorer immediate therapeutic responses to MR-HIFU ablation. Copyright © 2017 Elsevier B.V. All rights reserved.

Cytotoxic-T-lymphocyte antigen 4 receptor signaling for lymphocyte adhesion is mediated by C3G and Rap1.

PubMed

Kloog, Yoel; Mor, Adam

2014-03-01

T-lymphocyte adhesion plays a critical role in both inflammatory and autoimmune responses. The small GTPase Rap1 is the key coordinator mediating T-cell adhesion to endothelial cells, antigen-presenting cells, and virus-infected cells. We describe a signaling pathway, downstream of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, leading to Rap1-mediated adhesion. We identified a role for the Rap1 guanine nucleotide exchange factor C3G in the regulation of T-cell adhesion and showed that this factor is required for both T-cell receptor (TCR)-mediated and CTLA-4-mediated T-cell adhesion. Our data indicated that C3G translocates to the plasma membrane downstream of TCR signaling, where it regulates activation of Rap1. We also showed that CTLA-4 receptor signaling mediates tyrosine phosphorylation in the C3G protein, and that this is required for augmented activation of Rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (LFA-1). Zap70 is required for C3G translocation to the plasma membrane, whereas the Src family member Hck facilitates C3G phosphorylation. These findings point to C3G and Hck as promising potential therapeutic targets for the treatment of T-cell-dependent autoimmune disorders.

Cytotoxic-T-Lymphocyte Antigen 4 Receptor Signaling for Lymphocyte Adhesion Is Mediated by C3G and Rap1

PubMed Central

Kloog, Yoel

2014-01-01

T-lymphocyte adhesion plays a critical role in both inflammatory and autoimmune responses. The small GTPase Rap1 is the key coordinator mediating T-cell adhesion to endothelial cells, antigen-presenting cells, and virus-infected cells. We describe a signaling pathway, downstream of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor, leading to Rap1-mediated adhesion. We identified a role for the Rap1 guanine nucleotide exchange factor C3G in the regulation of T-cell adhesion and showed that this factor is required for both T-cell receptor (TCR)-mediated and CTLA-4-mediated T-cell adhesion. Our data indicated that C3G translocates to the plasma membrane downstream of TCR signaling, where it regulates activation of Rap1. We also showed that CTLA-4 receptor signaling mediates tyrosine phosphorylation in the C3G protein, and that this is required for augmented activation of Rap1 and increased adhesion mediated by leukocyte function-associated antigen type 1 (LFA-1). Zap70 is required for C3G translocation to the plasma membrane, whereas the Src family member Hck facilitates C3G phosphorylation. These findings point to C3G and Hck as promising potential therapeutic targets for the treatment of T-cell-dependent autoimmune disorders. PMID:24396067

Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus-dependent memory

PubMed Central

Sindreu, Carlos; Palmiter, Richard D.; Storm, Daniel R.

2011-01-01

The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus-dependent memory. PMID:21245308

Diagnosis of complications associated with acute cholecystitis using computed tomography and diffusion-weighted imaging with background body signal suppression/T2 image fusion.

PubMed

Tomizawa, Minoru; Shinozaki, Fuminobu; Tanaka, Satomi; Sunaoshi, Takafumi; Kano, Daisuke; Sugiyama, Eriko; Shite, Misaki; Haga, Ryouta; Fukamizu, Yoshiya; Fujita, Toshiyuki; Kagayama, Satoshi; Hasegawa, Rumiko; Shirai, Yoshinori; Motoyoshi, Yasufumi; Sugiyama, Takao; Yamamoto, Shigenori; Ishige, Naoki

2017-07-01

In a clinical setting, it is important to diagnose complications of acute cholecystitis accurately. Diffusion-weighted whole body imaging with background body signal suppression/T2-weighted image fusion (DWIBS/T2) provides high signal intensity with a strong contrast against surrounding tissues in anatomical settings. In the present study, patients who were being treated for acute cholecystitis and underwent DWIBS/T2 in the National Hospital Organization Shimoshizu Hospital between December 2012 and August 2015 were enrolled. A total of 10 men and 4 women underwent DWIBS/T2. Records, including DWIBS/T2 and computed tomography (CT) imaging, were retrospectively analyzed for patients with acute cholecystitis. CT images revealed thickened gallbladder walls in patients with acute cholecystitis, and high signal intensity was observed in DWIBS/T2 images for the thickened gallbladder wall. Inflammation of the pericholecystic space and the liver resulted in high intensity signals with DWIBS/T2 imaging, whereas CT imaging revealed a low-density area in the cholecystic space. Plain CT scanning identified a low-density area in the liver, which became more obvious with contrast-enhanced CT. DWIBS/T2 imaging showed the inflammation of the liver and pericholesyctic space as an area of high signal intensity. Detectability of inflammation of the pericholecystic space and the liver was the same for DWIBS/T2 and CT, which suggests that DWIBS/T2 has the same sensitivity as CT scanning for the diagnosis of complicated acute cholecystitis. However, the strong contrast shown by DWIBS/T2 allows for easier evaluation of acute cholecystitis than CT scanning.

33 CFR 86.05 - Sound signal intensity and range of audibility.

Code of Federal Regulations, 2011 CFR

2011-07-01

... direction of the forward axis of the whistle and at a distance of 1 meter from it, a sound pressure level in... 33 Navigation and Navigable Waters 1 2011-07-01 2011-07-01 false Sound signal intensity and range... HOMELAND SECURITY INLAND NAVIGATION RULES ANNEX III: TECHNICAL DETAILS OF SOUND SIGNAL APPLIANCES Whistles...

T Cell Calcium Signaling Regulation by the Co-Receptor CD5

PubMed Central

Freitas, Claudia M. Tellez

2018-01-01

Calcium influx is critical for T cell effector function and fate. T cells are activated when T cell receptors (TCRs) engage peptides presented by antigen-presenting cells (APC), causing an increase of intracellular calcium (Ca2+) concentration. Co-receptors stabilize interactions between the TCR and its ligand, the peptide-major histocompatibility complex (pMHC), and enhance Ca2+ signaling and T cell activation. Conversely, some co-receptors can dampen Ca2+ signaling and inhibit T cell activation. Immune checkpoint therapies block inhibitory co-receptors, such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), to increase T cell Ca2+ signaling and promote T cell survival. Similar to CTLA-4 and PD-1, the co-receptor CD5 has been known to act as a negative regulator of T cell activation and to alter Ca2+ signaling and T cell function. Though much is known about the role of CD5 in B cells, recent research has expanded our understanding of CD5 function in T cells. Here we review these recent findings and discuss how our improved understanding of CD5 Ca2+ signaling regulation could be useful for basic and clinical research. PMID:29701673

The T cell STAT signaling network is reprogrammed within hours of bacteremia via secondary signals1

PubMed Central

Hotson, Andrew N.; Hardy, Jonathan W.; Hale, Matthew B.; Contag, Christopher H.; Nolan, Garry P.

2014-01-01

The delicate balance between protective immunity and inflammatory disease is challenged during sepsis, a pathologic state characterized by aspects of both a hyper-active immune response and immunosuppression. The events driven by systemic infection by bacterial pathogens on the T cell signaling network that likely control these responses have not been illustrated in great detail. We characterized how intracellular signaling within the immune compartment is reprogrammed at the single cell level when the host is challenged with a high levels of pathogen. To accomplish this, we applied flow cytometry to measure the phosphorylation potential of key signal transduction proteins during acute bacterial challenge. We modeled the onset of sepsis by intravenous administration of avirulent strains of Listeria and E. coli to mice. Within six hours of bacterial challenge, T cells were globally restricted in their ability to respond to specific cytokine stimulations as determined by assessing the extent of STAT protein phosphorylation. Mechanisms by which this negative feedback response occurred included SOCS1 and SOCS3 gene up regulation and IL-6 induced endocystosis of the IL-6 receptor. In addition, macrophages were partially tolerized in their ability to respond to TLR agonists. Thus, in contrast to the view that there is a wholesale immune activation during sepsis, one immediate host response to blood borne bacteria was induction of a refractory period during which leukocyte activation by specific stimulations was attenuated. PMID:19494279

Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs.

PubMed

Cheng, Liang; Ma, Jianping; Li, Jingyun; Li, Dan; Li, Guangming; Li, Feng; Zhang, Qing; Yu, Haisheng; Yasui, Fumihiko; Ye, Chaobaihui; Tsao, Li-Chung; Hu, Zhiyuan; Su, Lishan; Zhang, Liguo

2017-01-03

Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1-associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.

Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor.

PubMed

Wolf, Insa M A; Diercks, Björn-Philipp; Gattkowski, Ellen; Czarniak, Frederik; Kempski, Jan; Werner, René; Schetelig, Daniel; Mittrücker, Hans-Willi; Schumacher, Valéa; von Osten, Manuel; Lodygin, Dimitri; Flügel, Alexander; Fliegert, Ralf; Guse, Andreas H

2015-10-13

The activation of T cells is the fundamental on switch for the adaptive immune system. Ca(2+) signaling is essential for T cell activation and starts as initial, short-lived, localized Ca(2+) signals. The second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) forms rapidly upon T cell activation and stimulates early Ca(2+) signaling. We developed a high-resolution imaging technique using multiple fluorescent Ca(2+) indicator dyes to characterize these early signaling events and investigate the channels involved in NAADP-dependent Ca(2+) signals. In the first seconds of activation of either primary murine T cells or human Jurkat cells with beads coated with an antibody against CD3, we detected Ca(2+) signals with diameters close to the limit of detection and that were close to the activation site at the plasma membrane. In Jurkat cells in which the ryanodine receptor (RyR) was knocked down or in primary T cells from RyR1(-/-) mice, either these early Ca(2+) signals were not detected or the number of signals was markedly reduced. Local Ca(2+) signals observed within 20 ms upon microinjection of Jurkat cells with NAADP were also sensitive to RyR knockdown. In contrast, TRPM2 (transient receptor potential channel, subtype melastatin 2), a potential NAADP target channel, was not required for the formation of initial Ca(2+) signals in primary T cells. Thus, through our high-resolution imaging method, we characterized early Ca(2+) release events in T cells and obtained evidence for the involvement of RyR and NAADP in such signals. Copyright © 2015, American Association for the Advancement of Science.

Quantifying facial expression signal and intensity use during development.

PubMed

Rodger, Helen; Lao, Junpeng; Caldara, Roberto

2018-06-12

Behavioral studies investigating facial expression recognition during development have applied various methods to establish by which age emotional expressions can be recognized. Most commonly, these methods employ static images of expressions at their highest intensity (apex) or morphed expressions of different intensities, but they have not previously been compared. Our aim was to (a) quantify the intensity and signal use for recognition of six emotional expressions from early childhood to adulthood and (b) compare both measures and assess their functional relationship to better understand the use of different measures across development. Using a psychophysical approach, we isolated the quantity of signal necessary to recognize an emotional expression at full intensity and the quantity of expression intensity (using neutral expression image morphs of varying intensities) necessary for each observer to recognize the six basic emotions while maintaining performance at 75%. Both measures revealed that fear and happiness were the most difficult and easiest expressions to recognize across age groups, respectively, a pattern already stable during early childhood. The quantity of signal and intensity needed to recognize sad, angry, disgust, and surprise expressions decreased with age. Using a Bayesian update procedure, we then reconstructed the response profiles for both measures. This analysis revealed that intensity and signal processing are similar only during adulthood and, therefore, cannot be straightforwardly compared during development. Altogether, our findings offer novel methodological and theoretical insights and tools for the investigation of the developing affective system. Copyright © 2018 Elsevier Inc. All rights reserved.

The signaling symphony: T cell receptor tunes cytokine-mediated T cell differentiation

PubMed Central

Huang, Weishan; August, Avery

2015-01-01

T cell development, differentiation, and maintenance are orchestrated by 2 key signaling axes: the antigen-specific TCR and cytokine-mediated signals. The TCR signals the recognition of self- and foreign antigens to control T cell homeostasis for immune tolerance and immunity, which is regulated by a variety of cytokines to determine T cell subset homeostasis and differentiation. TCR signaling can synergize with or antagonize cytokine-mediated signaling to fine tune T cell fate; however, the latter is less investigated. Murine models with attenuated TCR signaling strength have revealed that TCR signaling can function as regulatory feedback machinery for T cell homeostasis and differentiation in differential cytokine milieus, such as IL-2-mediated Treg development; IL-7-mediated, naïve CD8+ T cell homeostasis; and IL-4-induced innate memory CD8+ T cell development. In this review, we discuss the symphonic cross-talk between TCR and cytokine-mediated responses that differentially control T cell behavior, with a focus on the negative tuning by TCR activation on the cytokine effects. PMID:25525115

c-MPL provides tumor-targeted T-cell receptor-transgenic T cells with costimulation and cytokine signals.

PubMed

Nishimura, Christopher D; Brenner, Daniel A; Mukherjee, Malini; Hirsch, Rachel A; Ott, Leah; Wu, Meng-Fen; Liu, Hao; Dakhova, Olga; Orange, Jordan S; Brenner, Malcolm K; Lin, Charles Y; Arber, Caroline

2017-12-21

Adoptively transferred T-cell receptor (TCR)-engineered T cells depend on host-derived costimulation and cytokine signals for their full and sustained activation. However, in patients with cancer, both signals are frequently impaired. Hence, we developed a novel strategy that combines both essential signals in 1 transgene by expressing the nonlymphoid hematopoietic growth factor receptor c-MPL (myeloproliferative leukemia), the receptor for thrombopoietin (TPO), in T cells. c-MPL signaling activates pathways shared with conventional costimulatory and cytokine receptor signaling. Thus, we hypothesized that host-derived TPO, present in the tumor microenvironment, or pharmacological c-MPL agonists approved by the US Food and Drug Administration could deliver both signals to c-MPL-engineered TCR-transgenic T cells. We found that c-MPL + polyclonal T cells expand and proliferate in response to TPO, and persist longer after adoptive transfer in immunodeficient human TPO-transgenic mice. In TCR-transgenic T cells, c-MPL activation enhances antitumor function, T-cell expansion, and cytokine production and preserves a central memory phenotype. c-MPL signaling also enables sequential tumor cell killing, enhances the formation of effective immune synapses, and improves antileukemic activity in vivo in a leukemia xenograft model. We identify the type 1 interferon pathway as a molecular mechanism by which c-MPL mediates immune stimulation in T cells. In conclusion, we present a novel immunotherapeutic strategy using c-MPL-enhanced transgenic T cells responding to either endogenously produced TPO (a microenvironment factor in hematologic malignancies) or c-MPL-targeted pharmacological agents. © 2017 by The American Society of Hematology.

Human T Cell Leukemia Virus Type 1 Tax Inhibits Innate Antiviral Signaling via NF-κB-Dependent Induction of SOCS1▿

PubMed Central

Charoenthongtrakul, Soratree; Zhou, Qinjie; Shembade, Noula; Harhaj, Nicole S.; Harhaj, Edward W.

2011-01-01

Human T cell leukemia virus type 1 (HTLV-1) inhibits host antiviral signaling pathways although the underlying mechanisms are unclear. Here we found that the HTLV-1 Tax oncoprotein induced the expression of SOCS1, an inhibitor of interferon signaling. Tax required NF-κB, but not CREB, to induce the expression of SOCS1 in T cells. Furthermore, Tax interacted with SOCS1 in both transfected cells and in HTLV-1-transformed cell lines. Although SOCS1 is normally a short-lived protein, in the presence of Tax, the stability of SOCS1 was greatly increased. Accordingly, Tax enhanced the replication of a heterologous virus, vesicular stomatitis virus (VSV), in a SOCS1-dependent manner. Surprisingly, Tax required SOCS1 to inhibit RIG-I-dependent antiviral signaling, but not the interferon-induced JAK/STAT pathway. Inhibition of SOCS1 by RNA-mediated interference in the HTLV-1-transformed cell line MT-2 resulted in increased IFN-β expression accompanied by reduced HTLV-1 replication and p19Gag levels. Taken together, our results reveal that Tax inhibits antiviral signaling, in part, by hijacking an interferon regulatory protein. PMID:21593151

Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling.

PubMed

Kido, Masahiro; Watanabe, Norihiko; Okazaki, Taku; Akamatsu, Takuji; Tanaka, Junya; Saga, Kazuyuki; Nishio, Akiyoshi; Honjo, Tasuku; Chiba, Tsutomu

2008-10-01

Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.

Arterial spin-labeling assessment of normalized vascular intratumoral signal intensity as a predictor of histologic grade of astrocytic neoplasms.

PubMed

Furtner, J; Schöpf, V; Schewzow, K; Kasprian, G; Weber, M; Woitek, R; Asenbaum, U; Preusser, M; Marosi, C; Hainfellner, J A; Widhalm, G; Wolfsberger, S; Prayer, D

2014-03-01

Pulsed arterial spin-labeling is a noninvasive MR imaging perfusion method performed with the use of water in the arterial blood as an endogenous contrast agent. The purpose of this study was to determine the inversion time with the largest difference in normalized intratumoral signal intensity between high-grade and low-grade astrocytomas. Thirty-three patients with gliomas, histologically classified as low-grade (n = 7) or high-grade astrocytomas (n = 26) according to the World Health Organization brain tumor classification, were included. A 3T MR scanner was used to perform pulsed arterial spin-labeling measurements at 8 different inversion times (370 ms, 614 ms, 864 ms, 1114 ms, 1364 ms, 1614 ms, 1864 ms, and 2114 ms). Normalized intratumoral signal intensity was calculated, which was defined by the signal intensity ratio of the tumor and the contralateral normal brain tissue for all fixed inversion times. A 3-way mixed ANOVA was used to reveal potential differences in the normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas. The difference in normalized vascular intratumoral signal intensity between high-grade and low-grade astrocytomas obtained the most statistically significant results at 370 ms (P = .003, other P values ranged from .012-.955). The inversion time by which to differentiate high-grade and low-grade astrocytomas by use of normalized vascular intratumoral signal intensity was 370 ms in our study. The normalized vascular intratumoral signal intensity values at this inversion time mainly reflect the labeled intra-arterial blood bolus and therefore could be referred to as normalized vascular intratumoral signal intensity. Our data indicate that the use of normalized vascular intratumoral signal intensity values allows differentiation between low-grade and high-grade astrocytomas and thus may serve as a new, noninvasive marker for astrocytoma grading.

Closed-form expressions for flip angle variation that maximize total signal in T1-weighted rapid gradient echo MRI.

PubMed

Drobnitzky, Matthias; Klose, Uwe

2017-03-01

Magnetization-prepared rapid gradient-echo (MPRAGE) sequences are commonly employed for T1-weighted structural brain imaging. Following a contrast preparation radiofrequency (RF) pulse, the data acquisition proceeds under nonequilibrium conditions of the relaxing longitudinal magnetization. Variation of the flip angle can be used to maximize total available signal. Simulated annealing or greedy algorithms have so far been published to numerically solve this problem, with signal-to-noise ratios optimized for clinical imaging scenarios by adhering to a predefined shape of the signal evolution. We propose an unconstrained optimization of the MPRAGE experiment that employs techniques from resource allocation theory. A new dynamic programming solution is introduced that yields closed-form expressions for optimal flip angle variation. Flip angle series are proposed that maximize total transverse magnetization (Mxy) for a range of physiologic T1 values. A 3D MPRAGE sequence is modified to allow for a controlled variation of the excitation angle. Experiments employing a T1 contrast phantom are performed at 3T. 1D acquisitions without phase encoding permit measurement of the temporal development of Mxy. Image mean signal and standard deviation for reference flip angle trains are compared in 2D measurements. Signal profiles at sharp phantom edges are acquired to access image blurring related to nonuniform Mxy development. A novel closed-form expression for flip angle variation is found that constitutes the optimal policy to reach maximum total signal. It numerically equals previously published results of other authors when evaluated under their simplifying assumptions. Longitudinal magnetization (Mz) is exhaustively used without causing abrupt changes in the measured MR signal, which is a prerequisite for artifact free images. Phantom experiments at 3T verify the expected benefit for total accumulated k-space signal when compared with published flip angle series. Describing

Lung Parenchymal Signal Intensity in MRI: A Technical Review with Educational Aspirations Regarding Reversible Versus Irreversible Transverse Relaxation Effects in Common Pulse Sequences.

PubMed

Mulkern, Robert; Haker, Steven; Mamata, Hatsuho; Lee, Edward; Mitsouras, Dimitrios; Oshio, Koichi; Balasubramanian, Mukund; Hatabu, Hiroto

2014-03-01

Lung parenchyma is challenging to image with proton MRI. The large air space results in ~l/5th as many signal-generating protons compared to other organs. Air/tissue magnetic susceptibility differences lead to strong magnetic field gradients throughout the lungs and to broad frequency distributions, much broader than within other organs. Such distributions have been the subject of experimental and theoretical analyses which may reveal aspects of lung microarchitecture useful for diagnosis. Their most immediate relevance to current imaging practice is to cause rapid signal decays, commonly discussed in terms of short T 2 * values of 1 ms or lower at typical imaging field strengths. Herein we provide a brief review of previous studies describing and interpreting proton lung spectra. We then link these broad frequency distributions to rapid signal decays, though not necessarily the exponential decays generally used to define T 2 * values. We examine how these decays influence observed signal intensities and spatial mapping features associated with the most prominent torso imaging sequences, including spoiled gradient and spin echo sequences. Effects of imperfect refocusing pulses on the multiple echo signal decays in single shot fast spin echo (SSFSE) sequences and effects of broad frequency distributions on balanced steady state free precession (bSSFP) sequence signal intensities are also provided. The theoretical analyses are based on the concept of explicitly separating the effects of reversible and irreversible transverse relaxation processes, thus providing a somewhat novel and more general framework from which to estimate lung signal intensity behavior in modern imaging practice.

Lung Parenchymal Signal Intensity in MRI: A Technical Review with Educational Aspirations Regarding Reversible Versus Irreversible Transverse Relaxation Effects in Common Pulse Sequences

PubMed Central

MULKERN, ROBERT; HAKER, STEVEN; MAMATA, HATSUHO; LEE, EDWARD; MITSOURAS, DIMITRIOS; OSHIO, KOICHI; BALASUBRAMANIAN, MUKUND; HATABU, HIROTO

2014-01-01

Lung parenchyma is challenging to image with proton MRI. The large air space results in ~l/5th as many signal-generating protons compared to other organs. Air/tissue magnetic susceptibility differences lead to strong magnetic field gradients throughout the lungs and to broad frequency distributions, much broader than within other organs. Such distributions have been the subject of experimental and theoretical analyses which may reveal aspects of lung microarchitecture useful for diagnosis. Their most immediate relevance to current imaging practice is to cause rapid signal decays, commonly discussed in terms of short T2* values of 1 ms or lower at typical imaging field strengths. Herein we provide a brief review of previous studies describing and interpreting proton lung spectra. We then link these broad frequency distributions to rapid signal decays, though not necessarily the exponential decays generally used to define T2* values. We examine how these decays influence observed signal intensities and spatial mapping features associated with the most prominent torso imaging sequences, including spoiled gradient and spin echo sequences. Effects of imperfect refocusing pulses on the multiple echo signal decays in single shot fast spin echo (SSFSE) sequences and effects of broad frequency distributions on balanced steady state free precession (bSSFP) sequence signal intensities are also provided. The theoretical analyses are based on the concept of explicitly separating the effects of reversible and irreversible transverse relaxation processes, thus providing a somewhat novel and more general framework from which to estimate lung signal intensity behavior in modern imaging practice. PMID:25228852

Factors influencing the dosimetry for high-intensity focused ultrasound ablation of uterine fibroids: a retrospective study.

PubMed

Peng, Song; Zhang, Lian; Hu, Liang; Chen, Jinyun; Ju, Jin; Wang, Xi; Zhang, Rong; Wang, Zhibiao; Chen, Wenzhi

2015-04-01

The aim of this article is to analyze factors affecting sonication dose and build a dosimetry model of high-intensity focused ultrasound (HIFU) ablation for uterine fibroids. Four hundred and three patients with symptomatic uterine fibroids who underwent HIFU were retrospectively analyzed. The energy efficiency factor (EEF) was set as dependent variable, and the factors possibly affecting sonication dose included age, body mass index, size of uterine fibroid, abdominal wall thickness, the distance from uterine fibroid dorsal side to sacrum, the distance from uterine fibroid ventral side to skin, location of uterus, location of uterine fibroids, type of uterine fibroids, abdominal wall scar, signal intensity on T2-weighted imaging (T2WI), and enhancement type on T1-weighted imaging (T1WI) were set as predictors to build a multiple regression model. The size of uterine fibroid, distance from fibroid ventral side to skin, location of uterus, location of uterine fibroids, type of uterine fibroids, signal intensity on T2WI, and enhancement type on T1WI had a linear correlation with EEF. The distance from fibroid ventral side to skin, enhancement type on T1WI, size of uterine fibroid, and signal intensity on T2WI were eventually incorporated into the dosimetry model. The distance from fibroid ventral side to skin, enhancement type on T1WI, size of uterine fibroid, and signal intensity on T2WI can be used as dosimetric predictors for HIFU for uterine fibroids.

Profiling calcium signals of in vitro polarized human effector CD4+ T cells.

PubMed

Kircher, Sarah; Merino-Wong, Maylin; Niemeyer, Barbara A; Alansary, Dalia

2018-06-01

Differentiation of naïve CD4 + T cells into effector subtypes with distinct cytokine profiles and physiological roles is a tightly regulated process, the imbalance of which can lead to an inadequate immune response or autoimmune disease. The crucial role of Ca 2+ signals, mainly mediated by the store operated Ca 2+ entry (SOCE) in shaping the immune response is well described. However, it is unclear if human effector CD4 + T cell subsets show differential Ca 2+ signatures in response to different stimulation methods. Herein, we provide optimized in vitro culture conditions for polarization of human CD4 + effector T cells and characterize their SOCE following both pharmacological store depletion and direct T-cell receptor (TCR) activation. Moreover, we measured whole cell Ca 2+ release activated Ca 2+ currents (I CRAC ) and investigated whether the observed differences correlate to the expression of CRAC genes. Our results show that Ca 2+ profiles of helper CD4 + Th1, Th2 and Th17 are distinct and in part shaped by the intensity of stimulation. Regulatory T cells (Treg) are unique being the subtype with the most prominent SOCE response. Analysis of in vivo differentiated Treg unraveled the role of differential expression of ORAI2 in fine-tuning signals in Treg vs. conventional CD4 + T cells. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Prenatal diagnosis of fetal respiratory function: evaluation of fetal lung maturity using lung-to-liver signal intensity ratio at magnetic resonance imaging.

PubMed

Oka, Yasuko; Rahman, Mosfequr; Sasakura, Chihaya; Waseda, Tomoo; Watanabe, Yukio; Fujii, Ryota; Makinoda, Satoru

2014-12-01

The purpose of this retrospective study is to determine the fetal lung-to-liver signal intensity ratio (LLSIR) on T2-weighted images for the prediction of neonatal respiratory outcome. One hundred ten fetuses who underwent magnetic resonance imaging (MRI) examination for various indications after 22 weeks of gestation participated in this study. LLSIR was measured as the ratio of signal intensities of the fetal lung and liver on T2-weighted images at MRI. We examined the changes of the ratio with advancing gestation and the relations between LLSIR and the presence of the severe respiratory disorder (SRD) after birth. The best cut-off value of the LLSIR to predict respiratory outcome after birth was calculated using receiver operating characteristic (ROC) curve analysis. Lung-to-liver signal intensity ratio correlated significantly with advancing gestational age (R = 0.35, p < 0.001). The non-SRD group had higher LLSIR compared with the SRD group (2.15 ± 0.30 vs. 1.53 ± 0.40, p < 0.001). ROC curve analysis showed that fetuses with an LLSIR < 2.00 were more likely to develop SRD [sensitivity: 100%, 95% confidence interval (CI): 52-100%; specificity: 73%, 95% CI 54-88%]. The fetal LLSIR on T2-weighted images is an accurate marker to diagnose the fetal lung maturity. © 2014 The Authors. Prenatal Diagnosis published by John Wiley & Sons, Ltd.

T-bet Down-Modulation in Tolerized Th1 Effector CD4 Cells Confers a TCR-Distal Signaling Defect That Selectively Impairs IFN-γ Expression1

PubMed Central

Long, Meixiao; Slaiby, Aaron M.; Hagymasi, Adam T.; Mihalyo, Marianne A.; Lichtler, Alexander C.; Reiner, Steven L.; Adler, Adam J.

2010-01-01

When Th1 effector CD4 cells encounter tolerizing Ag in vivo, their capacity to express the effector cytokines IFN-γ and TNF-α is lost more rapidly than noneffector functions such as IL-2 production and proliferation. To localize the relevant intracellular signaling defects, cytokine expression was compared following restimulation with Ag vs agents that bypass TCR-proximal signaling. IFN-γ and TNF-α expression were both partially rescued when TCR-proximal signaling was bypassed, indicating that both TCR-proximal and -distal signaling defects impair the expression of these two effector cytokines. In contrast, bypassing TCR-proximal signaling fully rescued IL-2 expression. T-bet, a transcription and chromatin remodeling factor that is required to direct the differentiation of naive CD4 cells into IFN-γ -expressing Th1 effectors, was partially down-modulated in tolerized Th1 effectors. Enforcing T-bet expression during tolerization selectively rescued the ability to express IFN-γ, but not TNF-α. Conversely, expression of a dominant-negative T-bet in Th1 effectors selectively impaired the ability to express IFN-γ, but not TNF-α. Analysis of histone acetylation at the IFN-γ promoter further suggested that down-modulation of T-bet expression during Th1 effector CD4 cell tolerization does not impair IFN-γ expression potential through alterations in chromatin structure. PMID:16393991

T cell receptor for antigen induces linker for activation of T cell–dependent activation of a negative signaling complex involving Dok-2, SHIP-1, and Grb-2

PubMed Central

Dong, Shen; Corre, Béatrice; Foulon, Eliane; Dufour, Evelyne; Veillette, André; Acuto, Oreste; Michel, Frédérique

2006-01-01

Adaptor proteins positively or negatively regulate the T cell receptor for antigen (TCR) signaling cascade. We report that after TCR stimulation, the inhibitory adaptor downstream of kinase (Dok)-2 and its homologue Dok-1 are involved in a multimolecular complex including the lipid phosphatase Src homology 2 domain–containing inositol polyphosphate 5′-phosphatase (SHIP)-1 and Grb-2 which interacts with the membrane signaling scaffold linker for activation of T cells (LAT). Knockdown of LAT and SHIP-1 expression indicated that SHIP-1 favored recruitment of Dok-2 to LAT. Knockdown of Dok-2 and Dok-1 revealed their negative control on Akt and, unexpectedly, on Zap-70 activation. Our findings support the view that Dok-1 and -2 are critical elements of a LAT-dependent negative feedback loop that attenuates early TCR signal. Dok-1 and -2 may therefore exert a critical role in shaping the immune response and as gatekeepers for T cell tolerance. PMID:17043143

The Us3 Protein of Herpes Simplex Virus 1 Inhibits T Cell Signaling by Confining Linker for Activation of T Cells (LAT) Activation via TRAF6 Protein*

PubMed Central

Yang, Yin; Wu, Songfang; Wang, Yu; Pan, Shuang; Lan, Bei; Liu, Yaohui; Zhang, Liming; Leng, Qianli; Chen, Da; Zhang, Cuizhu; He, Bin; Cao, Youjia

2015-01-01

Herpes simplex virus 1 (HSV-1) is the most prevalent human virus and causes global morbidity because the virus is able to infect multiple cell types. Remarkably, HSV infection switches between lytic and latent cycles, where T cells play a critical role. However, the precise way of virus-host interactions is incompletely understood. Here we report that HSV-1 productively infected Jurkat T-cells and inhibited antigen-induced T cell receptor activation. We discovered that HSV-1-encoded Us3 protein interrupted TCR signaling and interleukin-2 production by inactivation of the linker for activation of T cells. This study unveils a mechanism by which HSV-1 intrudes into early events of TCR-mediated cell signaling and may provide novel insights into HSV infection, during which the virus escapes from host immune surveillance. PMID:25907557

Estradiol targets T cell signaling pathways in human systemic lupus.

PubMed

Walters, Emily; Rider, Virginia; Abdou, Nabih I; Greenwell, Cindy; Svojanovsky, Stan; Smith, Peter; Kimler, Bruce F

2009-12-01

The major risk factor for developing systemic lupus erythematosus (SLE) is being female. The present study utilized gene profiles of activated T cells from females with SLE and healthy controls to identify signaling pathways uniquely regulated by estradiol that could contribute to SLE pathogenesis. Selected downstream pathway genes (+/- estradiol) were measured by real time polymerase chain amplification. Estradiol uniquely upregulated six pathways in SLE T cells that control T cell function including interferon-alpha signaling. Measurement of interferon-alpha pathway target gene expression revealed significant differences (p= 0.043) in DRIP150 (+/- estradiol) in SLE T cell samples while IFIT1 expression was bimodal and correlated moderately (r= 0.55) with disease activity. The results indicate that estradiol alters signaling pathways in activated SLE T cells that control T cell function. Differential expression of transcriptional coactivators could influence estrogen-dependent gene regulation in T cell signaling and contribute to SLE onset and disease pathogenesis.

Lingering fat signals with CHESS in simultaneous imaging of both hands can be improved with rice pads in both 1.5T and 3.0T.

PubMed

Moriya, Susumu; Miki, Yukio; Kamishima, Tamotsu; Miyati, Tosiaki; Kanagaki, Mitsunori; Matsuno, Yukako; Yokobayashi, Tsuneo

2013-09-01

To investigate whether rice pads can eliminate lingering fat signals of the complex surface shape of both hands that occur with chemical shift selective (CHESS) at 1.5T and 3.0T. T1-weighted images were obtained with CHESS using 1.5T and 3.0T systems. The same imaging parameters were used with and without rice pads on the coronal plane of both hands in 10 healthy volunteers. The fat-suppression effects were classified into four categories and scored for images, and visual evaluations were performed by one radiologist and one radiologic technologist. At 1.5T, the mean evaluation score was 1.55 for images obtained without rice pads and 3.50 for images obtained with rice pads. At 3.0T, the mean evaluation score was 1.10 for images obtained without rice pads and 3.20 for images obtained with rice pads. With both systems, images obtained with the rice pads showed significantly better fat suppression effects than images obtained without rice pads (P<0.0001, P<0.0001). It was confirmed that lingering fat signals are eliminated and good fat-suppressed images are obtained with the use of rice pads at 1.5T and 3.0T. Rice pads are therefore useful with at 1.5T and 3.0T, which are currently becoming more widely used. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

IL-1R and MyD88 signalling in CD4+ T cells promote Th17 immunity and atherosclerosis.

PubMed

Engelbertsen, Daniel; Rattik, Sara; Wigren, Maria; Vallejo, Jenifer; Marinkovic, Goran; Schiopu, Alexandru; Björkbacka, Harry; Nilsson, Jan; Bengtsson, Eva

2018-01-01

The role of CD4+ T cells in atherosclerosis has been shown to be dependent on cytokine cues that regulate lineage commitment into mature T helper sub-sets. In this study, we tested the roles of IL-1R1 and MyD88 signalling in CD4+ T cells in atherosclerosis. We transferred apoe-/-myd88+/+ or apoe-/-myd88-/- CD4+ T cells to T- and B-cell-deficient rag1-/-apoe-/- mice fed high fat diet. Mice given apoe-/-myd88-/- CD4+ T cells exhibited reduced atherosclerosis compared with mice given apoe-/-myd88+/+ CD4+ T cells. CD4+ T cells from apoe-/-myd88-/- produced less IL-17 but similar levels of IFN-γ. Treatment of human CD4+ T cells with a MyD88 inhibitor inhibited IL-17 secretion in vitro. Transfer of il1r1-/- CD4+ T cells recapitulated the phenotype seen by transfer of myd88-/- CD4+ T cells with reduced lesion development and a reduction in Th17 and IL-17 production compared with wild type CD4+ T cell recipients. Relative collagen content of lesions was reduced in mice receiving il1r1-/- CD4+ T cells. We demonstrate that both IL1R and MyD88 signalling in CD4+ T cells promote Th17 immunity, plaque growth and may regulate plaque collagen levels. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

[Diagnostic significance of T2W hypointensity of the sella].

PubMed

Rousset, P; Cattin, F; Chiras, J; Bonneville, J F; Bonneville, F

2009-06-01

Normal anatomical structures and lesions characterized by low T2W signal intensity are reviewed in this pictorial essay. The purpose is to demonstrate how evaluation of the appearance, shape and exact anatomical location of the T2W hypointense sellar region structure, correlated with its T1W signal intensity, can based on the clinical context lead to an appropriate differential diagnosis.

Effect of eicosapentaenoic acid/docosahexaenoic acid on coronary high-intensity plaques detected with non-contrast T1-weighted imaging (the AQUAMARINE EPA/DHA study): study protocol for a randomized controlled trial.

PubMed

Nakao, Kazuhiro; Noguchi, Teruo; Asaumi, Yasuhide; Morita, Yoshiaki; Kanaya, Tomoaki; Fujino, Masashi; Hosoda, Hayato; Yoneda, Shuichi; Kawakami, Shoji; Nagai, Toshiyuki; Nishihira, Kensaku; Nakashima, Takahiro; Kumasaka, Reon; Arakawa, Tetsuo; Otsuka, Fumiyuki; Nakanishi, Michio; Kataoka, Yu; Tahara, Yoshio; Goto, Yoichi; Yamamoto, Haruko; Hamasaki, Toshimitsu; Yasuda, Satoshi

2018-01-08

Despite the success of HMG-CoA reductase inhibitor (statin) therapy in reducing atherosclerotic cardiovascular events, a residual risk for cardiovascular events in patients with coronary artery disease (CAD) remains. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are promising anti-atherosclerosis agents that might reduce the residual CAD risk. Non-contrast T1-weighted imaging (T1WI) with cardiac magnetic resonance (CMR) less invasively identifies high-risk coronary plaques as high-intensity signals. These high-intensity plaques (HIPs) are quantitatively assessed using the plaque-to-myocardium signal intensity ratio (PMR). Our goal is to assess the effect of EPA/DHA on coronary HIPs detected with T1WI in patients with CAD on statin treatment. This prospective, controlled, randomized, open-label study examines the effect of 12 months of EPA/DHA therapy and statin treatment on PMR of HIPs detected with CMR and computed tomography angiography (CTA) in patients with CAD. The primary endpoint is the change in PMR after EPA/DHA treatment. Secondary endpoints include changes in Hounsfield units, plaque volume, vessel area, and plaque area measured using CTA. Subjects are randomly assigned to either of three groups: the 2 g/day EPA/DHA group, the 4 g/day EPA/DHA group, or the no-treatment group. This trial will help assess whether EPA/DHA has an anti-atherosclerotic effect using PMR of HIPs detected by CMR. The trial outcomes will provide novel insights into the effect of EPA/DHA on high-risk coronary plaques and may provide new strategies for lowering the residual risk in patients with CAD on statin therapy. The University Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000015316 . Registered on 2 October 2014.

Charged Higgs signals in t t ¯ searches

NASA Astrophysics Data System (ADS)

Alves, Daniele S. M.; Hedri, Sonia El; Taki, Anna Maria; Weiner, Neal

2017-10-01

New scalars from an extended Higgs sector could have weak scale masses and still have escaped detection. In a type I two Higgs doublet model, for instance, even the charged Higgs can be lighter than the top quark. Because electroweak production of these scalars is modest, the greatest opportunity for their detection might come from rare top decays. For mass hierarchies of the type mt>mH+>mA0,H0, the natural signal can arise from top quark pair production, followed by the decay chain t →b H+, H+→W+(*)ϕ0, ϕ0→b b ¯,τ+τ-, where ϕ0=A0,H0. These final states largely overlap with those of the Standard Model t t ¯ HSM process, and therefore can potentially contaminate t t ¯ HSM searches. We demonstrate that existing t t ¯HSM analyses can already probe light extended Higgs sectors, and we derive new constraints from their results. Furthermore, we note that existing excesses in t t ¯HSM searches can be naturally explained by the contamination of rare top decays to new light Higgses. We discuss how to distinguish this signal from the Standard Model process.

Diffusion-weighted imaging of mucinous carcinoma of the breast: evaluation of apparent diffusion coefficient and signal intensity in correlation with histologic findings.

PubMed

Woodhams, Reiko; Kakita, Satoko; Hata, Hirofumi; Iwabuchi, Keiichi; Umeoka, Shigeaki; Mountford, Carolyn E; Hatabu, Hiroto

2009-07-01

The purposes of this study were to compare the apparent diffusion coefficient (ADC) of mucinous carcinoma of the breast with that of other breast tumors and to analyze correlations between signal intensity on diffusion-weighted images and the histologic features of mucinous carcinoma. Two hundred seventy-six patients with 277 lesions, including 15 mucinous carcinomas (13 pure type, two mixed type), 204 other malignant tumors, and 58 benign lesions, were examined with 1.5-T MRI at b values of 0 and 1,500 s/mm(2). The correlations between cellularity and ADC, homogeneity of signal intensity on diffusion-weighted images, and histopathologic findings were analyzed. The difference was statistically significant (p < 0.05). The mean ADC of mucinous carcinoma (1.8 +/- 0.4 x 10(-3) mm(2)/s) was statistically higher than that of benign lesions (1.3+/- 0.3 x 10(-3) mm(2)/s) and other malignant tumors (0.9 +/- 0.2 x 10(-3) mm(2)/s) (p < 0.001). The ADC of pure type mucinous carcinoma (1.8 +/- 0.3 x 10(-3) mm(2)/s) was higher than that of mixed type mucinous carcinoma (1.2 +/- 0.2 x 10(-3) mm(2)/s) (p < 0.001) and other histologic types (p > 0.05). The correlation between mean cellularity and the ADC of mucinous carcinoma was significant (rho(s) = -0.754; p = 0.001). The homogeneity of signal intensity on diffusion-weighted images correlated with the homogeneity of histologic structures of mucinous carcinoma (p < 0.001; kappa = 0.826). Mucinous carcinoma can be clearly differentiated from other breast tumors on the basis of ADC. The low signal intensity of mucinous carcinoma on diffusion-weighted images appears to reflect the presence of mucin and low cellularity. High signal intensity on diffusion-weighted images may reflect the presence of fibrovascular bundles, increased cell density, or a combination of these features.

Interleukin (IL)-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts1

PubMed Central

Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D.; Abe, Toyofumi; Su, Charles A.; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M.; Fairchild, Robert L.

2016-01-01

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared to complete MHC-mismatched wild type cardiac allografts, IL-1R−/− allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R−/− allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R−/− cardiac allografts took 3 weeks longer than wild type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R−/−/wild type chimeric donors indicated that IL-1R signaling on graft non-hematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli provoking development and elicitation of optimal alloimmune responses to the grafts. PMID:26856697

Regulation of human intestinal T-cell responses by type 1 interferon-STAT1 signaling is disrupted in inflammatory bowel disease.

PubMed

Giles, E M; Sanders, T J; McCarthy, N E; Lung, J; Pathak, M; MacDonald, T T; Lindsay, J O; Stagg, A J

2017-01-01

Type 1 interferon (IFN-1) promotes regulatory T-cell function to suppress inflammation in the mouse intestine, but little is known about IFN-1 in the human gut. We therefore assessed the influence of IFN-1 on CD4+ T-cells isolated from human colon tissue obtained from healthy controls or patients with inflammatory bowel disease (IBD). Immunofluorescent imaging revealed constitutive expression of IFNβ in human intestinal tissue, and colonic T-cells were responsive to exogenous IFN-1 as assessed by phosphorylation of signal transduction and activator of transcription 1 (pSTAT1) and induction of interferon stimulated genes (ISGs). Unlike their blood counterparts, intestinal T-cells from non-inflamed regions of IBD colon displayed enhanced responsiveness to IFN-1, increased frequency of pSTAT1+ cells, and greater induction of ISGs upon IFN-1 exposure in vitro. In healthy tissue, antibody neutralization of IFNβ selectively reduced T-cell production of the pro-regulatory cytokine interleukin-10 (IL-10) and increased IFNγ synthesis. In contrast, neutralization of IFNβ in IBD tissue cultures increased the frequency of T-cells producing inflammatory cytokines but did not alter IL-10 expression. These data support a role for endogenous IFN-1 as a context-dependent modulator of T-cell function that promotes regulatory activity in healthy human intestine, but indicate that the IFN-1/STAT1 pathway is dysregulated in inflammatory bowel disease.

Effect of signal intensity and camera quantization on laser speckle contrast analysis

PubMed Central

Song, Lipei; Elson, Daniel S.

2012-01-01

Laser speckle contrast analysis (LASCA) is limited to being a qualitative method for the measurement of blood flow and tissue perfusion as it is sensitive to the measurement configuration. The signal intensity is one of the parameters that can affect the contrast values due to the quantization of the signals by the camera and analog-to-digital converter (ADC). In this paper we deduce the theoretical relationship between signal intensity and contrast values based on the probability density function (PDF) of the speckle pattern and simplify it to a rational function. A simple method to correct this contrast error is suggested. The experimental results demonstrate that this relationship can effectively compensate the bias in contrast values induced by the quantized signal intensity and correct for bias induced by signal intensity variations across the field of view. PMID:23304650

Dectin-1 diversifies Aspergillus fumigatus–specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation

PubMed Central

Hohl, Tobias M.; Collins, Nichole; Leiner, Ingrid; Gallegos, Alena; Saijo, Shinobu; Coward, Jesse W.; Iwakura, Yoichiro

2011-01-01

Pulmonary infection of mice with Aspergillus fumigatus induces concurrent T helper type 1 (Th1) and Th17 responses that depend on Toll-like receptor/MyD88 and Dectin-1, respectively. However, the mechanisms balancing Th1 and Th17 CD4 T cell populations during infection remain incompletely defined. In this study, we show that Dectin-1 deficiency disproportionally increases Th1 responses and decreases Th17 differentiation after A. fumigatus infection. Dectin-1 signaling in A. fumigatus–infected wild-type mice reduces IFN-γ and IL-12p40 expression in the lung, thereby decreasing T-bet expression in responding CD4 T cells and enhancing Th17 responses. Absence of IFN-γ or IL-12p35 in infected mice or T-bet in responding CD4 T cells enhances Th17 differentiation, independent of Dectin-1 expression, in A. fumigatus–infected mice. Transient deletion of monocyte-derived dendritic cells also reduces Th1 and boosts Th17 differentiation of A. fumigatus–specific CD4 T cells. Our findings indicate that Dectin-1–mediated signals alter CD4 T cell responses to fungal infection by decreasing the production of IL-12 and IFN-γ in innate cells, thereby decreasing T-bet expression in A. fumigatus–specific CD4 T cells and enabling Th17 differentiation. PMID:21242294

Sargahydroquinoic acid inhibits TNFα-induced AP-1 and NF-κB signaling in HaCaT cells through PPARα activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jeon, Youngsic; Jung, Yujung; Kim, Min Cheol

2014-08-08

Highlights: • SHQA increases PPARα/γ transactivation and inhibits MMP-2/-9 expression. • SHQA inhibits TNFα-induced AP-1 and MAPK signaling. • SHQA inhibits TNFα-induced p65 translocation and IκBα phosphorylation. • SHQA inhibits TNFα-induced AP-1 and NF-κB signaling via PPARα. - Abstract: Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors and expressed in various cell types in the skin, including keratinocytes, fibroblasts and infiltrating immune cells. Thus, their ligands are targets for the treatment of various skin disorders, such as photo-aging and chronological aging of skin. Intensive studies have revealed that PPARα/γ functions in photo-agingmore » and age-related inflammation by regulating matrix metalloproteinases (MMPs) via activator protein-1 (AP-1) and nuclear factor kappa B (NF-κB). However, the detailed mechanism of PPARα/γ’s role in skin aging has not yet been elucidated. In this study, we confirmed that sargahydroquinoic acid (SHQA) as a PPARα/γ ligand significantly decreased Tumor Necrosis Factor-alpha (TNFα)-induced MMP-2/-9 expression by downregulating TNFα-induced transcription factors, subsequently reducing IκBα degradation and blocking NF-κB p65 nuclear translocation in HaCaT human epidermal keratinocyte cells. Treatment of cells with SHQA and GW6471 (PPARα antagonist) not bisphenol A diglycidyl ether (PPARγ antagonists), reversed the effect on TNFα-induced inflammatory signaling pathway activation. Taken together, our data suggest that SHQA inhibit TNFα-induced MMP-2/-9 expression and age-related inflammation by suppressing AP-1 and NF-κB pathway via PPARα.« less

Signaling via the CD2 receptor enhances HTLV-1 replication in T lymphocytes.

PubMed

Guyot, D J; Newbound, G C; Lairmore, M D

1997-07-21

Human T lymphotropic virus type 1 (HTLV-1) is considered the etiologic agent of adult T cell leukemia/lymphoma and several chronic progressive immune-mediated diseases. Approximately 1-4% of infected individuals develop disease, generally decades following infection. Increased proviral transcription, mediated by the viral 40-kDa trans-activating protein, Tax, has been implicated in the pathogenesis of HTLV-1-associated diseases. Since the HTLV-1 promoter contains sequences responsive to cyclic AMP and protein kinase C, we hypothesized that lymphocyte activation signals initiated through the TCR/CD3 complex or CD2 receptor promote viral replication in HTLV-1-infected lymphocytes. We demonstrate that mAbs directed against the CD2, but not the CD3 receptor increase viral p24 capsid protein 1.5- to 5.7-fold in CD2/CD3+ HTLV-1-infected cell culture supernatants. Northern blot analysis demonstrated a 2.5- to 4-fold increase in all species of viral mRNA following CD2 cross-linking of OSP2/4 cells, an immortalized HTLV-1 cell line. Consistent with transcriptional regulation, reporter gene activity increased approximately 11-fold in CD2-stimulated Jurkat T cells cotransfected with a Tax-expressing plasmid and a CAT reporter gene construct under control of the HTLV-1 promoter. These data suggest a possible physiologic mechanism, whereby CD2-mediated cell adhesion and lymphocyte activation may promote viral transcription in infected lymphocytes.

Signal transduction in T lymphocytes in microgravity

NASA Technical Reports Server (NTRS)

Cogoli, A.

1997-01-01

More than 120 experiments conducted in space in the last 15 years have shown that dramatic changes are occurring in several types of single cells during their exposure to microgravity. One focus of today's research on cells in space is on signal transduction, especially those steps involving the cytoskeleton and cell-cell interactions. Signal transduction is often altered in microgravity as well as in hypergravity. This leads to changes in cell proliferation, genetic expression and differentiation. Interesting examples are leukocytes, HeLa cells, epidermoid cells and osteoblastic cells. Signalling pathways were studied in T lymphocytes in microgravity by several investigators after the discovery that mitogenic activation in vitro is virtually nil at 0g. T cells are a good model to study signal transduction because three extracellular signals (mitogen, IL-1 and IL-2) are required for full activation, and two classical pathways (via proteins G and PKC) are activated within the cell. In addition, low molecular weight GTP-binding proteins (Ras and Rap) are interacting with the cytoskeleton. The data at 0g support the notion that the expression of IL-2 receptor is inhibited at 0g, while mitogen binding and the transmission of IL-1 by accessory cells occur normally. In addition, alterations of the cytoskeleton suggest that the interaction with Rap proteins is disturbed. Data obtained with phorbol esters indicate that the function of PKC is changed in microgravity. Similar conclusions are drawn from the results with epidermoid cells A431.

High glucose impaired estrogen receptor alpha signaling via β-catenin in osteoblastic MC3T3-E1.

PubMed

Wang, Rui; Gao, Dong; Zhou, Yin; Chen, Lu; Luo, Bin; Yu, Yanrong; Li, Hao; Hu, Jiawei; Huang, Qiren; He, Ming; Peng, Weijie; Luo, Dan

2017-11-01

Diabetic Mellitus is a risk factor for osteoporosis. It has been suggested that altered estrogen or estrogen receptor α/β (ERα/β) signaling may be involved in diabetic osteoporosis. The present study is to investigate the effects of high glucose on ERα/β signaling in osteoblastic MC3T3-E1 and how the altered signaling of ERα/β affect osteoblastic bone formation. ERα/β signaling was demonstrated as ERα/β protein expression (Western Blotting) and ER transcription activity (Luciferase Reporter assays). Proliferation (WSK-1 assaying), differentiation (ALP staining) and mineralization (Alizalard Red staining) of MC3T3-E1 were examined to evaluate bone formation function. It has been found that high glucose increased ERα/β expression dose-dependently and time-dependently, but high glucose (33mM) decreased ERα transcription activity. 17β-estradiol increased the ERα/β expression dose-dependently in normal medium, but decreased the ERα/β expression dose-dependently in medium with high glucose (33mM). High glucose decreased bone formation and also decreased the osteogenic effects of 17β-estradiol (10 -8 M). High glucose decreased β-catenin expression dose-dependently and time-dependently. LiCl, an inhibitor of β-catenin degradation, decreased ERα expression but increased ERα transcription activity. When compared with high glucose treatment, LiCl (5mM) increased ALP activity and calcified nodes. Besides, high glucose also decreased the protein expression PI-3K, pAKT/AKT, GSK-3β. In conclusion, the present study suggested that high glucose may impair ERα transcription activity by inhibiting β-catenin signaling in osteoblastic MC3T3-E1, leading decreased bone formation ligand-dependently or ligand-independently. Copyright © 2017 Elsevier Ltd. All rights reserved.

PD-1 signalling in CD4+ T cells restrains their clonal expansion to an immunogenic stimulus, but is not critically required for peptide-induced tolerance

PubMed Central

Konkel, Joanne E; Frommer, Friederike; Leech, Melanie D; Yagita, Hideo; Waisman, Ari; Anderton, Stephen M

2010-01-01

The ultimate outcome of T-cell recognition of peptide–major histocompatibility complex (MHC) complexes is determined by the molecular context in which antigen presentation is provided. The paradigm is that, after exposure to peptides presented by steady-state dendritic cells (DCs), inhibitory signals dominate, leading to the deletion and/or functional inactivation of antigen-reactive T cells. This has been utilized in a variety of models providing peptide antigen in soluble form in the absence of adjuvant. A co-inhibitory molecule of considerable current interest is PD-1. Here we show that there is the opportunity for the PD-1/PD-L1 interaction to function in inhibiting the T-cell response during tolerance induction. Using traceable CD4+ T-cell receptor (TCR) transgenic cells, together with a blocking antibody to disrupt PD-1 signalling, we explored the roles of PD-1 in the induction of tolerance versus a productive immune response. Intact PD-1 signalling played a role in limiting the extent of CD4+ T-cell accumulation in response to an immunogenic stimulus. However, PD-1 signalling was not required for either the induction, or the maintenance, of peptide-induced tolerance; a conclusion underlined by successful tolerance induction in TCR transgenic cells genetically deficient for PD-1. These observations contrast with the reported requirement for PD-1 signals in CD8+ T-cell tolerance. PMID:20113370

Low signal intensity in motor cortex on susceptibility-weighted MR imaging is correlated with clinical signs of amyotrophic lateral sclerosis: a pilot study.

PubMed

Endo, Hironobu; Sekiguchi, Kenji; Shimada, Hitoshi; Ueda, Takehiro; Kowa, Hisatomo; Kanda, Fumio; Toda, Tatsushi

2018-03-01

There is no reliable objective indicator for upper motor neuron dysfunction in amyotrophic lateral sclerosis (ALS). To determine the clinical significance and potential utility of magnetic resonance (MR) signals, we investigated the relationship between clinical symptoms and susceptibility changes in the motor cortex measured using susceptibility-weighted MR imaging taken by readily available 3-T MRI in clinical practice. Twenty-four ALS patients and 14 control subjects underwent 3-T MR T1-weighted imaging and susceptibility-weighted MR imaging with the principles of echo-shifting with a train of observations (PRESTO) sequence. We analysed relationships between relative susceptibility changes in the motor cortex assessed using voxel-based analysis (VBA) and clinical scores, including upper motor neuron score, ALS functional rating scale revised score, and Medical Research Council sum score on physical examination. Patients with ALS exhibited significantly lower signal intensity in the precentral gyrus on susceptibility-weighted MR imaging compared with controls. Clinical scores were significantly correlated with susceptibility changes. Importantly, the extent of the susceptibility changes in the bilateral precentral gyri was significantly correlated with upper motor neuron scores. The results of our pilot study using VBA indicated that low signal intensity in motor cortex on susceptibility-weighted MR imaging may correspond to clinical symptoms, particularly upper motor neuron dysfunction. Susceptibility-weighted MR imaging may be a useful diagnostic tool as an objective indicator of upper motor neuron dysfunction.

Phosphate Uptake-Independent Signaling Functions of the Type III Sodium-Dependent Phosphate Transporter, PiT-1, in Vascular Smooth Muscle Cells

PubMed Central

Chavkin, Nicholas W.; Jun Chia, Jia; Crouthamel, Matthew H.; Giachelli, Cecilia M.

2015-01-01

Vascular calcification (VC) is prevalent in chronic kidney disease and elevated serum inorganic phosphate (Pi) is a recognized risk factor. The type III sodium-dependent phosphate transporter, PiT-1, is required for elevated Pi-induced osteochondrogenic differentiation and matrix mineralization in vascular smooth muscle cells (VSMCs). However, the molecular mechanism(s) by which PiT-1 promotes these processes is unclear. In the present study, we confirmed that the Pi concentration required to induce osteochondrogenic differentiation and matrix mineralization of mouse VSMCs was well above that required for maximal Pi uptake, suggesting a signaling function of PiT-1 that was independent of Pi transport. Elevated Pi-induced signaling via ERK1/2 phosphorylation was abrogated in PiT-1 deficient VSMCs, but could be rescued by wild-type (WT) and a Pi transport-deficient PiT-1 mutant. Furthermore, both WT and transport-deficient PiT-1 mutants promoted osteochondrogenic differentiation as measured by decreased SM22α and increased osteopontin mRNA expression. Finally, compared to vector alone, expression of transport-deficient PiT-1 mutants promoted VSMC matrix mineralization, but not to the extent observed with PiT-1 WT. These data suggest that both Pi uptake-dependent and -independent functions of PiT-1 are important for VSMC processes mediating vascular calcification. PMID:25684711

The clerodane diterpene casearin J induces apoptosis of T-ALL cells through SERCA inhibition, oxidative stress, and interference with Notch1 signaling

PubMed Central

De Ford, C; Heidersdorf, B; Haun, F; Murillo, R; Friedrich, T; Borner, C; Merfort, I

2016-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy that preferentially affects children and adolescents. Over 50% of human T-ALLs possess activating mutations of Notch1. The clerodane diterpene casearin J (CJ) is a natural product that inhibits the sarcoendoplasmatic reticulum calcium ATPase (SERCA) pump and induces cell death in leukemia cells, but the molecular mechanism of cytotoxicity remains poorly understood. Here we show that owing to SERCA pump inhibition, CJ induces depletion of the endoplasmic reticulum calcium pools, oxidative stress, and apoptosis via the intrinsic signaling pathway. Moreover, Notch1 signaling is reduced in T-ALL cells with auto-activating mutations in the HD-domain of Notch1, but not in cells that do not depend on Notch1 signaling. CJ also provoked a slight activation of NF-κB, and consistent with this notion a combined treatment of CJ and the NF-κB inhibitor parthenolide (Pt) led to a remarkable synergistic cell death in T-ALL cells. Altogether, our data support the concept that inhibition of the SERCA pump may be a novel strategy for the treatment of T-ALL with HD-domain-mutant Notch1 receptors and that additional treatment with the NF-κB inhibitor parthenolide may have further therapeutic benefits. PMID:26821066

Interferon-β Inhibits Neurotrophin 3 Signalling and Pro-Survival Activity by Upregulating the Expression of Truncated TrkC-T1 Receptor.

PubMed

Dedoni, Simona; Olianas, Maria C; Ingianni, Angela; Onali, Pierluigi

2017-04-01

Although clinically useful for the treatment of various diseases, type I interferons (IFNs) have been implicated as causative factors of a number of neuroinflammatory disorders characterized by neuronal damage and altered CNS functions. As neurotrophin 3 (NT3) plays a critical role in neuroprotection, we examined the effects of IFN-β on the signalling and functional activity of the NT3/TrkC system. We found that prolonged exposure of differentiated human SH-SY5Y neuroblastoma cells to IFN-β impaired the ability of NT3 to induce transphosphorylation of the full-length TrkC receptor (TrkC-FL) and the phosphorylation of downstream signalling molecules, including PLCγ1, Akt, GSK-3β and ERK1/2. NT3 was effective in protecting the cells against apoptosis triggered by serum withdrawal or thapsigargin but not IFN-β. Prolonged exposure to the cytokine had little effects on TrkC-FL levels but markedly enhanced the messenger RNA (mRNA) and protein levels of the truncated isoform TrkC-T1, a dominant-negative receptor that inhibits TrkC-FL activity. Cell depletion of TrkC-T1 by small interfering RNA (siRNA) treatment enhanced NT3 signalling through TrkC-FL and allowed the neurotrophin to counteract IFN-β-induced apoptosis. Furthermore, the upregulation of TrkC-T1 by IFN-β was associated with the inhibition of NT3-induced recruitment of the scaffold protein tamalin to TrkC-T1 and tamalin tyrosine phosphorylation. These data indicate that IFN-β exerts a negative control on NT3 pro-survival signalling through a novel mechanism involving the upregulation of TrkC-T1.

Volumetric brain differences in children with periventricular T2-signal hyperintensities: a grouping by gestational age at birth.

PubMed

Panigrahy, A; Barnes, P D; Robertson, R L; Back, S A; Sleeper, L A; Sayre, J W; Kinney, H C; Volpe, J J

2001-09-01

The purpose of this study was to compare both the volumes of the lateral ventricles and the cerebral white matter with gestational age at birth of children with periventricular white matter (PVWM) T2-signal hyperintensities on MR images. The spectrum of neuromotor abnormalities associated with these hyperintensities was also determined. We retrospectively reviewed the MR images of 70 patients who were between the ages of 1 and 5 years and whose images showed PVWM T2-signal hyperintensities. The patients were divided into premature (n = 35 children) and term (n = 35) groups depending on their gestational age at birth. Volumetric analysis was performed on four standardized axial sections using T2-weighted images. Volumes of interest were digitized on the basis of gray-scale densities of signal intensities to define the hemispheric cerebral white matter and lateral ventricles. Age-adjusted comparisons of volumetric measurements between the premature and term groups were performed using analysis of covariance. The volume of the cerebral white matter was smaller in the premature group (54 +/- 2 cm(3)) than in the term group (79 +/- 3 cm(3), p < 0.0001). The volume of the lateral ventricles was greater among the patients in the premature group (30 +/- 2 cm(3)) than among those in the term group (13 +/- 1 cm(3), p < 0.0001). Fifty percent of all the premature children had spastic diplegia or quadriplegia. Thirty-two percent of all the term children had hypotonia. There were patients in both groups whose PVWM T2-signal hyperintensities did not correlate with any neuromotor abnormalities but were associated with seizures or developmental delays. The differences in volumetric measurements of cerebral white matter and lateral ventricles in children with PVWM T2-signal hyperintensities are related to their gestational age at birth. Several neurologic motor abnormalities are found in children with such hyperintensities.

Apoptosis in activated T cells: what are the triggers, and what the signal transducers?

PubMed

Häcker, Georg; Bauer, Anette; Villunger, Andreas

2006-11-01

At the end of an immune response, apoptosis drastically reduces the numbers of activated T cells. It has been a matter of intense research how this form of apoptosis is regulated and initiated, and a number of proteins have been identified that contribute to this process. The present, widely accepted model assumes that the interplay of pro- and anti -apoptotic Bcl-2 family members determines the onset of activated T cell death, with the BH3-only protein Bim activating pro-apoptotic Bax/Bak. In the search for up-stream signals, factors from other immune cells have been shown to play a role, and the NFkappaB family member Bcl-3 has been implicated as a signalling-intermediate in T cells. Recent work has tested the interrelation of these factors and has suggested that Bcl-3 acts as a regulator of Bim activation, that the induction of apoptosis through Bim can be complemented by its relative Puma, and that the presence of certain cytokines during T cell activation delays the activation of Bim and Puma. Here we discuss these recent insights and provide a view on how the regulation of activated T cell death is achieved and how extrinsic signals may translate into the activation of the apoptotic pathway.

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose

PubMed Central

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton

2016-01-01

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose–response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways. PMID:27702900

Architecture of a minimal signaling pathway explains the T-cell response to a 1 million-fold variation in antigen affinity and dose.

PubMed

Lever, Melissa; Lim, Hong-Sheng; Kruger, Philipp; Nguyen, John; Trendel, Nicola; Abu-Shah, Enas; Maini, Philip Kumar; van der Merwe, Philip Anton; Dushek, Omer

2016-10-25

T cells must respond differently to antigens of varying affinity presented at different doses. Previous attempts to map peptide MHC (pMHC) affinity onto T-cell responses have produced inconsistent patterns of responses, preventing formulations of canonical models of T-cell signaling. Here, a systematic analysis of T-cell responses to 1 million-fold variations in both pMHC affinity and dose produced bell-shaped dose-response curves and different optimal pMHC affinities at different pMHC doses. Using sequential model rejection/identification algorithms, we identified a unique, minimal model of cellular signaling incorporating kinetic proofreading with limited signaling coupled to an incoherent feed-forward loop (KPL-IFF) that reproduces these observations. We show that the KPL-IFF model correctly predicts the T-cell response to antigen copresentation. Our work offers a general approach for studying cellular signaling that does not require full details of biochemical pathways.

p38 Mitogen-Activated Protein Kinase/Signal Transducer and Activator of Transcription-3 Pathway Signaling Regulates Expression of Inhibitory Molecules in T Cells Activated by HIV-1–Exposed Dendritic Cells

PubMed Central

Che, Karlhans Fru; Shankar, Esaki Muthu; Muthu, Sundaram; Zandi, Sasan; Sigvardsson, Mikael; Hinkula, Jorma; Messmer, Davorka; Larsson, Marie

2012-01-01

Human immunodeficiency virus type 1 (HIV-1) infection enhances the expression of inhibitory molecules on T cells, leading to T-cell impairment. The signaling pathways underlying the regulation of inhibitory molecules and subsequent onset of T-cell impairment remain elusive. We showed that both autologous and allogeneic T cells exposed to HIV-pulsed dendritic cells (DCs) upregulated cytotoxic T-lymphocyte antigen (CTLA-4), tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), lymphocyte-activation gene-3 (LAG3), T-cell immunoglobulin mucin-3 (TIM-3), CD160 and certain suppression-associated transcription factors, such as B-lymphocyte induced maturation protein-1 (BLIMP-1), deltex homolog 1 protein (DTX1) and forkhead box P3 (FOXP3), leading to T-cell suppression. This induction was regulated by p38 mitogen-activated protein kinase/signal transducer and activator of transcription-3 (P38MAPK/STAT3) pathways, because their blockade significantly abrogated expression of all the inhibitory molecules studied and a subsequent recovery in T-cell proliferation. Neither interleukin-6 (IL-6) nor IL-10 nor growth factors known to activate STAT3 signaling events were responsible for STAT3 activation. Involvement of the P38MAPK/STAT3 pathways was evident because these proteins had a higher level of phosphorylation in the HIV-1–primed cells. Furthermore, blockade of viral CD4 binding and fusion significantly reduced the negative effects DCs imposed on primed T cells. In conclusion, HIV-1 interaction with DCs modulated their functionality, causing them to trigger the activation of the P38MAPK/STAT3 pathway in T cells, which was responsible for the upregulation of inhibitory molecules. PMID:22777388

Notch signalling in T cell lymphoblastic leukaemia/lymphoma and other haematological malignancies

PubMed Central

Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

2010-01-01

Notch receptors participate in a highly conserved signalling pathway that regulates normal development and tissue homeostasis in a context- and dose-dependent manner. Deregulated Notch signalling has been implicated in many diseases, but the clearest example of a pathogenic role is found in T cell lymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and murine tumours have acquired mutations that lead to aberrant increases in Notch1 signalling. Remarkably, it appears that the selective pressure for Notch mutations is virtually unique among cancers to T-LL, presumably reflecting a special context-dependent role for Notch in normal T cell progenitors. Nevertheless, there are some recent reports suggesting that Notch signalling has subtle yet important roles in other forms of hematologic malignancy as well. Here, we review the role of Notch signalling in various blood cancers, focusing on T-LL with an eye toward targeted therapeutics. PMID:20967796

Color-coded automated signal intensity curves for detection and characterization of breast lesions: preliminary evaluation of a new software package for integrated magnetic resonance-based breast imaging.

PubMed

Pediconi, Federica; Catalano, Carlo; Venditti, Fiammetta; Ercolani, Mauro; Carotenuto, Luigi; Padula, Simona; Moriconi, Enrica; Roselli, Antonella; Giacomelli, Laura; Kirchin, Miles A; Passariello, Roberto

2005-07-01

The objective of this study was to evaluate the value of a color-coded automated signal intensity curve software package for contrast-enhanced magnetic resonance mammography (CE-MRM) in patients with suspected breast cancer. Thirty-six women with suspected breast cancer based on mammographic and sonographic examinations were preoperatively evaluated on CE-MRM. CE-MRM was performed on a 1.5-T magnet using a 2D Flash dynamic T1-weighted sequence. A dosage of 0.1 mmol/kg of Gd-BOPTA was administered at a flow rate of 2 mL/s followed by 10 mL of saline. Images were analyzed with the new software package and separately with a standard display method. Statistical comparison was performed of the confidence for lesion detection and characterization with the 2 methods and of the diagnostic accuracy for characterization compared with histopathologic findings. At pathology, 54 malignant lesions and 14 benign lesions were evaluated. All 68 (100%) lesions were detected with both methods and good correlation with histopathologic specimens was obtained. Confidence for both detection and characterization was significantly (P < or = 0.025) better with the color-coded method, although no difference (P > 0.05) between the methods was noted in terms of the sensitivity, specificity, and overall accuracy for lesion characterization. Excellent agreement between the 2 methods was noted for both the determination of lesion size (kappa = 0.77) and determination of SI/T curves (kappa = 0.85). The novel color-coded signal intensity curve software allows lesions to be visualized as false color maps that correspond to conventional signal intensity time curves. Detection and characterization of breast lesions with this method is quick and easily interpretable.

A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation.

PubMed

Kassem, Sahar; Gaud, Guillaume; Bernard, Isabelle; Benamar, Mehdi; Dejean, Anne S; Liblau, Roland; Fournié, Gilbert J; Colacios, Céline; Malissen, Bernard; Saoudi, Abdelhadi

2016-07-01

The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1R63W mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1R63W variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation.

A Natural Variant of the T Cell Receptor-Signaling Molecule Vav1 Reduces Both Effector T Cell Functions and Susceptibility to Neuroinflammation

PubMed Central

Kassem, Sahar; Bernard, Isabelle; Dejean, Anne S.; Liblau, Roland; Fournié, Gilbert J.; Colacios, Céline

2016-01-01

The guanine nucleotide exchange factor Vav1 is essential for transducing T cell antigen receptor signals and therefore plays an important role in T cell development and activation. Our previous genetic studies identified a locus on rat chromosome 9 that controls the susceptibility to neuroinflammation and contains a non-synonymous polymorphism in the major candidate gene Vav1. To formally demonstrate the causal implication of this polymorphism, we generated a knock-in mouse bearing this polymorphism (Vav1R63W). Using this model, we show that Vav1R63W mice display reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 peptide immunization. This is associated with a lower production of effector cytokines (IFN-γ, IL-17 and GM-CSF) by autoreactive CD4 T cells. Despite increased proportion of Foxp3+ regulatory T cells in Vav1R63W mice, we show that this lowered cytokine production is intrinsic to effector CD4 T cells and that Treg depletion has no impact on EAE development. Finally, we provide a mechanism for the above phenotype by showing that the Vav1R63W variant has normal enzymatic activity but reduced adaptor functions. Together, these data highlight the importance of Vav1 adaptor functions in the production of inflammatory cytokines by effector T cells and in the susceptibility to neuroinflammation. PMID:27438086

Correlation between magnetic resonance T2 image signal intensity ratio and cell apoptosis in a rabbit spinal cord cervical myelopathy model.

PubMed

Ma, Lei; Zhang, Di; Chen, Wei; Shen, Yong; Zhang, Yingze; Ding, Wenyuan; Zhang, Wei; Wang, Linfeng; Yang, Dalong

2014-01-01

Cervical spondylotic myelopathy (CSM) is a common cause of disability in elderly patients. Previous studies have shown that spinal cord cell apoptosis due to spinal cord compression plays an important role in the pathology of myelopathy. Although changes in magnetic resonance imaging (MRI) T2 signal intensity ratio (SIR) are considered to be an indicator of CSM, little information is published supporting the correlation between changes in MRI signal and pathological changes. This study aims to testify the correlation between MRI T2 SIR changes and cell apoptosis using a CSM animal model. Forty-eight rabbits were randomly assigned to four groups: one control group and three experimental chronic compression groups, with each group containing 12 animals. Chronic compression of the cervical spinal cord was implemented in the experimental groups by implanting a screw in the C3 vertebra. The control group underwent sham surgery. Experimental groups were observed for 3, 6, or 9 months after surgery. MRI T2-weighted SIR Tarlov motor scores and cortical somatosensory-evoked potentials (CSEPs) were periodically monitored. At each time point, rabbits from one group were sacrificed to determine the level of apoptosis by histology (n = 6) and Western blotting (n = 6). Tarlov motor scores in the compression groups were lower at all time points than the control group scores, with the lowest score at 9 months (P < 0.001). Electrophysiological testing showed a significantly prolonged latency in CSEP in the compression groups compared with the control group. All rabbits in the compression groups showed higher MRI T2 SIR in the injury epicenter compared with controls, and higher SIR was also found at 9 months compared with 3 or 6 months. Histological analysis showed significant apoptosis in the spinal cord tissue in the compression groups, but not in the control group. There were significant differences in apoptosis degree over time (P < 0.001), with the 9-month group displaying the

46 CFR 35.10-5 - Muster lists, emergency signals, and manning-T/ALL.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 46 Shipping 1 2014-10-01 2014-10-01 false Muster lists, emergency signals, and manning-T/ALL. 35... Fire and Emergency Requirements § 35.10-5 Muster lists, emergency signals, and manning—T/ALL. The requirements for muster lists, emergency signals, and manning must be in accordance with subchapter W...

46 CFR 35.10-5 - Muster lists, emergency signals, and manning-T/ALL.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 46 Shipping 1 2013-10-01 2013-10-01 false Muster lists, emergency signals, and manning-T/ALL. 35... Fire and Emergency Requirements § 35.10-5 Muster lists, emergency signals, and manning—T/ALL. The requirements for muster lists, emergency signals, and manning must be in accordance with subchapter W...

46 CFR 35.10-5 - Muster lists, emergency signals, and manning-T/ALL.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 46 Shipping 1 2011-10-01 2011-10-01 false Muster lists, emergency signals, and manning-T/ALL. 35... Fire and Emergency Requirements § 35.10-5 Muster lists, emergency signals, and manning—T/ALL. The requirements for muster lists, emergency signals, and manning must be in accordance with subchapter W...

46 CFR 35.10-5 - Muster lists, emergency signals, and manning-T/ALL.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 46 Shipping 1 2012-10-01 2012-10-01 false Muster lists, emergency signals, and manning-T/ALL. 35... Fire and Emergency Requirements § 35.10-5 Muster lists, emergency signals, and manning—T/ALL. The requirements for muster lists, emergency signals, and manning must be in accordance with subchapter W...

Effect of Renal Function on Gadolinium-Related Signal Increases on Unenhanced T1-Weighted Brain Magnetic Resonance Imaging.

PubMed

Cao, Yan; Zhang, Yang; Shih, George; Zhang, Yan; Bohmart, Andrew; Hecht, Elizabeth M; Prince, Martin R

2016-11-01

The purpose of this study was to determine if renal function affects signal changes in the deep brain nuclei on unenhanced T1-weighted images after administration of linear gadolinium-based contrast agents (GBCAs). An electronic medical records search of 2 large medical centers identified 25 patients who received linear GBCA while on hemodialysis and had unenhanced T1-weighted images of the brain before and after. The dentate-to-cerebellar peduncle (DCP) ratio, globus pallidus-to-mid thalamus (GPT) ratio, and choroid plexus-to-nearby white matter ratio were measured and compared with 25 age/sex/GBCA exposure-matched control patients with normal or near-normal renal function (estimated glomerular filtration rate >60 mL/min per 1.73 m). Two additional control groups included 13 patients on hemodialysis without GBCA exposure and 13 age/sex-matched patients with estimated glomerular filtration rate greater than 60 mL/min per 1.73 m. Hemodialysis patients (n = 25) with an average of 1.8 linear GBCA administrations had a 4.9% mean increase (1.00 ± 0.04 vs 1.05 ± 0.05; P < 0.001) in DCP, which was greater than the 1.6% change (0.99 ± 0.04 vs 1.00 ± 0.05; P = 0.08) observed in matched controls (P = 0.01). There was no significant signal change in the DCP ratio in the 13 hemodialysis patients (0.99 ± 0.04 vs 0.99 ± 0.04; P = 0.78) and 13 age/sex-matched patients (0.99 ± 0.02 vs 0.99 ± 0.03; P = 0.78) who did not receive GBCA. The hemodialysis patients had a baseline GPT that was higher than nondialysis patients (P < 0.001). However, the GPT change after GBCA administration was not significantly different from controls. Increased signal in the choroid plexus on unenhanced T1-weighted images after GBCA administration was noted in hemodialysis patients (0.72 ± 0.20 vs 0.86 ± 0.23; P = 0.006); however, a multivariate analysis showed this to be primarily related to hemodialysis (P = 0.003) with only a trend toward relating to GBCA exposure (P = 0.07). Hemodialysis

Differential TCR signals for T helper cell programming.

PubMed

Morel, Penelope A

2018-05-02

Upon encounter with their cognate antigen naïve CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen presenting cells, cytokines and costimulatory molecules. The strength of the T cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength. This review examines the recent literature in this area and highlights important new developments in our understanding of Th cell differentiation and TCR signal strength. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Quantitative measurement of intervertebral disc signal using MRI.

PubMed

Niemeläinen, R; Videman, T; Dhillon, S S; Battié, M C

2008-03-01

To investigate the spinal cord as an alternative intra-body reference to cerebrospinal fluid (CSF) in evaluating thoracic disc signal intensity. T2-weighted magnetic resonance imaging (MRI) images of T6-T12 were obtained using 1.5 T machines for a population-based sample of 523 men aged 35-70 years. Quantitative data on the signal intensities were acquired using an image analysis program (SpEx). A random sample of 30 subjects and intraclass correlation coefficients (ICC) were used to examine the repeatability of the spinal cord measurements. The validity of using the spinal cord as a reference was examined by correlating cord and CSF samples. Finally, thoracic disc signal was validated by correlating it with age without adjustment and adjusting for either cord or CSF. Pearson's r was used for correlational analyses. The repeatability of the spinal cord signal measurements was extremely high (>or=0.99). The correlations between the signals of spinal cord and CSF by level were all above 0.9. The spinal cord-adjusted disc signal and age correlated similarly with CSF-adjusted disc signal and age (r=-0.30 to -0.40 versus r=-0.26 to -0.36). Adjacent spinal cord is a good alternative reference to the current reference standard, CSF, for quantitative measurements of disc signal intensity. Clearly fewer levels were excluded when using spinal cord as compared to CSF due to missing reference samples.

Pyroptosis drives CD4 T-cell depletion in HIV-1 infection

PubMed Central

Doitsh, Gilad; Galloway, Nicole LK; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

2014-01-01

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood. Apoptosis has been proposed as the key mechanism for CD4 T-cell loss. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of productively infected cells. The remaining >95% of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death where cytoplasmic contents and pro-inflammatory cytokines including IL-1β, are released. This death pathway thus links the two signature events in HIV infection––CD4 T-cell depletion and chronic inflammation––and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase-1 inhibitors shown to be safe in humans, raising the possibility of a new class of “anti-AIDS” therapeutics targeting the host rather than the virus. PMID:24356306

Whole brain myelin mapping using T1- and T2-weighted MR imaging data

PubMed Central

Ganzetti, Marco; Wenderoth, Nicole; Mantini, Dante

2014-01-01

Despite recent advancements in MR imaging, non-invasive mapping of myelin in the brain still remains an open issue. Here we attempted to provide a potential solution. Specifically, we developed a processing workflow based on T1-w and T2-w MR data to generate an optimized myelin enhanced contrast image. The workflow allows whole brain mapping using the T1-w/T2-w technique, which was originally introduced as a non-invasive method for assessing cortical myelin content. The hallmark of our approach is a retrospective calibration algorithm, applied to bias-corrected T1-w and T2-w images, that relies on image intensities outside the brain. This permits standardizing the intensity histogram of the ratio image, thereby allowing for across-subject statistical analyses. Quantitative comparisons of image histograms within and across different datasets confirmed the effectiveness of our normalization procedure. Not only did the calibrated T1-w/T2-w images exhibit a comparable intensity range, but also the shape of the intensity histograms was largely corresponding. We also assessed the reliability and specificity of the ratio image compared to other MR-based techniques, such as magnetization transfer ratio (MTR), fractional anisotropy (FA), and fluid-attenuated inversion recovery (FLAIR). With respect to these other techniques, T1-w/T2-w had consistently high values, as well as low inter-subject variability, in brain structures where myelin is most abundant. Overall, our results suggested that the T1-w/T2-w technique may be a valid tool supporting the non-invasive mapping of myelin in the brain. Therefore, it might find important applications in the study of brain development, aging and disease. PMID:25228871

46 CFR 35.10-5 - Muster lists, emergency signals, and manning-T/ALL.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 46 Shipping 1 2010-10-01 2010-10-01 false Muster lists, emergency signals, and manning-T/ALL. 35.10-5 Section 35.10-5 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY TANK VESSELS OPERATIONS Fire and Emergency Requirements § 35.10-5 Muster lists, emergency signals, and manning—T/ALL. The requirements for muster lists, emergency signals, and...

Light intensity and temperature affect systemic spread of silencing signal in transient agroinfiltration studies.

PubMed

Patil, Basavaprabhu L; Fauquet, Claude M

2015-06-01

RNA silencing is a sequence-specific post-transcriptional gene inactivation mechanism that operates in diverse organisms and that can extend beyond its site of initiation, owing to the movement of the silencing signal, called non-autonomous gene silencing. Previous studies have shown that several factors manifest the movement of the silencing signal, such as the size (21 or 24 nucleotides) of the secondary small interfering RNA (siRNA) produced, the steady-state concentration of siRNAs and their cognate messenger RNA (mRNA) or a change in the sink-source status of plant parts affecting phloem translocation. Our study shows that both light intensity and temperature have a significant impact on the systemic movement of the silencing signal in transient agroinfiltration studies in Nicotiana benthamiana. At higher light intensities (≥ 450 μE/m(2)/s) and higher temperatures (≥ 30 °C), gene silencing was localized to leaf tissue that was infiltrated, without any systemic spread. Interestingly, in these light and temperature conditions (≥ 450 μE/m(2) /s and ≥ 30 °C), the N. benthamiana plants showed recovery from the viral symptoms. However, the reduced systemic silencing and reduced viral symptom severity at higher light intensities were caused by a change in the sink-source status of the plant, ultimately affecting the phloem translocation of small RNAs or the viral genome. In contrast, at lower light intensities (<300 μE/m(2)/s) with a constant temperature of 25 °C, there was strong systemic movement of the silencing signal in the N. benthamiana plants and reduced recovery from virus infections. The accumulation of gene-specific siRNAs was reduced at higher temperature as a result of a reduction in the accumulation of transcript on transient agroinfiltration of RNA interference (RNAi) constructs, mostly because of poor T-DNA transfer activity of Agrobacterium, possibly also accompanied by reduced phloem translocation. © 2014 BSPP AND JOHN WILEY & SONS

Low-intensity pulsed ultrasound (LIPUS) stimulates mineralization of MC3T3-E1 cells through calcium and phosphate uptake.

PubMed

Tassinary, João Alberto Fioravante; Lunardelli, Adroaldo; Basso, Bruno de Souza; Dias, Henrique Bregolin; Catarina, Anderson Velasque; Stülp, Simone; Haute, Gabriela Viegas; Martha, Bianca Andrade; Melo, Denizar Alberto da Silva; Nunes, Fernanda Bordignon; Donadio, Márcio Vinícius Fagundes; Oliveira, Jarbas Rodrigues de

2018-03-01

The present study aimed to evaluate the effect of low-intensity pulsed ultrasound (LIPUS) on pre-osteoblast mineralization using in vitro bioassays. Pre-osteoblastic MC3T3-E1 cells were exposed to LIPUS at 1 MHz frequency, 0.2 W/cm 2 intensity and 20% duty cycle for 30 min. The analyses were carried out up to 336 h (14 days) after exposure. The concentration of collagen, phosphate, alkaline phosphatase, calcium and transforming growth factor beta 1 (TGF-β1) in cell supernatant and the presence of calcium deposits in the cells were analyzed. Our results showed that LIPUS promotes mineralized nodules formation. Collagen, phosphate, and calcium levels were decreased in cell supernatant at 192 h after LIPUS exposure. However, alkaline phosphatase and TGF-β1 concentrations remained unchanged. Therapeutic pulsed ultrasound is capable of stimulating differentiation and mineralization of pre-osteoblastic MC3T3-E1 cells by calcium and phosphate uptake with consequent hydroxyapatite formation. Copyright © 2017 Elsevier B.V. All rights reserved.

Na+ influx via Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation.

PubMed

Miao, Yong; Bhushan, Jaya; Dani, Adish; Vig, Monika

2017-05-11

T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation via calcium channels remain unknown. α-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that α-SNAP hypomorph, hydrocephalus with hopping gait, Napa hyh/hyh mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. Mechanistically, TCR stimulation induced rapid sodium influx in Napa hyh/hyh CD4 T cells, which reduced intracellular ATP, [ATP] i . Depletion of [ATP] i inhibited mTORC2 dependent NFκB activation in Napa hyh/hyh cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in Napa hyh/hyh signaling and Treg differentiation, but not IL-2 expression. Thus, non-specific sodium influx via bonafide calcium channels disrupts unexpected signaling nodes and may provide mechanistic insights into some divergent phenotypes associated with Orai1 function.

Na+ influx via Orai1 inhibits intracellular ATP-induced mTORC2 signaling to disrupt CD4 T cell gene expression and differentiation

PubMed Central

Miao, Yong; Bhushan, Jaya; Dani, Adish; Vig, Monika

2017-01-01

T cell effector functions require sustained calcium influx. However, the signaling and phenotypic consequences of non-specific sodium permeation via calcium channels remain unknown. α-SNAP is a crucial component of Orai1 channels, and its depletion disrupts the functional assembly of Orai1 multimers. Here we show that α-SNAP hypomorph, hydrocephalus with hopping gait, Napahyh/hyh mice harbor significant defects in CD4 T cell gene expression and Foxp3 regulatory T cell (Treg) differentiation. Mechanistically, TCR stimulation induced rapid sodium influx in Napahyh/hyh CD4 T cells, which reduced intracellular ATP, [ATP]i. Depletion of [ATP]i inhibited mTORC2 dependent NFκB activation in Napahyh/hyh cells but ablation of Orai1 restored it. Remarkably, TCR stimulation in the presence of monensin phenocopied the defects in Napahyh/hyh signaling and Treg differentiation, but not IL-2 expression. Thus, non-specific sodium influx via bonafide calcium channels disrupts unexpected signaling nodes and may provide mechanistic insights into some divergent phenotypes associated with Orai1 function. DOI: http://dx.doi.org/10.7554/eLife.25155.001 PMID:28492364

The use of a selective saturation pulse to suppress t1 noise in two-dimensional 1H fast magic angle spinning solid-state NMR spectroscopy

NASA Astrophysics Data System (ADS)

Robertson, Aiden J.; Pandey, Manoj Kumar; Marsh, Andrew; Nishiyama, Yusuke; Brown, Steven P.

2015-11-01

A selective saturation pulse at fast magic angle spinning (MAS) frequencies (60+ kHz) suppresses t1 noise in the indirect dimension of two-dimensional 1H MAS NMR spectra. The method is applied to a synthetic nucleoside with an intense methyl 1H signal due to triisopropylsilyl (TIPS) protecting groups. Enhanced performance in terms of suppressing the methyl signal while minimising the loss of signal intensity of nearby resonances of interest relies on reducing spin diffusion - this is quantified by comparing two-dimensional 1H NOESY-like spin diffusion spectra recorded at 30-70 kHz MAS. For a saturation pulse centred at the methyl resonance, the effect of changing the nutation frequency at different MAS frequencies as well as the effect of changing the pulse duration is investigated. By applying a pulse of duration 30 ms and nutation frequency 725 Hz at 70 kHz MAS, a good compromise of significant suppression of the methyl resonance combined with the signal intensity of resonances greater than 5 ppm away from the methyl resonance being largely unaffected is achieved. The effectiveness of using a selective saturation pulse is demonstrated for both homonuclear 1H-1H double quantum (DQ)/single quantum (SQ) MAS and 14N-1H heteronuclear multiple quantum coherence (HMQC) two-dimensional solid-state NMR experiments.

The use of a selective saturation pulse to suppress t1 noise in two-dimensional (1)H fast magic angle spinning solid-state NMR spectroscopy.

PubMed

Robertson, Aiden J; Pandey, Manoj Kumar; Marsh, Andrew; Nishiyama, Yusuke; Brown, Steven P

2015-11-01

A selective saturation pulse at fast magic angle spinning (MAS) frequencies (60+kHz) suppresses t1 noise in the indirect dimension of two-dimensional (1)H MAS NMR spectra. The method is applied to a synthetic nucleoside with an intense methyl (1)H signal due to triisopropylsilyl (TIPS) protecting groups. Enhanced performance in terms of suppressing the methyl signal while minimising the loss of signal intensity of nearby resonances of interest relies on reducing spin diffusion--this is quantified by comparing two-dimensional (1)H NOESY-like spin diffusion spectra recorded at 30-70 kHz MAS. For a saturation pulse centred at the methyl resonance, the effect of changing the nutation frequency at different MAS frequencies as well as the effect of changing the pulse duration is investigated. By applying a pulse of duration 30 ms and nutation frequency 725 Hz at 70 kHz MAS, a good compromise of significant suppression of the methyl resonance combined with the signal intensity of resonances greater than 5 ppm away from the methyl resonance being largely unaffected is achieved. The effectiveness of using a selective saturation pulse is demonstrated for both homonuclear (1)H-(1)H double quantum (DQ)/single quantum (SQ) MAS and (14)N-(1)H heteronuclear multiple quantum coherence (HMQC) two-dimensional solid-state NMR experiments. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

IL-1 Receptor Signaling on Graft Parenchymal Cells Regulates Memory and De Novo Donor-Reactive CD8 T Cell Responses to Cardiac Allografts.

PubMed

Iida, Shoichi; Tsuda, Hidetoshi; Tanaka, Toshiaki; Kish, Danielle D; Abe, Toyofumi; Su, Charles A; Abe, Ryo; Tanabe, Kazunari; Valujskikh, Anna; Baldwin, William M; Fairchild, Robert L

2016-03-15

Reperfusion of organ allografts induces a potent inflammatory response that directs rapid memory T cell, neutrophil, and macrophage graft infiltration and their activation to express functions mediating graft tissue injury. The role of cardiac allograft IL-1 receptor (IL-1R) signaling in this early inflammation and the downstream primary alloimmune response was investigated. When compared with complete MHC-mismatched wild-type cardiac allografts, IL-1R(-/-) allografts had marked decreases in endogenous memory CD8 T cell and neutrophil infiltration and expression of proinflammatory mediators at early times after transplant, whereas endogenous memory CD4 T cell and macrophage infiltration was not decreased. IL-1R(-/-) allograft recipients also had marked decreases in de novo donor-reactive CD8, but not CD4, T cell development to IFN-γ-producing cells. CD8 T cell-mediated rejection of IL-1R(-/-) cardiac allografts took 3 wk longer than wild-type allografts. Cardiac allografts from reciprocal bone marrow reconstituted IL-1R(-/-)/wild-type chimeric donors indicated that IL-1R signaling on graft nonhematopoietic-derived, but not bone marrow-derived, cells is required for the potent donor-reactive memory and primary CD8 T cell alloimmune responses observed in response to wild-type allografts. These studies implicate IL-1R-mediated signals by allograft parenchymal cells in generating the stimuli-provoking development and elicitation of optimal alloimmune responses to the grafts. Copyright © 2016 by The American Association of Immunologists, Inc.

Impact of high-intensity interval training and moderate-intensity continuous training on resting and postexercise cardiac troponin T concentration.

PubMed

Nie, Jinlei; Zhang, Haifeng; Kong, Zhaowei; George, Keith; Little, Jonathan P; Tong, Tomas K; Li, Feifei; Shi, Qingde

2018-03-01

What is the central question of this study? Does exercise training impact resting and postexercise cardiac troponin T (cTnT) concentration? What is the main finding and its importance? This randomized controlled intervention study demonstrated that 12 weeks of either high-intensity interval training or moderate-intensity continuous training largely abolished the exercise-induced elevation in cTnT when exercise was performed at the same absolute intensity. There was no impact of training on resting cTnT or postexercise appearance of cTnT when exercise was performed at the same relative intensity. These findings provide new information that might help clinicians with decision-making in relationship to basal and postexercise values of cTnT in individuals with different training status. We evaluated the influence of 12 weeks of high-intensity interval training [HIIT; repeated 4 min cycling at 90% of maximal oxygen uptake (V̇O2max) interspersed with 3 min rest, 200-300 kJ per session, 3 or 4 days each week] and work-equivalent moderate-intensity continuous training (MICT; continuous cycling at 60% V̇O2max) on resting cardiac troponin T (cTnT) and the appearance of exercise-induced cTnT. Forty-eight sedentary obese young women were randomly assigned to HIIT, MICT or a control group. The V̇O2max and body composition were measured before and after training. At baseline, cTnT was assessed using a high-sensitivity assay at rest and immediately, 2 and 4 h after 45 min cycling at 60% V̇O2max. After a 12 week training period, cTnT was assessed before and after 45 min cycling at the same relative and absolute intensities as before training. Training led to higher V̇O2max and lower fat mass in both HIIT and MICT groups (all P < 0.05). Before training, cTnT was significantly elevated in all three groups (by 35-118%, all P < 0.05) with acute exercise. After training, both resting and postexercise cTnT concentrations (same relative intensity) were similar to

Cerebral signal intensity abnormalities on T2-weighted MR images in HIV patients with highly active antiretroviral therapy: relationship with clinical parameters and interval changes.

PubMed

Hanning, Uta; Husstedt, Ingo W; Niederstadt, Thomas-Ulrich; Evers, Stefan; Heindel, Walter; Kloska, Stephan P

2011-09-01

The aim of this study was to assess the relationship between immune state and cerebral signal intensity abnormalities (SIAs) on T2-weighted magnetic resonance images in subjects with human immunodeficiency virus type 1 infection and highly active antiretroviral therapy. Thirty-two subjects underwent a total of 109 magnetic resonance studies. The presence of human immunodeficiency virus-associated neurocognitive disorder, categorized CD4(+) T lymphocyte count, and plasma viral load were assessed for relationship with the severity and interval change of SIAs for different anatomic locations of the brain. Subjects with multifocal patterns of SIAs had CD4(+) cell counts < 200 cells/μL in 66.0%, whereas subjects with diffuse patterns of SIAs had CD4(+) cell counts < 200 cells/μL in only 31.4% (P < .001). Subjects without SIAs in the basal ganglia had CD4(+) cell counts < 200 cells/μL in 37.0%, whereas subjects with minor and moderate SIAs in the basal ganglia had CD4(+) cell counts < 200 cells/μL in 78.3% and 80.0%, respectively (P < .005). The percentage of subjects with CD4(+) cell counts < 200 cells/μL was 85.7% when there were progressive periventricular SIA changes and 45.5% when periventricular SIA changes were stable in follow-up (P < .05). The presence and progression of cerebral SIAs on T2-weighted magnetic resonance images reflecting cerebral infection with human immunodeficiency virus are significantly related to impaired immune state as measured by CD4(+) cell count. Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.

MicroRNA-24 promotes 3T3-L1 adipocyte differentiation by directly targeting the MAPK7 signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jin, Min, E-mail: min_jin@zju.edu.cn; Wu, Yutao; Wang, Jing

Over the past years, MicroRNAs (miRNAs) act as a vital role in harmony with gene regulation and maintaining cellular homeostasis. It is well testified that miRNAshave been involved in numerous physiological and pathological processes, including embryogenesis, cell fate decision, and cellular differentiation. Adipogenesis is an organized process of cellular differentiation by which pre-adipocytes differentiate towards mature adipocytes, and it is tightly modulated by a series of transcription factors such as peroxisome proliferator-activated receptor γ (PPAR-γ) and sterol regulatory-element binding proteins 1 (SREBP1). However, the molecular mechanisms underlying the connection between miRNAs and adipogenesis-related transcription factors remain obscure. In this study,more » we unveiled that miR- 24 was remarkably upregulated during 3T3-L1 adipogenesis. Overexpression of miR-24 significantly promoted 3T3-L1 adipogenesis, as evidenced by its ability to increase the expression of PPAR-γ and SREBP1, lipid droplet formation and triglyceride (TG) accumulation. Furthermore, we found that neither ectopic expression of miR-24nor miR-24 inhibitor affect cell proliferation and cell cycle progression. Finally, we demonstrated that miR-24 plays the modulational role by directly repressing MAPK7, a key number in the MAPK signaling pathway. These data indicate that miR-24 is a novel positive regulator of adipocyte differentiation by targeting MAPK7, which provides new insights into the molecular mechanism of miRNA-mediated cellular differentiation. -- Highlights: •We firstly found miR-24 was upregulated in 3T3-L1 pre-adipocytes differentiation. •miR-24 promoted 3T3-L1 pre-adipocytes differentiation while silencing the expression of miR-24 had an opposite function. •miR-24 regulated 3T3-L1 differentiation by directly targeting MAPK7 signaling pathway. •miR-24did not affect 3T3-L1 pre-adipocytes cellular proliferation.« less

Acid sphingomyelinase mediates human CD4+ T-cell signaling: potential roles in T-cell responses and diseases

PubMed Central

Bai, Aiping; Guo, Yuan

2017-01-01

Acid sphingomyelinase (ASM) is a lipid hydrolase. By generating ceramide, ASM had been reported to have an important role in regulating immune cell functions inclusive of macrophages, NK cells, and CD8+ T cells, whereas the role of ASM bioactivity in regulation of human CD4+ T-cell functions remained uncertain. Recent studies have provided novel findings in this field. Upon stimulation of CD3 and/or CD28, ASM-dependent ceramide signaling mediates intracellular downstream signal cascades of CD3 and CD28, and regulates CD4+ T-cell activation and proliferation. Meanwhile, CD39 and CD161 have direct interactions with ASM, which mediates downstream signals inclusive of STAT3 and mTOR and thus defines human Th17 cells. Intriguingly, ASM mediates Th1 responses, but negatively regulates Treg functions. In this review, we summarized the pivotal roles of ASM in regulation of human CD4+ T-cell activation and responses. ASM/sphingolipid signaling may be a novel target for the therapy of human autoimmune diseases. PMID:28749465

The postsynaptic t-SNARE Syntaxin 4 controls traffic of Neuroligin 1 and Synaptotagmin 4 to regulate retrograde signaling.

PubMed

Harris, Kathryn P; Zhang, Yao V; Piccioli, Zachary D; Perrimon, Norbert; Littleton, J Troy

2016-05-25

Postsynaptic cells can induce synaptic plasticity through the release of activity-dependent retrograde signals. We previously described a Ca(2+)-dependent retrograde signaling pathway mediated by postsynaptic Synaptotagmin 4 (Syt4). To identify proteins involved in postsynaptic exocytosis, we conducted a screen for candidates that disrupted trafficking of a pHluorin-tagged Syt4 at Drosophila neuromuscular junctions (NMJs). Here we characterize one candidate, the postsynaptic t-SNARE Syntaxin 4 (Syx4). Analysis of Syx4 mutants reveals that Syx4 mediates retrograde signaling, modulating the membrane levels of Syt4 and the transsynaptic adhesion protein Neuroligin 1 (Nlg1). Syx4-dependent trafficking regulates synaptic development, including controlling synaptic bouton number and the ability to bud new varicosities in response to acute neuronal stimulation. Genetic interaction experiments demonstrate Syx4, Syt4, and Nlg1 regulate synaptic growth and plasticity through both shared and parallel signaling pathways. Our findings suggest a conserved postsynaptic SNARE machinery controls multiple aspects of retrograde signaling and cargo trafficking within the postsynaptic compartment.

The PreS2 activator MHBs(t) of hepatitis B virus activates c-raf-1/Erk2 signaling in transgenic mice.

PubMed

Hildt, Eberhard; Munz, Barbara; Saher, Gesine; Reifenberg, Kurt; Hofschneider, Peter Hans

2002-02-15

The large hepatitis B virus (HBV) surface protein (LHBs) and C-terminally truncated middle size surface proteins (MHBs(t)) form the family of the PreS2 activator proteins of HBV. Their transcriptional activator function is based on the cytoplasmic orientation of the PreS2 domain. MHBs(t) activators are paradigmatic for this class of activators. Here we report that MHBs(t) is protein kinase C (PKC)-dependently phosphorylated at Ser28. The integrity of the phosphorylation site is essential for the activator function. MHBs(t) triggers PKC-dependent activation of c-Raf-1/Erk2 signaling that is a prerequisite for MHBs(t)-dependent activation of AP-1 and NF-kappaB. To analyze the pathophysiological relevance of these data in vivo, transgenic mice were established that produce the PreS2 activator MHBs(t) specifically in the liver. In these mice, a permanent PreS2-dependent specific activation of c-Raf-1/Erk2 signaling was observed, resulting in an increased hepatocyte proliferation rate. In transgenics older than 15 months, an increased incidence of liver tumors occurs. These data suggest that PreS2 activators LHBs and MHBs(t) exert a tumor promoter-like function by activation of key enzymes of proliferation control.

Role of T Cell TGF-β Signaling in Intestinal Cytokine Responses and Helminthic Immune Modulation

PubMed Central

Ince, M. Nedim; Elliott, David E.; Setiawan, Tommy; Metwali, Ahmed; Blum, Arthur; Chen, Hung-lin; Urban, Joseph F.; Flavell, Richard A.; Weinstock, Joel V.

2010-01-01

Colonization with helminthic parasites induces mucosal regulatory cytokines, like IL-10 or TGF-β that are important in suppressing colitis. Helminths induce mucosal T cell IL-10 secretion and regulate lamina propria mononuclear cell Th1 cytokine generation in an IL-10 dependent manner in wild-type mice. Helminths also stimulate mucosal TGF-β release. As TGF-β exerts major regulatory effects on T lymphocytes, we investigated the role of T lymphocyte TGF-β signaling in helminthic modulation of intestinal immunity. T cell TGF-β signaling is interrupted in TGF-βRII DN mice by T cell-specific over-expression of a dominant negative TGF-β receptor II. We studied lamina propria mononuclear cell responses in wild-type and TGF-βRII DN mice that were uninfected or colonized with the nematode, Heligmosomoides polygyrus. Our results indicate an essential role of T cell TGF-β signaling in limiting mucosal Th1 and Th2 responses. Furthermore, we demonstrate that helminthic induction of intestinal T cell IL-10 secretion requires intact T cell TGF-β signaling pathway. Helminths fail to curtail robust, dysregulated intestinal Th1 cytokine production and chronic colitis in TGF-βRII DN mice. Thus, T cell TGF-β signaling is essential for helminthic stimulation of mucosal IL-10 production, helminthic modulation of intestinal interferon-γ generation and H. polygyrus-mediated suppression of chronic colitis. PMID:19544487

XUV pulse effect on signal modulations of harmonic spectra from H2+ and T2+

NASA Astrophysics Data System (ADS)

Feng, Liqiang; Liu, Hang; Kapteyn, Henry J.; Feng, April Y.

2018-05-01

The effects of signal modulations on the molecular high-order harmonic generations in H2^{+ } and T2+ have been theoretically investigated. It is found that with the introduction of the XUV pulse, due to the absorption of the extra XUV photons in the recombination process, multiplateaus on the harmonic spectra, separated by the XUV photon energy can be found. Moreover, this multiplateau structure is insensitive to the wavelength of the XUV pulse. In shorter pulse duration, the intensities of the multiplateaus from H2+ are higher than those from T2+; while in longer pulse duration, the opposite results can be found. Finally, by changing the delay time of the XUV pulse, the signal modulations (including the amplitude and the frequency modulations) of the multiplateaus can be controlled.

Predicting the intensity mapping signal for multi-J CO lines

NASA Astrophysics Data System (ADS)

Mashian, Natalie; Sternberg, Amiel; Loeb, Abraham

2015-11-01

We present a novel approach to estimating the intensity mapping signal of any CO rotational line emitted during the Epoch of Reionization (EoR). Our approach is based on large velocity gradient (LVG) modeling, a radiative transfer modeling technique that generates the full CO spectral line energy distribution (SLED) for a specified gas kinetic temperature, volume density, velocity gradient, molecular abundance, and column density. These parameters, which drive the physics of CO transitions and ultimately dictate the shape and amplitude of the CO SLED, can be linked to the global properties of the host galaxy, mainly the star formation rate (SFR) and the SFR surface density. By further employing an empirically derived SFR-M relation for high redshift galaxies, we can express the LVG parameters, and thus the specific intensity of any CO rotational transition, as functions of the host halo mass M and redshift z. Integrating over the range of halo masses expected to host CO-luminous galaxies, we predict a mean CO(1-0) brightness temperature ranging from ~ 0.6 μK at z = 6 to ~ 0.03 μK at z = 10 with brightness temperature fluctuations of ΔCO2 ~ 0.1 and 0.005 μK respectively, at k = 0.1 Mpc-1. In this model, the CO emission signal remains strong for higher rotational levels at z = 6, with langle TCO rangle ~ 0.3 and 0.05 μK for the CO J = 6arrow5 and CO J = 10arrow9 transitions respectively. Including the effects of CO photodissociation in these molecular clouds, especially at low metallicities, results in the overall reduction in the amplitude of the CO signal, with the low- and high-J lines weakening by 2-20% and 10-45%, respectively, over the redshift range 4 < z < 10.

Measurement of T1 of the Ultrashort T2* Components in White Matter of the Brain at 3T

PubMed Central

Du, Jiang; Sheth, Vipul; He, Qun; Carl, Michael; Chen, Jun; Corey-Bloom, Jody; Bydder, Graeme M.

2014-01-01

Recent research demonstrates that white matter of the brain contains not only long T2 components, but a minority of ultrashort T2* components. Adiabatic inversion recovery prepared dual echo ultrashort echo time (IR-dUTE) sequences can be used to selectively image the ultrashort T2* components in white matter of the brain using a clinical whole body scanner. The T2*s of the ultrashort T2* components can be quantified using mono-exponential decay fitting of the IR-dUTE signal at a series of different TEs. However, accurate T1 measurement of the ultrashort T2* components is technically challenging. Efficient suppression of the signal from the majority of long T2 components is essential for robust T1 measurement. In this paper we describe a novel approach to this problem based on the use of IR-dUTE data acquisitions with different TR and TI combinations to selectively detect the signal recovery of the ultrashort T2* components. Exponential recovery curve fitting provides efficient T1 estimation, with minimized contamination from the majority of long T2 components. A rubber phantom and a piece of bovine cortical bone were used for validation of this approach. Six healthy volunteers were studied. An averaged T2* of 0.32±0.09 ms, and a short mean T1 of 226±46 ms were demonstrated for the healthy volunteers at 3T. PMID:25093859

Metallothioneins regulate the adipogenic differentiation of 3T3-L1 cells via the insulin signaling pathway

PubMed Central

Toriuchi, Yuriko; Aki, Yuka; Mizuno, Yuto; Kawakami, Takashige; Nakaya, Tomoko; Sato, Masao; Suzuki, Shinya

2017-01-01

Knockout of metallothionein (MT) genes contributes to a heavier body weight in early life and the potential to become obese through the intake of a high fat diet (HFD) in mice. It has thus been suggested that MT genes regulate the formation of adipose tissue, which would become the base for later HFD-induced obesity. We evaluated the fat pads of mice during the lactation stage. The fat mass and adipocyte size of MT1 and MT2 knockout mice were greater than those of wild type mice. Next, we assayed the ability of small interfering RNA (siRNA) to silence MT genes in the 3T3-L1 cell line. The expressions of MT1 and MT2 genes were transiently upregulated during adipocyte differentiation, and the siRNA pretreatment led to the suppression of the expression of both MT mRNAs and proteins. The MT siRNA promoted lipid accumulation in adipocytes and caused proliferation of post-confluent preadipocytes; these effects were suppressed by an inhibitor of phosphatidylinositol 3-kinase (LY294002). In addition, MT siRNA promoted insulin-stimulated phosphorylation of Akt, a downstream kinase of the insulin signaling pathway. Enhanced lipid accumulation in 3T3-L1 cells resulting from MT-gene silencing was inhibited by pretreatment with an antioxidant, N-acetylcysteine, used as a substitute for antioxidant protein MTs. These results suggest that interference in MT expression enhanced the activation of the insulin signaling pathway, resulting in higher lipid accumulation in 3T3-L1 adipocytes. PMID:28426713

Intensity ratio curve analysis of small renal masses on T2-weighted magnetic resonance imaging: Differentiation of fat-poor angiomyolipoma from renal cell carcinoma.

PubMed

Moriyama, Shingo; Yoshida, Soichiro; Tanaka, Hajime; Tanaka, Hiroshi; Yokoyama, Minato; Ishioka, Junichiro; Matsuoka, Yoh; Saito, Kazutaka; Kihara, Kazunori; Fujii, Yasuhisa

2018-03-25

To assess the diagnostic ability of a pixel intensity-based analysis in evaluating the magnetic resonance imaging characteristics of small renal masses, especially in differentiating fat-poor angiomyolipoma from renal cell carcinoma. T2-weighted images from 121 solid small renal masses (<4 cm) without visible fat (14 fat-poor angiomyolipomas, 92 clear cell renal cell carcinomas, six chromophobe renal cell carcinomas and nine papillary renal cell carcinomas) were retrospectively evaluated. An intensity ratio curve was plotted using intensity ratios, which were ratios of signal intensities of tumor pixels (each pixel along a linear region of interest drawn across the renal tumor on T2-weighted image) to the signal intensity of a normal renal cortex. The diagnostic ability of the intensity ratio curve analysis was evaluated. The tumors were classified into three types: intensity ratio fat-poor angiomyolipoma (n = 19) with no pseudocapsule, iso-low intensity and no heterogeneity; intensity ratio clear cell renal cell carcinoma (n = 76) with a pseudocapsule, iso-high intensity and heterogeneity; and other type of intensity ratio (n = 26), including tumors that did not fall into the above two categories. The sensitivity/specificity/accuracy of the intensity ratio curve analysis in diagnosing fat-poor angiomyolipoma was 93%/94%/94%, respectively. When the intensity ratio curve analysis was applied only to the tumor with undetermined radiological diagnosis, the sensitivity for diagnosing fat-poor angiomyolipoma compared with subjective reading alone significantly improved (93% vs 50%; P = 0.014). Our novel semiquantitative model for combined assessment of key features of fat-poor angiomyolipoma, including low intensity, homogeneity and absence of a pseudocapsule on T2-weighted image, might make diagnosis of fat-poor angiomyolipoma more accurate. © 2018 The Japanese Urological Association.

Heparan Sulfate Modification of the Transmembrane Receptor CD47 Is Necessary for Inhibition of T Cell Receptor Signaling by Thrombospondin-1*

PubMed Central

Kaur, Sukhbir; Kuznetsova, Svetlana A.; Pendrak, Michael L.; Sipes, John M.; Romeo, Martin J.; Li, Zhuqing; Zhang, Lijuan; Roberts, David D.

2011-01-01

Cell surface proteoglycans on T cells contribute to retroviral infection, binding of chemokines and other proteins, and are necessary for some T cell responses to the matricellular glycoprotein thrombospondin-1. The major cell surface proteoglycans expressed by primary T cells and Jurkat T cells have an apparent Mr > 200,000 and are modified with chondroitin sulfate and heparan sulfate chains. Thrombospondin-1 bound in a heparin-inhibitable manner to this proteoglycan and to a soluble form released into the medium. Based on mass spectrometry, knockdown, and immunochemical analyses, the proteoglycan contains two major core proteins as follows: amyloid precursor-like protein-2 (APLP2, apparent Mr 230,000) and CD47 (apparent Mr > 250,000). CD47 is a known thrombospondin-1 receptor but was not previously reported to be a proteoglycan. This proteoglycan isoform of CD47 is widely expressed on vascular cells. Mutagenesis identified glycosaminoglycan modification of CD47 at Ser64 and Ser79. Inhibition of T cell receptor signaling by thrombospondin-1 was lost in CD47-deficient T cells that express the proteoglycan isoform of APLP2, indicating that binding to APLP2 is not sufficient. Inhibition of CD69 induction was restored in CD47-deficient cells by re-expressing CD47 or an S79A mutant but not by the S64A mutant. Therefore, inhibition of T cell receptor signaling by thrombospondin-1 is mediated by CD47 and requires its modification at Ser64. PMID:21343308

Immunomodulatory effect of tea saponin in immune T-cells and T-lymphoma cells via regulation of Th1, Th2 immune response and MAPK/ERK2 signaling pathway.

PubMed

Bhardwaj, Jyoti; Chaudhary, Narendra; Seo, Hyo-Jin; Kim, Min-Yong; Shin, Tai-Sun; Kim, Jong-Deog

2014-06-01

The anti-cancer activity of saponins and phenolic compounds present in green tea was previously reported. However, the immunomodulatory and adjuvanticity activity of tea saponin has never been studied. In this study, we investigated the immunomodulatory effect of tea saponin in T-lymphocytes and EL4 cells via regulation of cytokine response and mitogen-activated protein kinases (MAPK) signaling pathway. Quantitative analysis of mRNA expression level of cytokines were performed by reverse transcription polymerase chain reaction following stimulation with tea saponin, ovalbumin (OVA) alone or tea saponin in combination with OVA. Tea saponin inhibited the proliferation of EL4 cells measured in a dose-dependent manner. No cytotoxicity effect of tea saponin was detected in T-lymphocytes; rather, tea saponin enhanced the proliferation of T-lymphocytes. Tea saponin with OVA increased the expression of interleukin (IL)-1, IL-2, IL-12, interferon-γ and tumor necrosis factor (TNF)-α and decreased the expression level of IL-10 and IL-8 in T-lymphocytes. Furthermore, tea saponin, in the presence of OVA, downregulated the MAPK signaling pathway via inhibition of IL-4, IL-8 and nuclear factor kappaB (NF-κB) in EL4 cells. Th1 cytokines enhancer and Th2 cytokines and NF-κB inhibitor, tea saponin can markedly inhibit the proliferation and invasiveness of T-lymphoma (EL4) cells, possibly due to TNF-α- and NF-κB-mediated regulation of MAPK signaling pathway.

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells

PubMed Central

Thomas, Audrey; Mariani-Floderer, Charlotte; López-Huertas, Maria Rosa; Gros, Nathalie; Hamard-Péron, Elise; Favard, Cyril; Ohlmann, Theophile; Alcamí, José

2015-01-01

ABSTRACT During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. IMPORTANCE During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in

Integration of T Cell Receptor, Notch and Cytokine Signals Programs in Mouse γδ T Cell Effector Differentiation.

PubMed

Zarin, Payam; In, Tracy S H; Chen, Edward L Y; Singh, Jastaranpreet; Wong, Gladys W; Mohtashami, Mahmood; Wiest, David L; Anderson, Michele K; Zúñiga-Pflücker, Juan Carlos

2018-05-13

γδ T-cells perform a wide range of tissue and disease specific functions that are dependent on the effector cytokines produced by these cells. However, the aggregate signals required for the development of interferon-γ (IFNγ) and interleukin-17 (IL-17) producing γδ T-cells remain unknown. Here, we define the cues involved in the functional programming of γδ T-cells, by examining the roles of T-cell receptor (TCR), Notch, and cytokine-receptor signaling. KN6 γδTCR-transduced Rag2 -/- T-cell progenitors were cultured on stromal cells variably expressing TCR and Notch ligands, supplemented with different cytokines. We found that distinct combinations of these signals are required to program IFNγ versus IL-17 producing γδ T cell subsets, with Notch and weak TCR ligands optimally enabling development of γδ17 cells in the presence of IL-1β, IL-21 and IL-23. Notably, these cytokines were also shown to be required for the intrathymic development of γδ17 cells. Together, this work provides a framework of how signals downstream of TCR, Notch and cytokine receptors integrate to program the effector function of IFNγ and IL-17 producing γδ T-cell subsets. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

T-type α1H Ca2+ channels are involved in Ca2+ signaling during terminal differentiation (fusion) of human myoblasts

PubMed Central

Bijlenga, Philippe; Liu, Jian-Hui; Espinos, Estelle; Haenggeli, Charles-Antoine; Fischer-Lougheed, Jacqueline; Bader, Charles R.; Bernheim, Laurent

2000-01-01

Mechanisms underlying Ca2+ signaling during human myoblast terminal differentiation were studied using cell cultures. We found that T-type Ca2+ channels (T-channels) are expressed in myoblasts just before fusion. Their inhibition by amiloride or Ni2+ suppresses fusion and prevents an intracellular Ca2+ concentration increase normally observed at the onset of fusion. The use of antisense oligonucleotides indicates that the functional T-channels are formed by α1H subunits. At hyperpolarized potentials, these channels allow a window current sufficient to increase [Ca2+]i. As hyperpolarization is a prerequisite to myoblast fusion, we conclude that the Ca2+ signal required for fusion is produced when the resting potential enters the T-channel window. A similar mechanism could operate in other cell types of which differentiation implicates membrane hyperpolarization. PMID:10861024

Signal intensity on fluid-attenuated inversion recovery images of condylar marrow changes correspond with slight pain in patients with temporomandibular joint disorders.

PubMed

Kodama, Sayaka; Otonari-Yamamoto, Mika; Sano, Tsukasa; Sakamoto, Junichirou; Imoto, Kenichi; Wakoh, Mamoru

2014-01-01

Edema and necrosis of the temporomandibular joint (TMJ) have been described in terms of bone marrow signal abnormalities in magnetic resonance imaging (MRI). However, painful joints often show no such signaling abnormalities, making the diagnosis of TMJ disorders difficult in the clinical setting. An association has been suggested between TMJ bone marrow change and TMJ pain, but even when such change results in slight pain, it may be too slight to be visually apparent on MR images. We hypothesized that fluid-attenuated inversion recovery (FLAIR) can be used to detect such minimal changes. The purpose of this study was to determine whether there is an association between signal intensity on FLAIR images and pain in the TMJ. The study included 85 TMJs in 45 patients referred to our department for MRI. The signal intensity on FLAIR images was measured. Pain was evaluated based on the visual analog scale. An unpaired t test and Pearson's product-moment correlation coefficient were used for the statistical analysis. A p value of <0.05 was considered statistically significant. Signal intensity on the FLAIR images was significantly higher in painful than in nonpainful TMJs, although a significant correlation was not observed between the signal intensity and the pain score. The results of this study suggest an association between abnormalities in the marrow of the mandibular condyle and pain. They also indicate that FLAIR imaging is a useful tool in the clinical diagnosis of painful TMJs.

T1 bright appendix sign to exclude acute appendicitis in pregnant women.

PubMed

Shin, Ilah; An, Chansik; Lim, Joon Seok; Kim, Myeong-Jin; Chung, Yong Eun

2017-08-01

To evaluate the diagnostic value of the T1 bright appendix sign for the diagnosis of acute appendicitis in pregnant women. This retrospective study included 125 pregnant women with suspected appendicitis who underwent magnetic resonance (MR) imaging. The T1 bright appendix sign was defined as a high intensity signal filling more than half length of the appendix on T1-weighted imaging. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the T1 bright appendix sign for normal appendix identification were calculated in all patients and in those with borderline-sized appendices (6-7 mm). The T1 bright appendix sign was seen in 51% of patients with normal appendices, but only in 4.5% of patients with acute appendicitis. The overall sensitivity, specificity, PPV, and NPV of the T1 bright appendix sign for normal appendix diagnosis were 44.9%, 95.5%, 97.6%, and 30.0%, respectively. All four patients with borderline sized appendix with appendicitis showed negative T1 bright appendix sign. The T1 bright appendix sign is a specific finding for the diagnosis of a normal appendix in pregnant women with suspected acute appendicitis. • Magnetic resonance imaging is increasingly used in emergency settings. • Acute appendicitis is the most common cause of acute abdomen. • Magnetic resonance imaging is widely used in pregnant population. • T1 bright appendix sign can be a specific sign representing normal appendix.

GLP-1 secretion is stimulated by 1,10-phenanthroline via colocalized T2R5 signal transduction in human enteroendocrine L cell

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Jiyoung; Kim, Ki-Suk; Kim, Kang-Hoon

Glucagon-like peptide-1 (GLP-1) hormone is known to regulate blood glucose by an insulinotropic effect and increases proliferation as and also prevents apoptosis of pancreatic β cells. We know that GLP-1 is secreted by nutrients such as fatty acids and sweet compounds but also bitter compounds via stimulation of G-protein coupled receptors (GPCRs) in the gut. Among these, bitter compounds are multiply-contained in phytochemicals or artificial materials and perceived as ligands of various bitter taste receptors. We hypothesized that GLP-1 hormone is secreted through stimulation of a single bitter taste receptor by 1,10-phenanthroline which is known agonist of taste receptor typemore » 2 member 5 (T2R5). To prove this hypothesis, we used the representatively well-known 1,10-phenanthroline as ligand of single receptor and evaluated the existence of T2R5 by double-labeling immunofluorescence and then 1,10-phenanthroline is able to secrete GLP-1 hormone through stimulation of T2R5 in human enteroendocrine cells. Consequently, we verify that GLP-1 hormone is colocalized with T2R5 in the human duodenum and ileum tissue and is secreted by 1,10-phenanthroline via T2R5 signal transduction in differentiated human enteroendocrine L cells. - Highlights: • Taste receptor type 2 member 5 (T2R5) is colocalized with GLP-1 hormone in human enteroendocrine cells. • GLP-1 secretion is stimulated by 1,10-phenanthroline via stimulation of T2R5. • Inhibition of the bitter taste pathway reduce GLP-1 secretion.« less

CD4(+) T-cell help amplifies innate signals for primary CD8(+) T-cell immunity.

PubMed

Bedoui, Sammy; Heath, William R; Mueller, Scott N

2016-07-01

CD8(+) T cells provide an important component of protection against intracellular infections and cancer. Immune responses by these T cells involve a primary phase of effector expansion and differentiation, followed by a contraction phase leading to memory formation and, if antigen is re-encountered, a secondary expansion phase with more rapid differentiation. Both primary and secondary phases of CD8(+) T-cell immunity have been shown to depend on CD4(+) T-cell help, although during certain infections the primary phase is variable in this requirement. One explanation for such variability relates to the strength of associated inflammatory signals, with weak signals requiring help. Here, we focus on our studies that have dissected the requirements for help in the primary phase of the CTL response to herpes simplex virus, elucidating intricate interactions and communications between CD4(+) T cells, various dendritic cell subsets, and CD8(+) T cells. We place our studies in the context of others and describe a simple model of help where CD40 signaling amplifies innate signals to enable efficient CD8(+) T-cell expansion and differentiation. This model facilitates CTL induction to various different agents, without altering the qualitative innate signals that direct other important arms of immunity. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Paramagnet induced signal quenching in MAS-DNP experiments in frozen homogeneous solutions

NASA Astrophysics Data System (ADS)

Corzilius, Björn; Andreas, Loren B.; Smith, Albert A.; Ni, Qing Zhe; Griffin, Robert G.

2014-03-01

The effects of nuclear signal quenching induced by the presence of a paramagnetic polarizing agent are documented for conditions used in magic angle spinning (MAS)-dynamic nuclear polarization (DNP) experiments on homogeneous solutions. In particular, we present a detailed analysis of three time constants: (1) the longitudinal build-up time constant TB for 1H; (2) the rotating frame relaxation time constant T1ρ for 1H and 13C and (3) T2 of 13C, the transverse relaxation time constant in the laboratory frame. These relaxation times were measured during microwave irradiation at a magnetic field of 5 T (140 GHz) as a function of the concentration of four polarizing agents: TOTAPOL, 4-amino-TEMPO, trityl (OX063), and Gd-DOTA and are compared to those obtained for a sample lacking paramagnetic doping. We also report the EPR relaxation time constants T1S and T2S, the DNP enhancements, ε, and the parameter E, defined below, which measures the sensitivity enhancement for the four polarizing agents as a function of the electron concentration. We observe substantial intensity losses (paramagnetic quenching) with all of the polarizing agents due to broadening mechanisms and cross relaxation during MAS. In particular, the monoradical trityl and biradical TOTAPOL induce ∼40% and 50% loss of signal intensity. In contrast there is little suppression of signal intensity in static samples containing these paramagnetic species. Despite the losses due to quenching, we find that all of the polarizing agents provide substantial gains in signal intensity with DNP, and in particular that the net enhancement is optimal for biradicals that operate with the cross effect. We discuss the possibility that much of this polarization loss can be regained with the development of instrumentation and methods to perform electron decoupling.

The T1R2/T1R3 sweet receptor and TRPM5 ion channel taste targets with therapeutic potential.

PubMed

Sprous, Dennis; Palmer, Kyle R

2010-01-01

Taste signaling is a critical determinant of ingestive behaviors and thereby linked to obesity and related metabolic dysfunctions. Recent evidence of taste signaling pathways in the gut suggests the link to be more direct, raising the possibility that taste receptor systems could be regarded as therapeutic targets. T1R2/T1R3, the G protein coupled receptor that mediates sweet taste, and the TRPM5 ion channel have been the focus of discovery programs seeking novel compounds that could be useful in modifying taste. We review in this chapter the hypothesis of gastrointestinal taste signaling and discuss the potential for T1R2/T1R3 and TRPM5 as targets of therapeutic intervention in obesity and diabetes. Critical to the development of a drug discovery program is the creation of libraries that enhance the likelihood of identifying novel compounds that modulate the target of interest. We advocate a computer-based chemoinformatic approach for assembling natural and synthetic compound libraries as well as for supporting optimization of structure activity relationships. Strategies for discovering modulators of T1R2/T1R3 and TRPM5 using methods of chemoinformatics are presented herein. Copyright 2010 Elsevier Inc. All rights reserved.

Substance P Activates the Wnt Signal Transduction Pathway and Enhances the Differentiation of Mouse Preosteoblastic MC3T3-E1 Cells

PubMed Central

Mei, Gang; Zou, Zhenlv; Fu, Su; Xia, Liheng; Zhou, Jian; Zhang, Yongtao; Tuo, Yonghua; Wang, Zhao; Jin, Dan

2014-01-01

Recent experiments have explored the impact of Wnt/β-catenin signaling and Substance P (SP) on the regulation of osteogenesis. However, the molecular regulatory mechanisms of SP on the formation of osteoblasts is still unknown. In this study, we investigated the impact of SP on the differentiation of MC3T3-E1 cells. The osteogenic effect of SP was observed at different SP concentrations (ranging from 10−10 to 10−8 M). To unravel the underlying mechanism, the MC3T3-E1 cells were treated with SP after the pretreatment by neurokinin-1 (NK1) antagonists and Dickkopf-1 (DKK1) and gene expression levels of Wnt/β-catenin signaling pathway components, as well as osteoblast differentiation markers (collagen type I, alkaline phosphatase, osteocalcin, and Runx2), were measured using quantitative polymerase chain reaction (PCR). Furthermore, protein levels of Wnt/β-catenin signaling pathway were detected using Western blotting and the effects of SP, NK1 antagonist, and DKK1 on β-catenin activation were investigated by immunofluorescence staining. Our data indicated that SP (10−9 to 10−8 M) significantly up-regulated the expressions of osteoblastic genes. SP (10−8 M) also elevated the mRNA level of c-myc, cyclin D1, and lymphocyte enhancer factor-1 (Lef1), as well as c-myc and β-catenin protein levels, but decreased the expression of Tcf7 mRNA. Moreover, SP (10−8 M) promoted the transfer of β-catenin into nucleus. The effects of SP treatment were inhibited by the NK1 antagonist and DKK1. These findings suggest that SP may enhance differentiation of MC3T3-E1 cells via regulation of the Wnt/β-catenin signaling pathway. PMID:24733069

Proposal and Implementation of a Robust Sensing Method for DVB-T Signal

NASA Astrophysics Data System (ADS)

Song, Chunyi; Rahman, Mohammad Azizur; Harada, Hiroshi

This paper proposes a sensing method for TV signals of DVB-T standard to realize effective TV White Space (TVWS) Communication. In the TVWS technology trial organized by the Infocomm Development Authority (iDA) of Singapore, with regard to the sensing level and sensing time, detecting DVB-T signal at the level of -120dBm over an 8MHz channel with a sensing time below 1 second is required. To fulfill such a strict sensing requirement, we propose a smart sensing method which combines feature detection and energy detection (CFED), and is also characterized by using dynamic threshold selection (DTS) based on a threshold table to improve sensing robustness to noise uncertainty. The DTS based CFED (DTS-CFED) is evaluated by computer simulations and is also implemented into a hardware sensing prototype. The results show that the DTS-CFED achieves a detection probability above 0.9 for a target false alarm probability of 0.1 for DVB-T signals at the level of -120dBm over an 8MHz channel with the sensing time equals to 0.1 second.

Signal-Switchable Electrochemiluminescence System Coupled with Target Recycling Amplification Strategy for Sensitive Mercury Ion and Mucin 1 Assay.

PubMed

Jiang, Xinya; Wang, Huijun; Wang, Haijun; Yuan, Ruo; Chai, Yaqin

2016-09-20

In the present work, we first found that mercury ion (Hg(2+)) has an efficient quenching effect on the electrochemiluminescence (ECL) of N-(aminobutyl)-N-(ethylisoluminol) (ABEI). Since we were inspired by this discovery, an aptamer-based ECL sensor was fabricated based on a Hg(2+) triggered signal switch coupled with an exonuclease I (Exo I)-stimulated target recycling amplification strategy for ultrasensitive determination of Hg(2+) and mucin 1 (MUC1). Concretely, the ECL intensity of ABEI-functionalized silver nanoparticles decorated graphene oxide nanocomposite (GO-AgNPs-ABEI) was initially enhanced by ferrocene labeled ssDNA (Fc-S1) (first signal switch "on" state) in the existence of H2O2. With the aid of aptamer, assistant ssDNA (S2) and full thymine (T) bases ssDNA (S3) modified Au nanoparticles (AuNPs-S2-S3) were immobilized on the sensing surface through the hybridization reaction. Then, via the strong and stable T-Hg(2+)-T interaction, an abundance of Hg(2+) was successfully captured on the AuNPs-S2-S3 and effectively inhibited the ECL reaction of ABEI (signal switch "off" state). Finally, the signal switch "on" state was executed by utilizing MUC1 as an aptamer-specific target to bind aptamer, leading to the large decrease of the captured Hg(2+). To further improve the sensitivity of the aptasensor, Exo I was implemented to digest the binded aptamer, which resulted in the release of MUC1 for achieving target recycling with strong detectable ECL signal even in a low level of MUC1. By integrating the quenching effect of Hg(2+) to reduce the background signal and target recycling for signal amplification, this proposed ECL aptasensor was successfully used to detect Hg(2+) and MUC1 sensitively with a wide linear response.

Crammed signaling motifs in the T-cell receptor.

PubMed

Borroto, Aldo; Abia, David; Alarcón, Balbino

2014-09-01

Although the T cell antigen receptor (TCR) is long known to contain multiple signaling subunits (CD3γ, CD3δ, CD3ɛ and CD3ζ), their role in signal transduction is still not well understood. The presence of at least one immunoreceptor tyrosine-based activation motif (ITAM) in each CD3 subunit has led to the idea that the multiplication of such elements essentially serves to amplify signals. However, the evolutionary conservation of non-ITAM sequences suggests that each CD3 subunit is likely to have specific non-redundant roles at some stage of development or in mature T cell function. The CD3ɛ subunit is paradigmatic because in a relatively short cytoplasmic sequence (∼55 amino acids) it contains several docking sites for proteins involved in intracellular trafficking and signaling, proteins whose relevance in T cell activation is slowly starting to be revealed. In this review we will summarize our current knowledge on the signaling effectors that bind directly to the TCR and we will propose a hierarchy in their response to TCR triggering. Copyright © 2014 Elsevier B.V. All rights reserved.

The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development.

PubMed

Castro, Iris; Yu, Aixin; Dee, Michael J; Malek, Thomas R

2011-11-15

Recent work suggests that IL-2 and IL-15 induce distinctive levels of signaling through common receptor subunits and that such varied signaling directs the fate of Ag-activated CD8(+) T cells. In this study, we directly examined proximal signaling by IL-2 and IL-15 and CD8(+) T cell primary and memory responses as a consequence of varied CD122-dependent signaling. Initially, IL-2 and IL-15 induced similar p-STAT5 and p-S6 activation, but these activities were only sustained by IL-2. Transient IL-15-dependent signaling is due to limited expression of IL-15Rα. To investigate the outcome of varied CD122 signaling for CD8(+) T cell responses in vivo, OT-I T cells were used from mouse models where CD122 signals were attenuated by mutations within the cytoplasmic tail of CD122 or intrinsic survival function was provided in the absence of CD122 expression by transgenic Bcl-2. In the absence of CD122 signaling, generally normal primary response occurred, but the primed CD8(+) T cells were not maintained. In marked contrast, weak CD122 signaling supported development and survival of T central-memory (T(CM)) but not T effector-memory (T(EM)) cells. Transgenic expression of Bcl-2 in CD122(-/-) CD8(+) T cells also supported the survival and persistence of T(CM) cells but did not rescue T(EM) development. These data indicate that weak CD122 signals readily support T(CM) development largely through providing survival signals. However, stronger signals, independent of Bcl-2, are required for T(EM) development. Our findings are consistent with a model whereby low, intermediate, and high CD122 signaling support T(CM) memory survival, T(EM) programming, and terminal T effector cell differentiation, respectively.

Involvement of the Rac1-IRSp53-Wave2-Arp2/3 Signaling Pathway in HIV-1 Gag Particle Release in CD4 T Cells.

PubMed

Thomas, Audrey; Mariani-Floderer, Charlotte; López-Huertas, Maria Rosa; Gros, Nathalie; Hamard-Péron, Elise; Favard, Cyril; Ohlmann, Theophile; Alcamí, José; Muriaux, Delphine

2015-08-01

During HIV-1 assembly, the Gag viral proteins are targeted and assemble at the inner leaflet of the cell plasma membrane. This process could modulate the cortical actin cytoskeleton, located underneath the plasma membrane, since actin dynamics are able to promote localized membrane reorganization. In addition, activated small Rho GTPases are known for regulating actin dynamics and membrane remodeling. Therefore, the modulation of such Rho GTPase activity and of F-actin by the Gag protein during virus particle formation was considered. Here, we studied the implication of the main Rac1, Cdc42, and RhoA small GTPases, and some of their effectors, in this process. The effect of small interfering RNA (siRNA)-mediated Rho GTPases and silencing of their effectors on Gag localization, Gag membrane attachment, and virus-like particle production was analyzed by immunofluorescence coupled to confocal microscopy, membrane flotation assays, and immunoblot assays, respectively. In parallel, the effect of Gag expression on the Rac1 activation level was monitored by G-LISA, and the intracellular F-actin content in T cells was monitored by flow cytometry and fluorescence microscopy. Our results revealed the involvement of activated Rac1 and of the IRSp53-Wave2-Arp2/3 signaling pathway in HIV-1 Gag membrane localization and particle release in T cells as well as a role for actin branching and polymerization, and this was solely dependent on the Gag viral protein. In conclusion, our results highlight a new role for the Rac1-IRSp53-Wave2-Arp2/3 signaling pathway in the late steps of HIV-1 replication in CD4 T lymphocytes. During HIV-1 assembly, the Gag proteins are targeted and assembled at the inner leaflet of the host cell plasma membrane. Gag interacts with specific membrane phospholipids that can also modulate the regulation of cortical actin cytoskeleton dynamics. Actin dynamics can promote localized membrane reorganization and thus can be involved in facilitating Gag assembly

Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4+ T Cell Proliferation.

PubMed

Celada, Lindsay J; Rotsinger, Joseph E; Young, Anjuli; Shaginurova, Guzel; Shelton, Debresha; Hawkins, Charlene; Drake, Wonder P

2017-01-01

Patients with progressive sarcoidosis exhibit increased expression of programmed death-1 (PD-1) receptor on their CD4 + T cells. Up-regulation of this marker of T cell exhaustion is associated with a reduction in the proliferative response to T cell receptor (TCR) stimulation, a defect that is reversed by PD-1 pathway blockade. Genome-wide association studies and microarray analyses have correlated signaling downstream from the TCR with sarcoidosis disease severity, but the mechanism is not yet known. Reduced phosphatidylinositol 3-kinase (PI3K)/AKT expression inhibits proliferation by inhibiting cell cycle progression. To test the hypothesis that PD-1 expression attenuates TCR-dependent activation of PI3K/AKT activity in progressive systemic sarcoidosis, we analyzed PI3K/AKT/mechanistic target of rapamycin (mTOR) expression at baseline and after PD-1 pathway blockade in CD4 + T cells isolated from patients with sarcoidosis and healthy control subjects. We confirmed an increased percentage of PD-1 + CD4 + T cells and reduced proliferative capacity in patients with sarcoidosis compared with healthy control subjects (P < 0.001). There was a negative correlation with PD-1 expression and proliferative capacity (r = -0.70, P < 0.001). Expression of key mediators of cell cycle progression, including PI3K and AKT, were significantly decreased. Gene and protein expression levels reverted to healthy control levels after PD-1 pathway blockade. Reduction in sarcoidosis CD4 + T cell proliferative capacity is secondary to altered expression of key mediators of cell cycle progression, including the PI3K/AKT/mTOR pathway, via PD-1 up-regulation. This supports the concept that PD-1 up-regulation drives the immunologic deficits associated with sarcoidosis severity by inducing signaling aberrancies in key mediators of cell cycle progression.

Programmed Death-1 Inhibition of Phosphatidylinositol 3-Kinase/AKT/Mechanistic Target of Rapamycin Signaling Impairs Sarcoidosis CD4+ T Cell Proliferation

PubMed Central

Celada, Lindsay J.; Rotsinger, Joseph E.; Young, Anjuli; Shaginurova, Guzel; Shelton, Debresha; Hawkins, Charlene

2017-01-01

Patients with progressive sarcoidosis exhibit increased expression of programmed death-1 (PD-1) receptor on their CD4+ T cells. Up-regulation of this marker of T cell exhaustion is associated with a reduction in the proliferative response to T cell receptor (TCR) stimulation, a defect that is reversed by PD-1 pathway blockade. Genome-wide association studies and microarray analyses have correlated signaling downstream from the TCR with sarcoidosis disease severity, but the mechanism is not yet known. Reduced phosphatidylinositol 3-kinase (PI3K)/AKT expression inhibits proliferation by inhibiting cell cycle progression. To test the hypothesis that PD-1 expression attenuates TCR-dependent activation of PI3K/AKT activity in progressive systemic sarcoidosis, we analyzed PI3K/AKT/mechanistic target of rapamycin (mTOR) expression at baseline and after PD-1 pathway blockade in CD4+ T cells isolated from patients with sarcoidosis and healthy control subjects. We confirmed an increased percentage of PD-1+ CD4+ T cells and reduced proliferative capacity in patients with sarcoidosis compared with healthy control subjects (P < 0.001). There was a negative correlation with PD-1 expression and proliferative capacity (r = −0.70, P < 0.001). Expression of key mediators of cell cycle progression, including PI3K and AKT, were significantly decreased. Gene and protein expression levels reverted to healthy control levels after PD-1 pathway blockade. Reduction in sarcoidosis CD4+ T cell proliferative capacity is secondary to altered expression of key mediators of cell cycle progression, including the PI3K/AKT/mTOR pathway, via PD-1 up-regulation. This supports the concept that PD-1 up-regulation drives the immunologic deficits associated with sarcoidosis severity by inducing signaling aberrancies in key mediators of cell cycle progression. PMID:27564547

Comparison of high MRI T1 signals with manganese concentration in brains of cynomolgus monkeys after 8 months of stainless steel welding-fume exposure.

PubMed

Park, Jung Duck; Chung, Yong Hyun; Kim, Choong Yong; Ha, Chang Soo; Yang, Seoung Oh; Khang, Hyun Soo; Yu, In Kyu; Cheong, Hae Kwan; Lee, Jong Seong; Song, Chang-Woo; Kwon, Il Hoon; Han, Jeong Hee; Sung, Jae Hyuck; Heo, Jeong Doo; Choi, Byung Sun; Im, Ruth; Jeong, Jayoung; Yu, Il Je

2007-09-01

Several pharmacokinetic studies on inhalation exposure to manganese (Mn) have already demonstrated that Mn readily accumulates in the olfactory and brain regions. However, a shortening of the magnetic resonance imaging (MRI) T1 relaxation time or high T1 signal intensity in specific sites of the brain, including the globus pallidus and subcortical frontal white matter, as indicative of tissue manganese accumulation has not yet been clearly established for certain durations of known doses of welding-fume exposure in experimental animals. Accordingly, to investigate the movement of manganese after welding-fume exposure, six cynomolgus monkeys were acclimated and assigned to three dose groups: unexposed, low dose (31 mg/m(3) total suspended particulate [TSP], 0.9 mg/m(3) of Mn), and high dose (62 mg/m(3) TSP, 1.95 mg/m(3) of Mn) of total suspended particulate. The primates were exposed to manual metal arc stainless steel (MMA-SS) welding fumes for 2 h per day in an inhalation chamber system equipped with an automatic fume generator. Magnetic resonance imaging (MRI) studies were conducted before the initiation of exposure and thereafter every month. The tissue Mn concentrations were then measured after a plateau was reached regarding the shortening of the MRI T1 relaxation time. A dose-dependent increase in the Mn concentration was found in the lungs, while noticeable increases in the Mn concentrations were found in certain tissues, such as the liver, kidneys, and testes. Slight increases in the Mn concentrations were found in the caudate, putamen, frontal lobe, and substantia nigra, while a dose-dependent noticeable increase was only found in the globus pallidus. Therefore, the present results indicated that a shortening of the MRI T1 relaxation time corresponded well with the Mn concentration in the globus pallidus after prolonged welding-fume exposure.

Placing Ion Channels into a Signaling Network of T Cells: From Maturing Thymocytes to Healthy T Lymphocytes or Leukemic T Lymphoblasts

PubMed Central

Delgado-Enciso, Iván; Best-Aguilera, Carlos; Rojas-Sotelo, Rocío Monserrat; Pottosin, Igor

2015-01-01

T leukemogenesis is a multistep process, where the genetic errors during T cell maturation cause the healthy progenitor to convert into the leukemic precursor that lost its ability to differentiate but possesses high potential for proliferation, self-renewal, and migration. A new misdirecting “leukemogenic” signaling network appears, composed by three types of participants which are encoded by (1) genes implicated in determined stages of T cell development but deregulated by translocations or mutations, (2) genes which normally do not participate in T cell development but are upregulated, and (3) nondifferentially expressed genes which become highly interconnected with genes expressed differentially. It appears that each of three groups may contain genes coding ion channels. In T cells, ion channels are implicated in regulation of cell cycle progression, differentiation, activation, migration, and cell death. In the present review we are going to reveal a relationship between different genetic defects, which drive the T cell neoplasias, with calcium signaling and ion channels. We suggest that changes in regulation of various ion channels in different types of the T leukemias may provide the intracellular ion microenvironment favorable to maintain self-renewal capacity, arrest differentiation, induce proliferation, and enhance motility. PMID:25866806

Barcoding T Cell Calcium Response Diversity with Methods for Automated and Accurate Analysis of Cell Signals (MAAACS)

PubMed Central

Sergé, Arnauld; Bernard, Anne-Marie; Phélipot, Marie-Claire; Bertaux, Nicolas; Fallet, Mathieu; Grenot, Pierre; Marguet, Didier; He, Hai-Tao; Hamon, Yannick

2013-01-01

We introduce a series of experimental procedures enabling sensitive calcium monitoring in T cell populations by confocal video-microscopy. Tracking and post-acquisition analysis was performed using Methods for Automated and Accurate Analysis of Cell Signals (MAAACS), a fully customized program that associates a high throughput tracking algorithm, an intuitive reconnection routine and a statistical platform to provide, at a glance, the calcium barcode of a population of individual T-cells. Combined with a sensitive calcium probe, this method allowed us to unravel the heterogeneity in shape and intensity of the calcium response in T cell populations and especially in naive T cells, which display intracellular calcium oscillations upon stimulation by antigen presenting cells. PMID:24086124

Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection

NASA Astrophysics Data System (ADS)

Doitsh, Gilad; Galloway, Nicole L. K.; Geng, Xin; Yang, Zhiyuan; Monroe, Kathryn M.; Zepeda, Orlando; Hunt, Peter W.; Hatano, Hiroyu; Sowinski, Stefanie; Muñoz-Arias, Isa; Greene, Warner C.

2014-01-01

The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1β, are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of `anti-AIDS' therapeutics targeting the host rather than the virus.

Intravenous injection of gadobutrol in an epidemiological study group did not lead to a difference in relative signal intensities of certain brain structures after 5 years.

PubMed

Kromrey, Marie-Luise; Liedtke, Kim Rouven; Ittermann, Till; Langner, Sönke; Kirsch, Michael; Weitschies, Werner; Kühn, Jens-Peter

2017-02-01

To investigate if application of macrocyclic gadolinium-based contrast agents in volunteers is associated with neuronal deposition detected by magnetic resonance imaging in a 5-year longitudinal survey. Three hundred eighty-seven volunteers who participated in a population-based study were enrolled. Subjects underwent plain T1-weighted brain MRI at baseline and 5 years later with identical sequence parameters. At baseline, 271 participants additionally received intravenous injection of the macrocyclic contrast agent gadobutrol (0.15 mmol/kg). A control group including 116 subjects received no contrast agent. Relative signal intensities of thalamus, pallidum, pons and dentate nucleus were compared at baseline and follow-up. No difference in relative signal intensities was observed between contrast group (thalamus, p = 0.865; pallidum, p = 0.263; pons, p = 0.533; dentate nucleus, p = 0.396) and control group (thalamus, p = 0.683; pallidum; p = 0.970; pons, p = 0.773; dentate nucleus, p = 0.232) at both times. Comparison between both groups revealed no significant differences in relative signal intensities (thalamus, p = 0.413; pallidum, p = 0.653; pons, p = 0.460; dentate nucleus, p = 0.751). The study showed no significant change in globus pallidus-to-thalamus or dentate nucleus-to-pons ratios. Five years after administration of a 1.5-fold dose gadobutrol to normal subjects, signal intensity of thalamus, pallidum, pons and dentate nucleus did not differ from participants who had not received gadobutrol. • Gadobutrol does not lead to neuronal signal alterations after 5 years. • Neuronal deposition of macrocyclic contrast agent could not be confirmed. • Macrocyclic contrast agents in a proven dosage are safe.

Segmentation and intensity estimation of microarray images using a gamma-t mixture model.

PubMed

Baek, Jangsun; Son, Young Sook; McLachlan, Geoffrey J

2007-02-15

We present a new approach to the analysis of images for complementary DNA microarray experiments. The image segmentation and intensity estimation are performed simultaneously by adopting a two-component mixture model. One component of this mixture corresponds to the distribution of the background intensity, while the other corresponds to the distribution of the foreground intensity. The intensity measurement is a bivariate vector consisting of red and green intensities. The background intensity component is modeled by the bivariate gamma distribution, whose marginal densities for the red and green intensities are independent three-parameter gamma distributions with different parameters. The foreground intensity component is taken to be the bivariate t distribution, with the constraint that the mean of the foreground is greater than that of the background for each of the two colors. The degrees of freedom of this t distribution are inferred from the data but they could be specified in advance to reduce the computation time. Also, the covariance matrix is not restricted to being diagonal and so it allows for nonzero correlation between R and G foreground intensities. This gamma-t mixture model is fitted by maximum likelihood via the EM algorithm. A final step is executed whereby nonparametric (kernel) smoothing is undertaken of the posterior probabilities of component membership. The main advantages of this approach are: (1) it enjoys the well-known strengths of a mixture model, namely flexibility and adaptability to the data; (2) it considers the segmentation and intensity simultaneously and not separately as in commonly used existing software, and it also works with the red and green intensities in a bivariate framework as opposed to their separate estimation via univariate methods; (3) the use of the three-parameter gamma distribution for the background red and green intensities provides a much better fit than the normal (log normal) or t distributions; (4) the

T1 mapping combined with Gd-EOB-DTPA-enhanced magnetic resonance imaging in predicting the pathologic grading of hepatocellular carcinoma.

PubMed

Chen, C Y; Chen, J; Xia, C C; Huang, Z X; Song, B

2017-01-01

The aim of this study was to investigate the value of Gd-EOB-DTPA-enhanced MRI on hepatobiliary phase (HBP) imaging and T1 mapping sequence in the differentiation of hepatocellular carcinoma (HCC). A total of 45 patients with HCC who were to undergo a resection were enrolled in this study. Gd-EOB-DTPA-enhanced magnetic resonance examination was performed prior to resection. T1 mapping was performed before and 20 min after injection of Gd-EOB-DTPA. T1 values of the lesions were measured on pre-contrast (T1p) and during HBP (T1-HBP) on T1 maps. The signal intensity, the diameter and the margin of HCC lesions on HBP images were analyzed. The reduction in T1 value (T1d) and the reduction rate (ΔT1%) of T1 mapping between pre-contrast and HBP were calculated. The Edmondson-Steiner classification of each lesion was made after surgery. The SPSS software package was used for statistical analysis and the analysis of receiver operator characteristic (ROC) curve and area under the curve (AUC) were carried out by using MedCalc software package. Mean values of T1p and T1-HBP were 1935.4±730.8 ms and 1257.1±529.1 ms, respectively. T1p accuracy (AUC = 0.685, p = 0.037) in predicting pathological grading was similar to that of T1-HBP (AUC = 0.751, p = 0.005). A T1p of 1648.2 ms or greater had a sensitivity and specificity of 85.19% and 61.11%, respectively. A T1-HBP of 1006 ms or greater had a sensitivity and specificity of 81.84% and 61.11%, respectively. The number of HCCs with a non-smooth tumor margin was 20 (44.4%), and a non-smooth tumor margin correlated moderately with the Edmondson-Steiner grade (Spearman r = 0.491, p = 0.041). There was no significant correlation between T1d, ΔT1%, HCC signal intensity on HBP image and lesion diameter with pathologic grading. T1 mapping in pre-contrast and HBP of Gd-EOB-DTPA-enhanced MRI, a non-smooth tumor margin in the HBP of Gd-EOB-DTPA-enhanced MRI, are useful in predicting the pathologic grading of HCC.

Tax-dependent stimulation of G1 phase-specific cyclin-dependent kinases and increased expression of signal transduction genes characterize HTLV type 1-transformed T cells.

PubMed

Haller, K; Ruckes, T; Schmitt, I; Saul, D; Derow, E; Grassmann, R

2000-11-01

Human T cell leukemia virus protein induces T cells to permanent IL-2-dependent growth. These cells occasionally convert to factor independence. The viral oncoprotein Tax acts as an essential growth factor of transformed lymphocytes and stimulates the cell cycle in the G(1) phase. In T cells and fibroblasts Tax enhances the activity of the cyclin-dependent kinases (CDK) CDK4 and CDK6. These kinases, which require binding to cyclin D isotypes for their activity, control the G(1) phase. Coimmunoprecipitation from these cells revealed that Tax associates with cyclin D3/CDK6, suggesting a direct activation of this kinase. The CDK stimulation may account in part for the mitogenic Tax effect, which causes IL-2-dependent T cell growth by Tax. To address the conversion to IL-2-independent proliferation and to identify overexpressed genes, which contribute to the transformed growth, the gene expression patterns of HTLV-1-transformed T cells were compared with that of peripheral blood lymphocytes. Potentially overexpressed cDNAs were cloned, sequenced, and used to determine the RNA expression. Genes found to be up-regulated are involved in signal transduction (STAT5a, cyclin G(1), c-fgr, hPGT) and also glycoprotein synthesis (LDLC, ribophorin). Many of these are also activated during T cell activation and implicated in the regulation of growth and apoptosis. The transcription factor STAT5a, which is involved in IL-2 signaling, was strongly up-regulated only in IL-2-independent cells, thus suggesting that it contributes to factor-independent growth. Thus, the differentially expressed genes could cooperate with the Tax-induced cell cycle stimulation in the maintenance of IL-2-dependent and IL-2-independent growth of HTLV-transformed lymphocytes.

Heat shock protein 70 (Hsp70) interacts with the Notch1 intracellular domain and contributes to the activity of Notch signaling in myelin-reactive CD4 T cells.

PubMed

Juryńczyk, Maciej; Lewkowicz, Przemysław; Domowicz, Małgorzata; Mycko, Marcin P; Selmaj, Krzysztof W

2015-10-15

Notch receptors (Notch1-4) are involved in the differentiation of CD4 T cells and the development of autoimmunity. Mechanisms regulating Notch signaling in CD4 T cells are not fully elucidated. In this study we investigated potential crosstalk between Notch pathway molecules and heat shock protein 70 (Hsp70), the major intracellular chaperone involved in the protein transport during immune responses and other stress conditions. Using Hsp70(-/-) mice we found that Hsp70 is critical for up-regulation of NICD1 and induction of Notch target genes in Jagged1- and Delta-like1-stimulated CD4 T cells. Co-immunoprecipitation analysis of wild-type CD4 T cells stimulated with either Jagged1 or Delta-like1 showed a direct interaction between NICD1 and Hsp70. Both molecules co-localized within the nucleus of CD4 T cells stimulated with Notch ligands. Molecular interaction and nuclear colocalization of NICD1 and Hsp70 were also detected in CD4 T cells reactive against myelin oligodendrocyte glycoprotein (MOG)35-55, which showed Hsp70-dependent up-regulation of both NICD1 and Notch target genes. In conclusion, we demonstrate for the first time that Hsp70 interacts with NICD1 and contributes to the activity of Notch signaling in CD4 T cells. Interaction between Hsp70 and NICD1 may represent a novel mechanism regulating Notch signaling in activated CD4 T cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Perturbed thymopoiesis in vitro in the absence of Suppressor of Cytokine Signalling 1 and 3

PubMed Central

Croom, Hayley A.; Izon, David J.; Chong, Mark M.; Curtis, David J.; Roberts, Andrew W.; Kay, Thomas W.H.; Hilton, Douglas J.; Alexander, Warren S.; Starr, Robyn

2014-01-01

Cytokine signals are central to the differentiation of thymocytes and their stepwise progression through defined developmental stages. The intensity and duration of cytokine signals are regulated by the suppressor of cytokine signalling (SOCS) proteins. A clear role for SOCS1 during the later stages of thymopoiesis has been established, but little is known about its role during early thymopoiesis, nor the function of its closest relative, SOCS3. Here, we find that both SOCS1 and SOCS3 are expressed during early thymopoiesis, with expression coincident during the double negative (DN)2 and DN3 stages. We examined thymocyte differentiation in vitro by co-culture of SOCS-deficient bone marrow cells with OP9 cells expressing the Notch ligand Delta-like1 (OP9-DL1). Cells lacking SOCS1 were retarded at the DN3:DN4 transition and appeared unable to differentiate into double positive (DP) thymocytes. Cells lacking both SOCS1 and SOCS3 were more severely affected, and displayed an earlier block in T cell differentiation at DN2, the stage at which expression of SOCS1 and SOCS3 coincides. This indicates that, in addition to their specific roles, SOCS1 and SOCS3 share overlapping roles during thymopoiesis. This is the first demonstration of functional redundancy within the SOCS family, and has uncovered a vital role for SOCS1 and SOCS3 during two important checkpoints in early T cell development. PMID:18321577

Low-Intensity Pulsed Ultrasound Enhances Nerve Growth Factor-Induced Neurite Outgrowth through Mechanotransduction-Mediated ERK1/2-CREB-Trx-1 Signaling.

PubMed

Zhao, Lu; Feng, Yi; Hu, Hong; Shi, Aiwei; Zhang, Lei; Wan, Mingxi

2016-12-01

Enhancing the action of nerve growth factor (NGF) is a potential therapeutic approach to neural regeneration. To facilitate neural regeneration, we investigated whether combining low-intensity pulsed ultrasound (LIPUS) and NGF could promote neurite outgrowth, an essential process in neural regeneration. In the present study, PC12 cells were subjected to a combination of LIPUS (1 MHz, 30 or 50 mW/cm 2 , 20% duty cycle and 100-Hz pulse repetition frequency, 10 min every other day) and NGF (50 ng/mL) treatment, and then neurite outgrowth was compared. Our findings indicated that the combined treatment with LIPUS (50 mW/cm 2 ) and NGF (50 ng/mL) promotes neurite outgrowth that is comparable to that achieved by NGF (100 ng/mL) treatment alone. LIPUS significantly increased NGF-induced neurite length, but not neurite branching. These effects were attributed to the enhancing effects of LIPUS on NGF-induced phosphorylation of ERK1/2 and CREB and the expression of thioredoxin (Trx-1). Furthermore, blockage of stretch-activated ion channels with Gd 3+ suppressed the stimulating effects of LIPUS on NGF-induced neurite outgrowth and the downstream signaling activation. Taken together, our findings suggest that LIPUS enhances NGF-induced neurite outgrowth through mechanotransduction-mediated signaling of the ERK1/2-CREB-Trx-1 pathway. The combination of LIPUS and NGF could potentially be used for the treatment of nerve injury and neurodegenerative diseases. Copyright © 2016 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

CD25 and CD69 induction by α4β1 outside-in signalling requires TCR early signalling complex proteins

PubMed Central

Cimo, Ann-Marie; Ahmed, Zamal; McIntyre, Bradley W.; Lewis, Dorothy E.; Ladbury, John E.

2013-01-01

Distinct signalling pathways producing diverse cellular outcomes can utilize similar subsets of proteins. For example, proteins from the TCR (T-cell receptor) ESC (early signalling complex) are also involved in interferon-α receptor signalling. Defining the mechanism for how these proteins function within a given pathway is important in understanding the integration and communication of signalling networks with one another. We investigated the contributions of the TCR ESC proteins Lck (lymphocyte-specific kinase), ZAP-70 (ζ-chain-associated protein of 70 kDa), Vav1, SLP-76 [SH2 (Src homology 2)-domain-containing leukocyte protein of 76 kDa] and LAT (linker for activation of T-cells) to integrin outside-in signalling in human T-cells. Lck, ZAP-70, SLP-76, Vav1 and LAT were activated by α4β1 outside-in signalling, but in a manner different from TCR signalling. TCR stimulation recruits ESC proteins to activate the mitogen-activated protein kinase ERK (extracellular-signal-regulated kinase). α4β1 outside-in-mediated ERK activation did not require TCR ESC proteins. However, α4β1 outside-in signalling induced CD25 and co-stimulated CD69 and this was dependent on TCR ESC proteins. TCR and α4β1 outside-in signalling are integrated through the common use of TCR ESC proteins; however, these proteins display functionally distinct roles in these pathways. These novel insights into the cross-talk between integrin outside-in and TCR signalling pathways are highly relevant to the development of therapeutic strategies to overcome disease associated with T-cell deregulation. PMID:23758320

[Study of the effect of JNK signal transduction pathway in intense noise-induced apoptosis in cochlea of guinea pig].

PubMed

Xue, Qiuhong; Chen, Jia; Gong, Shusheng; Xie, Jing; He, Jian; Chen, Xiaolin

2009-12-01

To investigate the mechanism of intense noise-induced cochlea cells death in guinea pig, and the effect of JNK signal transduction pathway in the procedure of cochlea cells apoptosis by intense noise-induced. Thirty-two guinea pigs were randomly divided into 4 groups. The guinea pigs in the experiment groups were exposed to 4 kHz narrow band noise at 120 dB SPL for 4 h. After the noise expose for 1, 4, 14 days of the experiment guinea pigs, ABR of the guinea pigs on experiment and control groups were tested before put them to death. Four guinea pig's cochleas of every group were taken to paraffin section, and the rest was extracted the total cochlear's protein. Apoptosis was tested by terminal deoxynucleotidyl Transferase (TdT)-mediated deoxyuridine triphosphate (d-UTP) nick and labeling method (TUNEL). The phosphorylation of JNK and c-Jun were tested by immunohistochemistry and western blot methods. Tunel-Positive cells in the Corti's, SGC and SV of experiment groups, and there have significant differences compared with the control group (P<0.01) and Tunel-Positive cells are most in 1 d experiment group. The positive cells of P-JNK and P-c-Jun could be detected in guinea pig's cochleas after noise exposed, but no positive cells were found in the control. Protein levels of P-JNK and P-c-Jun were risen up and activated quickly after noise exposed, and achieved peak in 1 d, 4 d and then fallen-offs, but still maintained higher levels within 14 d. Intense noise causes cochlea cell lesion by inducing apoptosis to result in and JNK signal transduction pathway plays an important role in the procedure of apoptosis.

CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

PubMed Central

Lindquist, Jonathan A.; Arhel, Nathalie; Felder, Edward; Karl, Sabine; Haas, Tobias L.; Fulda, Simone; Walczak, Henning; Kirchhoff, Frank; Debatin, Klaus-Michael

2009-01-01

CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain–associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion. PMID:19487421

PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation.

PubMed

Platonova, Natalia; Manzo, Teresa; Mirandola, Leonardo; Colombo, Michela; Calzavara, Elisabetta; Vigolo, Emilia; Cermisoni, Greta Chiara; De Simone, Daria; Garavelli, Silvia; Cecchinato, Valentina; Lazzari, Elisa; Neri, Antonino; Chiaramonte, Raffaella

2015-06-06

The pathways of NOTCH and PI3K/AKT are dysregulated in about 60% and 48% of T-cell acute lymphoblastic leukemia (T-ALL) patients, respectively. In this context, they interact and cooperate in controlling tumor cell biology. Here, we propose a novel mechanism by which the PI3K/AKT pathway regulates NOTCH1 in T-ALL, starting from the evidence that the inhibition of PI3K/AKT signaling induced by treatment with LY294002 or transient transfection with a dominant negative AKT mutant downregulates NOTCH1 protein levels and activity, without affecting NOTCH1 transcription. We showed that the withdrawal of PI3K/AKT signaling was associated to NOTCH1 phosphorylation in tyrosine residues and monoubiquitination of NOTCH1 detected by Ubiquitin capture assay. Co-immunoprecipitation assay and colocalization analysis further showed that the E3 ubiquitin ligase c-Cbl interacts and monoubiquitinates NOTCH1, activating its lysosomal degradation. These results suggest that the degradation of NOTCH1 could represent a mechanism of control by which NOTCH1 receptors are actively removed from the cell surface. This mechanism is finely regulated by the PI3K/AKT pathway in physiological conditions. In pathological conditions characterized by PI3K/AKT hyperactivation, such as T-ALL, the excessive AKT signaling could lead to NOTCH1 signaling dysregulation. Therefore, a therapeutic strategy directed to PI3K/AKT in T-ALL could contemporaneously inhibit the dysregulated NOTCH1 signaling. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Ultra-low field T1 vs. T1rho at 3T and 7T: study of rotationally immobilized protein gels and animal brain tissues

NASA Astrophysics Data System (ADS)

Dong, Hui; Inglis, Ben; Barr, Ian; Clarke, John

2015-03-01

Clinical magnetic resonance imaging (MRI) machines operating in static fields of typically 1.5 T or 3 T can capture information on slow molecular dynamics utilizing the so-called T1rho technique. This technique, in which a radiofrequency (RF) spin-lock field is applied with microtesla amplitude, has been used, for example, to determine the onset time of stroke in studies on rats. The long RF pulse, however, may exceed the specific absorption rate (SAR) limit, putting subjects at risk. Ultra-low-field (ULF) MRI, based on Superconducting Quantum Interference Devices (SQUIDs), directly detects proton signals at a static magnetic field of typically 50-250 μT. Using our ULF MRI system with adjustable static field of typically 55 to 240 μT, we systematically measured the T1 and T2 dispersion profiles of rotationally immobilized protein gels (bovine serum albumin), ex vivo pig brains, and ex vivo rat brains with induced stroke. Comparing the ULF results with T1rho dispersion obtained at 3 T and 7 T, we find that the degree of protein immobilization determines the frequency-dependence of both T1 and T1rho. Furthermore, T1rho and ULF T1 show similar results for stroke, suggesting that ULF MRI may be used to image traumatic brain injury with negligible SAR. This research was supported by the Henry H. Wheeler, Jr. Brain Imaging Center and the Donaldson Trust.

Simple Carotid-Sparing Intensity-Modulated Radiotherapy Technique and Preliminary Experience for T1-2 Glottic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenthal, David I., E-mail: dirosenthal@mdanderson.or; Fuller, Clifton D.; Barker, Jerry L.

2010-06-01

Purpose: To investigate the dosimetry and feasibility of carotid-sparing intensity-modulated radiotherapy (IMRT) for early glottic cancer and to report preliminary clinical experience. Methods and Materials: Digital Imaging and Communications in Medicine radiotherapy (DICOM-RT) datasets from 6 T1-2 conventionally treated glottic cancer patients were used to create both conventional IMRT plans. We developed a simplified IMRT planning algorithm with three fields and limited segments. Conventional and IMRT plans were compared using generalized equivalent uniform dose and dose-volume parameters for in-field carotid arteries, target volumes, and organs at risk. We have treated 11 patients with this simplified IMRT technique. Results: Intensity-modulated radiotherapymore » consistently reduced radiation dose to the carotid arteries (p < 0.05) while maintaining the clinical target volume coverage. With conventional planning, median carotid V35, V50, and V63 were 100%, 100%, and 69.0%, respectively. With IMRT planning these decreased to 2%, 0%, and 0%, respectively (p < 0.01). Radiation planning and treatment times were similar for conventional radiotherapy and IMRT. Treatment results have been excellent thus far. Conclusions: Intensity-modulated radiotherapy significantly reduced unnecessary radiation dose to the carotid arteries compared with conventional lateral fields while maintaining clinical target volume coverage. Further experience and longer follow-up will be required to demonstrate outcomes for cancer control and carotid artery effects.« less

Radiological changes with magnetic resonance imaging and computed tomography after irradiating minipig mandibles: The role of T2-SPIR mixed signal intensities in the detection of osteoradionecrosis.

PubMed

Poort, Lucas J; Postma, Alida A; Stadler, Annika A R; Böckmann, Roland A; Hoebers, Frank J; Kessler, Peter A W H

2017-05-01

Radiotherapy in the head and neck can induce several radiologically detectable changes in bone, osteoradionecrosis (ORN) among them. The purpose is to investigate radiological changes in mandibular bone after irradiation with various doses with and without surgery and to determine imaging characteristics of radiotherapy and ORN in an animal model. Sixteen Göttingen minipigs were divided into groups and were irradiated with two fractions with equivalent doses of 0, 25, 50 and 70 Gray. Thirteen weeks after irradiation, left mandibular teeth were removed and dental implants were placed. CT-scans and MR-imaging were made before irradiation and twenty-six weeks after. Alterations in the bony structures were recorded on CT-scan and MR-imaging and scored by two head-neck radiologists. Increased signal changes on MR-imaging were associated with higher radiation doses. Two animals developed ORN clinically. Radiologically mixed signal intensities on T2-SPIR were seen. On CT-scans cortical destruction was found in three animals. Based on imaging, three animals were diagnosed with ORN. Irradiation of minipig mandibles with various doses induced damages of the mandibular bone. Imaging with CT-scan and MR-imaging showed signal and structural changes that can be interpreted as prolonged and insufficient repair of radiation induced bone damages. Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

IFNγ Signaling Endows DCs with the Capacity to Control Type I Inflammation during Parasitic Infection through Promoting T-bet+ Regulatory T Cells

PubMed Central

Lee, Hyang-Mi; Fleige, Anne; Forman, Ruth; Cho, Sunglim; Khan, Aly Azeem; Lin, Ling-Li; Nguyen, Duc T.; O'Hara-Hall, Aisling; Yin, Zhinan; Hunter, Christopher A.; Muller, Werner; Lu, Li-Fan

2015-01-01

IFNγ signaling drives dendritic cells (DCs) to promote type I T cell (Th1) immunity. Here, we show that activation of DCs by IFNγ is equally crucial for the differentiation of a population of T-bet+ regulatory T (Treg) cells specialized to inhibit Th1 immune responses. Conditional deletion of IFNγ receptor in DCs but not in Treg cells resulted in a severe defect in this specific Treg cell subset, leading to exacerbated immune pathology during parasitic infections. Mechanistically, IFNγ-unresponsive DCs failed to produce sufficient amount of IL-27, a cytokine required for optimal T-bet induction in Treg cells. Thus, IFNγ signalling endows DCs with the ability to efficiently control a specific type of T cell immunity through promoting a corresponding Treg cell population. PMID:25658840

Magnetic resonance T1 gradient-echo imaging in hepatolithiasis.

PubMed

Safar, F; Kamura, T; Okamuto, K; Sasai, K; Gejyo, F

2005-01-01

We examined the role of magnetic resonance T1-weighted gradient-echo (MRT1-GE) imaging in hepatolithiasis. MRT1-GE, precontrast computed tomography (CT), and magnetic resonance cholangiopancreatography (MRCP) of 10 patients with hepatolithiasis were compared for their diagnostic accuracies in the detection and localization of intrahepatic calculi. The diagnosis of hepatolithiasis was confirmed by surgery. For localization of the stone, we divided the bile ducts into six areas: right and left hepatic ducts and bile ducts of the lateral, medial, right anterior, and right posterior segments of the liver. Chemical analysis of the stones was performed in eight patients. The total number of segments proved by surgery to contain stones was 18. Although not significantly different, the sensitivity of MRT1-GE was 77.8% (14 of 18 segments), higher than that of MRCP (66.7%, 12 of 18 segments) and that of CT (50%, nine of 18 segments). The sensitivity of magnetic resonance imaging (MRCP + MRT1) was significantly higher than that of CT (p < 0.01). Multiple logistic regression analysis showed that the result of surgery was significantly affected only by the result of magnetic resonance imaging. On MRT1-GE, all the depicted stones appeared as high-intensity signal areas within the low-intensity bile duct irrespective of their chemical composition. MRT1-GE imaging provides complementary information concerning hepatolithiasis.

Cortical pathology in multiple sclerosis detected by the T1/T2‐weighted ratio from routine magnetic resonance imaging

PubMed Central

Righart, Ruthger; Biberacher, Viola; Jonkman, Laura E.; Klaver, Roel; Schmidt, Paul; Buck, Dorothea; Berthele, Achim; Kirschke, Jan S.; Zimmer, Claus; Hemmer, Bernhard; Geurts, Jeroen J. G.

2017-01-01

Objective In multiple sclerosis, neuropathological studies have shown widespread changes in the cerebral cortex. In vivo imaging is critical, because the histopathological substrate of most measurements is unknown. Methods Using a novel magnetic resonance imaging analysis technique, based on the ratio of T1‐ and T2‐weighted signal intensities, we studied the cerebral cortex of a large cohort of patients in early stages of multiple sclerosis. A total of 168 patients with clinically isolated syndrome or relapsing–remitting multiple sclerosis (Expanded Disability Status Scale: median = 1, range = 0–3.5) and 80 age‐ and sex‐matched healthy controls were investigated. We also searched for the histopathological substrate of the T1/T2‐weighted ratio by combining postmortem imaging and histopathology in 9 multiple sclerosis brain donors. Results Patients showed lower T1/T2‐weighted ratio values in parietal and occipital areas. The 4 most significant clusters appeared in the medial occipital and posterior cingulate cortex (each left and right). The decrease of the T1/T2‐weighted ratio in the posterior cingulate was related to performance in attention. Analysis of the T1/T2‐weighted ratio values of postmortem imaging yielded a strong correlation with dendrite density but none of the other parameters including myelin. Interpretation The T1/T2‐weighted ratio decreases in early stages of multiple sclerosis in a widespread manner, with a preponderance of posterior areas and with a contribution to attentional performance; it seems to reflect dendrite pathology. As the method is broadly available and applicable to available clinical scans, we believe that it is a promising candidate for studying and monitoring cortical pathology or therapeutic effects in multiple sclerosis. Ann Neurol 2017;82:519–529 PMID:28833433

The fast track to canonical Wnt signaling in MC3T3-E1 cells protected by substance P against serum deprivation-induced apoptosis.

PubMed

Yang, Jianguo; Nie, Jiping; Fu, Su; Liu, Song; Wu, Jianqun; Cui, Liang; Zhang, Yongtao; Yu, Bin

2017-01-01

The canonical Wnt pathway is vital to bone physiology by increasing bone mass through elevated osteoblast survival. Although investigated extensively in stem cells, its role in osteoblastic MC3T3-E1 cells has not been completely determined. To explore how this pathway is regulated by different conditions, we assessed the anti-apoptotic effects of substance P on the canonical Wnt pathway in MC3T3-E1 cells by treating cells with serum deprivation or serum starving with "substance P," a neuropeptide demonstrated to promote bone growth and stimulate Wnt signaling. The results showed that serum deprivation both induced apoptosis and activated Wnt signal transduction while substance P further stimulated the Wnt pathway via the NK-1 receptor but protected the cells from apoptotic death. Fast-tracking of Wnt signaling by substance P was also noted. These results indicate that nutritional deprivation and substance P synergistically activated the canonical Wnt pathway, a finding that helps to reveal the role of Wnt signaling in bone physiology affected by nutritional deprivation and neuropeptide substance P. © 2016 International Federation for Cell Biology.

Diffusion tensor imaging and T2 mapping in early denervated skeletal muscle in rats.

PubMed

Ha, Dong-Ho; Choi, Sunseob; Kang, Eun-Ju; Park, Hwan Tae

2015-09-01

To evaluate the temporal changes of diffusion tensor imaging (DTI) indices, T2 values, and visual signal intensity on various fat suppression techniques in the early state of denervated skeletal muscle in a rat model. Institutional Animal Care and Use Committee approval was obtained. Sciatic nerves of eight rats were transected for irreversible neurotmesis model. We examined normal lower leg and denervated muscles at 3 days, 1 week, and 2 weeks on a 3 Tesla MR. fractional anisotropy (FA), mean apparent diffusion coefficient (mADC), and T2 values were measured by using DTI and T2 mapping scan. We subjectively classified the signal intensity change on various fat suppression images into the following three grades: negative, suspicious, and definite change. Wilcoxon-sign rank test and Kruskal-Wallis test were used for the comparison of FA, mADC, T2 values. McNemar's test was used for comparing signal intensity change among fat suppression techniques. FA values of denervated muscles at 3 days (0.35 ± 0.06), 1 week (0.29 ± 0.04), and 2 weeks (0.34 ± 0.05) were significantly (P < 0.05) lower than that in the control group (0.54 ± 0.17). mADC of denervated muscles decreased without statistically significant (P > 0.05) change. T2 values were significantly increased at 1 week (38.11 ± 6.42 ms, P = 0.017) and markedly increased at 2 weeks (46.53 ± 5.17 ms, P = 0.012). The grade of visual signal intensity change on chemical shift selective fat saturation, STIR and IDEAL images were identical in all cases (P = 1.000). FA and T2 values can demonstrate the early temporal changes in denervated rat skeletal muscle. © 2014 Wiley Periodicals, Inc.

Mechanism and function of Vav1 localisation in TCR signalling.

PubMed

Ksionda, Olga; Saveliev, Alexander; Köchl, Robert; Rapley, Jonathan; Faroudi, Mustapha; Smith-Garvin, Jennifer E; Wülfing, Christoph; Rittinger, Katrin; Carter, Tom; Tybulewicz, Victor L J

2012-11-15

The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signalling proteins to microclusters at the cell-cell interface known as the immunological synapse (IS). The Vav1 guanine nucleotide exchange factor plays a critical role in T cell antigen receptor (TCR) signalling, leading to the activation of multiple pathways. We now show that it is recruited to microclusters and to the IS in primary CD4(+) and CD8(+) T cells. Furthermore, we show that this recruitment depends on the SH2 and C-terminal SH3 (SH3(B)) domains of Vav1, and on phosphotyrosines 112 and 128 of the SLP76 adaptor protein. Biophysical measurements show that Vav1 binds directly to these residues on SLP76 and that efficient binding depends on the SH2 and SH3(B) domains of Vav1. Finally, we show that the same two domains are critical for the phosphorylation of Vav1 and its signalling function in TCR-induced calcium flux. We propose that Vav1 is recruited to the IS by binding to SLP76 and that this interaction is critical for the transduction of signals leading to calcium flux.

SDF-1 signaling via the CXCR4-TCR heterodimer requires PLC-β3 and PLC-γ1 for distinct cellular responses 1

PubMed Central

Kremer, Kimberly N.; Clift, Ian C.; Miamen, Alexander G.; Bamidele, Adebowale O.; Qian, Nan-Xin; Humphreys, Troy D.; Hedin, Karen E.

2011-01-01

The CXCR4 chemokine receptor is a G protein-coupled receptor (GPCR) that signals in T lymphocytes by forming a heterodimer with the T cell antigen receptor (TCR). CXCR4 and TCR functions are consequently highly cross-regulated, affecting T cell immune activation, cytokine secretion, and T cell migration. The CXCR4-TCR heterodimer stimulates T cell migration and activation of the ERK MAP kinase and downstream AP-1-dependent cytokine transcription in response to SDF-1, the sole chemokine ligand of CXCR4. These responses require Gi-type G proteins as well as TCR ITAM domains and the ZAP-70 tyrosine kinase, thus indicating that the CXCR4-TCR heterodimer signals to integrate GPCR-associated and TCR-associated signaling molecules in response to SDF-1. Yet, the phospholipase C (PLC) isozymes responsible for coupling the CXCR4-TCR heterodimer to distinct downstream cellular responses are incompletely characterized. Here, we demonstrate that PLC activity is required for SDF-1 to induce ERK activation, migration, and CXCR4 endocytosis in human T cells. SDF-1 signaling via the CXCR4-TCR heterodimer uses PLC-β3 to activate the Ras-ERK pathway and increase intracellular Ca2+ concentrations, while PLC-γ1 is dispensable for these outcomes. In contrast, PLC-γ1, but not PLC-β3, is required for SDF-1-mediated migration, via a mechanism independent of LAT. These results increase understanding of the signaling mechanisms employed by the CXCR4-TCR heterodimer, characterize new roles for PLC-β3 and PLC-γ1 in T cells, and suggest that multiple PLCs may also be activated downstream of other chemokine receptors in order to distinctly regulate migration versus other signaling functions. PMID:21705626

S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3

PubMed Central

Priceman, Saul J.; Shen, Shudan; Wang, Lin; Deng, Jiehui; Yue, Chanyu; Kujawski, Maciej; Yu, Hua

2014-01-01

Summary S1PR1 signaling has been shown to restrain the number and function of Tregs in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8+ T cell recruitment and activation, and promotes tumor growth. S1PR1 intrinsic in T cells affects Tregs, but not CD8+ T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. We further investigated the molecular mechanism(s) underlying S1PR1-mediated Treg accumulation in tumors, showing that increasing S1PR1 in CD4+ T cells promotes STAT3 activation and JAK/STAT3-dependent Treg tumor migration. Furthermore functionally ablating STAT3 in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast of the consequences by the same signaling receptor, namely S1PR1, in regulating Tregs in the periphery and in tumors. PMID:24630990

Sepsis-induced alteration in T-cell Ca(2+) signaling in neonatal rats.

PubMed

Alattar, M H; Ravindranath, T M; Choudhry, M A; Muraskas, J K; Namak, S Y; Dallal, O; Sayeed, M M

2001-01-01

Sepsis-induced suppression in T-cell proliferation follows deranged Ca(2+) signaling in adult rats. In preliminary studies, we observed suppression in T-cell proliferation in septic neonatal rats as well. In this study, we assessed splenic T-cell cytosolic Ca(2+) concentration, [Ca(2+)](i), as its elevation plays an important role in T-cell proliferation. Also, we investigated the role of PGE(2) in sepsis-related changes in T-cell [Ca(2+)](i) in animals pretreated with cyclooxygenase-1 (COX-1) inhibitor (resveratrol) and cyclooxygenase-2 (COX-2) inhibitor (NS-398). Sepsis was induced in 15-day-old rat pups by intraperitoneal implantation of fecal pellets containing Escherichia coli and Bacteroides fragilis. The sham group consisted of pups implanted with sterile fecal pellets. Septic and sham pups were sacrificed 24 h after implantation and their spleens were removed. The spleens from sham and septic pups, along with spleens from unoperated control pups, were processed for single cell suspensions, and T cells were isolated using nylon wool columns. Fura-2 fluorophotometry was employed for the measurement of [Ca(2+)](i) (in nM units) in T cells stimulated with concanavalin A (ConA). Our results show that ConA-mediated T-cell [Ca(2+)](i) response is significantly suppressed in septic neonatal rats. Pretreatment of pups with COX-2, but not COX-1 inhibitor, prevented the decrease in the [Ca(2+)](i) response. These findings suggest that PGE(2) might induce the attenuation in T-cell Ca(2+) signaling during sepsis in neonatal rats. Copyright 2001 S. Karger AG, Basel

4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors

PubMed Central

Long, Adrienne H.; Haso, Waleed M.; Shern, Jack F.; Wanhainen, Kelsey M.; Murgai, Meera; Ingaramo, Maria; Smith, Jillian P.; Walker, Alec J.; Kohler, M. Eric; Venkateshwara, Vikas R.; Kaplan, Rosandra N.; Patterson, George H.; Fry, Terry J.; Orentas, Rimas J.; Mackall, Crystal L.

2015-01-01

Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic anti-tumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We discovered that tonic CAR CD3ζ phosphorylation, triggered by antigen-independent clustering of CAR scFvs, can induce early exhaustion of CAR T cells that limits anti-tumor efficacy. Such activation is present to varying degrees in all CARs studied, with the exception of the highly effective CD19 CAR. We further identify that CD28 costimulation augments, while 4-1BB costimulation ameliorates, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the dramatic anti-tumor effects of CD19 CARs and for the observations that CD19.BBz CAR T cells are more persistent than CD19.28z CAR T cells in clinical trials. PMID:25939063

Evaluation of neonatal brain myelination using the T1- and T2-weighted MRI ratio.

PubMed

Soun, Jennifer E; Liu, Michael Z; Cauley, Keith A; Grinband, Jack

2017-09-01

To validate the T1- and T2-weighted (T1w/T2w) MRI ratio technique in evaluating myelin in the neonatal brain. T1w and T2w MR images of 10 term neonates with normal-appearing brain parenchyma were obtained from a single 1.5 Tesla MRI and retrospectively analyzed. T1w/T2w ratio images were created with a postprocessing pipeline and qualitatively compared with standard clinical sequences (T1w, T2w, and apparent diffusion coefficient [ADC]). Quantitative assessment was also performed to assess the ratio technique in detecting areas of known myelination (e.g., posterior limb of the internal capsule) and very low myelination (e.g., optic radiations) using linear regression analysis and the Michelson Contrast equation, a measure of luminance contrast intensity. The ratio image provided qualitative improvements in the ability to visualize regional variation in myelin content of neonates. Linear regression analysis demonstrated a significant inverse relationship between the ratio intensity values and ADC values in the posterior limb of the internal capsule and the optic radiations (R 2  = 0.96 and P < 0.001). The Michelson Contrast equation showed that contrast differences between these two regions for the ratio images were 1.6 times higher than T1w, 2.6 times higher than T2w, and 1.8 times higher than ADC (all P < 0.001). Finally, the ratio improved visualization of the corticospinal tract, one of the earliest myelinated pathways. The T1w/T2w ratio accentuates contrast between myelinated and less myelinated structures and may enhance our diagnostic ability to detect myelination patterns in the neonatal brain. 2 Technical Efficacy: Stage2 J. MAGN. RESON. IMAGING 2017;46:690-696. © 2016 International Society for Magnetic Resonance in Medicine.

Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy

PubMed Central

Shi, Lewis Zhichang; Fu, Tihui; Guan, Baoxiang; Chen, Jianfeng; Blando, Jorge M.; Allison, James P.; Xiong, Liangwen; Subudhi, Sumit K.; Gao, Jianjun; Sharma, Padmanee

2016-01-01

Combination therapy with α-CTLA-4 and α-PD-1 has shown significant clinical responses in different types of cancer. However, the underlying mechanisms remain elusive. Here, combining detailed analysis of human tumour samples with preclinical tumour models, we report that concomitant blockade of CTLA-4 and PD-1 improves anti-tumour immune responses and synergistically eradicates tumour. Mechanistically, combination therapy relies on the interdependence between IL-7 and IFN-γ signalling in T cells, as lack of either pathway abrogates the immune-boosting and therapeutic effects of combination therapy. Combination treatment increases IL-7Rα expression on tumour-infiltrating T cells in an IFN-γ/IFN-γR signalling-dependent manner, which may serve as a potential biomarker for clinical trials with immune checkpoint blockade. Our data suggest that combining immune checkpoint blockade with IL-7 signalling could be an effective modality to improve immunotherapeutic efficacy. Taken together, we conclude that combination therapy potently reverses immunosuppression and eradicates tumours via an intricate interplay between IFN-γ/IFN-γR and IL-7/IL-7R pathways. PMID:27498556

Inter- and Intra-individual Variability in Response to Transcranial Direct Current Stimulation (tDCS) at Varying Current Intensities.

PubMed

Chew, Taariq; Ho, Kerrie-Anne; Loo, Colleen K

2015-01-01

Translation of transcranial direct current stimulation (tDCS) from research to clinical practice is hindered by a lack of consensus on optimal stimulation parameters, significant inter-individual variability in response, and in sufficient intra-individual reliability data. Inter-individual differences in response to anodal tDCS at a range of current intensities were explored. Intra-individual reliability in response to anodal tDCS across two identical sessions was also investigated. Twenty-nine subjects participated in a crossover study. Anodal-tDCS using four different current intensities (0.2, 0.5, 1 and 2 mA), with an anode size of 16 cm2, was tested. The 0.5 mA condition was repeated to assess intra-individual variability. TMS was used to elicit 40 motor-evoked potentials (MEPs) before 10 min of tDCS, and 20 MEPs at four time-points over 30 min following tDCS. ANOVA revealed no main effect of TIME for all conditions except the first 0.5 mA condition, and no differences in response between the four current intensities. Cluster analysis identified two clusters for the 0.2 and 2 mA conditions only. Frequency distributions based on individual subject responses (excitatory, inhibitory or no response) to each condition indicate possible differential responses between individuals to different current intensities. Test-retest reliability was negligible (ICC(2,1) = -0.50). Significant inter-individual variability in response to tDCS across a range of current intensities was found. 2 mA and 0.2 mA tDCS were most effective at inducing a distinct response. Significant intra-individual variability in response to tDCS was also found. This has implications for interpreting results of single-session tDCS experiments. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation.

PubMed

Li, Yinghui; Zhou, Qi-Ling; Sun, Wenjie; Chandrasekharan, Prashant; Cheng, Hui Shan; Ying, Zhe; Lakshmanan, Manikandan; Raju, Anandhkumar; Tenen, Daniel G; Cheng, Shi-Yuan; Chuang, Kai-Hsiang; Li, Jun; Prabhakar, Shyam; Li, Mengfeng; Tergaonkar, Vinay

2015-10-01

Transcriptional reactivation of TERT, the catalytic subunit of telomerase, is necessary for cancer progression in about 90% of human cancers. The recent discovery of two prevalent somatic mutations-C250T and C228T-in the TERT promoter in various cancers has provided insight into a plausible mechanism of TERT reactivation. Although the two hotspot mutations create a similar binding motif for E-twenty-six (ETS) transcription factors, we show that they are functionally distinct, in that the C250T unlike the C228T TERT promoter is driven by non-canonical NF-κB signalling. We demonstrate that binding of ETS to the mutant TERT promoter is insufficient in driving its transcription but this process requires non-canonical NF-κB signalling for stimulus responsiveness, sustained telomerase activity and hence cancer progression. Our findings highlight a previously unrecognized role of non-canonical NF-κB signalling in tumorigenesis and elucidate a fundamental mechanism for TERT reactivation in cancers, which if targeted could have immense therapeutic implications.

HIV-1 Activates T Cell Signaling Independently of Antigen to Drive Viral Spread.

PubMed

Len, Alice C L; Starling, Shimona; Shivkumar, Maitreyi; Jolly, Clare

2017-01-24

HIV-1 spreads between CD4 T cells most efficiently through virus-induced cell-cell contacts. To test whether this process potentiates viral spread by activating signaling pathways, we developed an approach to analyze the phosphoproteome in infected and uninfected mixed-population T cells using differential metabolic labeling and mass spectrometry. We discovered HIV-1-induced activation of signaling networks during viral spread encompassing over 200 cellular proteins. Strikingly, pathways downstream of the T cell receptor were the most significantly activated, despite the absence of canonical antigen-dependent stimulation. The importance of this pathway was demonstrated by the depletion of proteins, and we show that HIV-1 Env-mediated cell-cell contact, the T cell receptor, and the Src kinase Lck were essential for signaling-dependent enhancement of viral dissemination. This study demonstrates that manipulation of signaling at immune cell contacts by HIV-1 is essential for promoting virus replication and defines a paradigm for antigen-independent T cell signaling. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Lipid rafts in T cell signalling and disease

PubMed Central

Jury, Elizabeth C.; Flores-Borja, Fabian; Kabouridis, Panagiotis S.

2007-01-01

Lipid rafts is a blanket term used to describe distinct areas in the plasma membrane rich in certain lipids and proteins and which are thought to perform diverse functions. A large number of studies report on lipid rafts having a key role in receptor signalling and activation of lymphocytes. In T cells, lipid raft involvement was demonstrated in the early steps during T cell receptor (TCR) stimulation. Interestingly, recent evidence has shown that signalling in these domains differs in T cells isolated from patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we discuss these findings and explore the potential of lipid rafts as targets for the development of a new class of agents to downmodulate immune responses and for the treatment of autoimmune diseases. PMID:17890113

Construction and 13C NMR signal-amplification efficiency of a dynamic nuclear polarizer at 6.4 T and 1.4 K

NASA Astrophysics Data System (ADS)

Kiswandhi, Andhika; Niedbalski, Peter; Parish, Christopher; Ferguson, Sarah; Taylor, David; McDonald, George; Lumata, Lloyd

Dissolution dynamic nuclear polarization (DNP) is a rapidly emerging technique in biomedical and metabolic imaging since it amplifies the liquid-state nuclear magnetic resonance (NMR) and imaging (MRI) signals by >10,000-fold. Originally used in nuclear scattering experiments, DNP works by creating a non-Boltzmann nuclear spin distribution by transferring the high electron (γ = 28,000 MHz/T) thermal polarization to the nuclear spins via microwave irradiation of the sample at high magnetic field and low temperature. A dissolution device is used to rapidly dissolve the frozen sample and consequently produces an injectable ``hyperpolarized'' liquid at physiologically-tolerable temperature. Here we report the construction and performance evaluation of a dissolution DNP hyperpolarizer at 6.4 T and 1.4 K using a continuous-flow cryostat. The solid and liquid-state 13C NMR signal enhancement levels of 13C acetate samples doped with trityl OX063 and 4-oxo-TEMPO free radicals will be discussed and compared with the results from the 3.35 T commercial hyperpolarizer. This work is supported by US Dept of Defense Award No. W81XWH-14-1-0048 and Robert A. Welch Foundation Grant No. AT-1877.

BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes.

PubMed

Xu, Qi; Luo, Jiao; Wu, Ning; Zhang, Renshuai; Shi, Dayong

2018-01-01

Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Mode 1 stress intensity factors for round compact specimens

NASA Technical Reports Server (NTRS)

Gross, B.

1976-01-01

The mode 1 stress intensity factors were computed for round compact specimens by the boundary collocation method. Results are presented for ratios A sub T/R sub 0 in the range 0.3 to 0.8, where A sub t is the distance from the specimen center to the crack tip for a specimen of diameter 2R sub 0.

Improving the Molecular Ion Signal Intensity for In Situ Liquid SIMS Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou, Yufan; Yao, Juan; Ding, Yuanzhao

In situ liquid secondary ion mass spectrometry (SIMS) enabled by system for analysis at the liquid vacuum interface (SALVI) has proven to be a promising new tool to provide molecular information at solid–liquid and liquid–vacuum interfaces. However, the initial data showed that useful signals in positive ion spectra are too weak to be meaningful in most cases. In addition, it is difficult to obtain strong negative molecular ion signals when m/z>200. These two drawbacks have been the biggest obstacle towards practical use of this new analytical approach. In this study, we report that strong and reliable positive and negative molecularmore » signals are achievable after optimizing the SIMS experimental conditions. Four model systems, including a 1,8-diazabicycloundec-7-ene (DBU)-base switchable ionic liquid, a live Shewanella oneidensis biofilm, a hydrated mammalian epithelia cell, and an electrolyte popularly used in Li ion batteries were studied. A signal enhancement of about two orders of magnitude was obtained in comparison with non-optimized conditions. Therefore, molecular ion signal intensity has become very acceptable to use for in situ liquid SIMS to study solid–liquid and liquid–vacuum interfaces.« less

Improving the Molecular Ion Signal Intensity for In Situ Liquid SIMS Analysis.

PubMed

Zhou, Yufan; Yao, Juan; Ding, Yuanzhao; Yu, Jiachao; Hua, Xin; Evans, James E; Yu, Xiaofei; Lao, David B; Heldebrant, David J; Nune, Satish K; Cao, Bin; Bowden, Mark E; Yu, Xiao-Ying; Wang, Xue-Lin; Zhu, Zihua

2016-12-01

In situ liquid secondary ion mass spectrometry (SIMS) enabled by system for analysis at the liquid vacuum interface (SALVI) has proven to be a promising new tool to provide molecular information at solid-liquid and liquid-vacuum interfaces. However, the initial data showed that useful signals in positive ion spectra are too weak to be meaningful in most cases. In addition, it is difficult to obtain strong negative molecular ion signals when m/z>200. These two drawbacks have been the biggest obstacle towards practical use of this new analytical approach. In this study, we report that strong and reliable positive and negative molecular signals are achievable after optimizing the SIMS experimental conditions. Four model systems, including a 1,8-diazabicycloundec-7-ene (DBU)-base switchable ionic liquid, a live Shewanella oneidensis biofilm, a hydrated mammalian epithelia cell, and an electrolyte popularly used in Li ion batteries were studied. A signal enhancement of about two orders of magnitude was obtained in comparison with non-optimized conditions. Therefore, molecular ion signal intensity has become very acceptable for use of in situ liquid SIMS to study solid-liquid and liquid-vacuum interfaces. Graphical Abstract ᅟ.

Technical aspects of MRI signal change quantification after gadolinium-based contrast agents' administration.

PubMed

Ramalho, Joana; Ramalho, Miguel; AlObaidy, Mamdoh; Semelka, Richard C

2016-12-01

Over the last 2years several studies have been published regarding gadolinium deposition in brain structures in patients with normal renal function after repeated administrations of gadolinium-based contrast agents (GBCAs). Most of the publications are magnetic resonance imaging (MRI) based retrospective studies, where gadolinium deposition may be indirectly measured by evaluating changes in T1 signal intensity (SI) in brain tissue, particularly in the dentate nucleus (DN) and/or globus pallidi (GP). The direct correlation between T1 signal changes and gadolinium deposition was validated by human pathology studies. However, the variability of the MR equipment and parameters used across different publications, along with the inherent limitations of MRI to assess gadolinium in human tissues should be acknowledged when interpreting those studies. Nevertheless, MRI studies remain essential regarding gadolinium bio-distribution knowledge. The aim of this paper is to overview current knowledge of technical aspects of T1 signal intensity evaluation by MRI and describe confounding factors, with the intention to achieve higher accuracy and maximize reproducibility. Copyright © 2016 Elsevier Inc. All rights reserved.

ESR signals in a core from the lake Baikal: implications for climate change

NASA Astrophysics Data System (ADS)

Toyoda, S.; Hidaka, K.; Takamatsu, N.

2002-12-01

Electron spin resonance dating method has been used for obtaining ages of Quaternary events using speleothem, corals, shells, hydroxyapatite in tooth enamel, gypsum, and quartz (Ikeya, 1993). Recently, it was also found that an ESR signal in quartz of loess is useful to discuss the variation of its origin (e. g. Ono et al., 1998). The method is based on the signal intensity of the heat treated (gamma ray irradiation and heating, Toyoda and Ikeya, 1991) E 1_f center (an unpaired electron at an oxygen vacancy) correlates the original (crystallization) age of quartz (e.g. Toyoda and Hattori, 2000). If there is variation in ages of basement rocks (origin of loess), ESR signal intensity may differentiate the origins. We applied the present method to sediments taken from the core of the lake Baikal with the length of 600m. The ESR intensity of the heat treated E1_f center was determined by an ESR measurement at room temperature for about 100 mg of the bulk samples, with a microwave power of 0.01 mW, field modulation amplitude of 0.1 mT, and with a scan range of 5 mT around g=2.001 after gamma ray irradiation to 1 kGy and subsequent heating at 300C. The ESR signal of the E1_f center was clearly observed although other minerals are also included in the bulk sample. The peak to peak height was taken as the signal intensity after normalizing the height with the gain (the instrumental setting at the time of measurement), mass, and the intensity of the standard simultaneously measured with the sample. The concentrations of the quartz in the bulk samples were obtained by the X ray diffraction study, normalizing the peak intensity with a standard CeO sample. The variation of the ESR signal intensity with depth of the core will be presented together with the possible climate change which may have caused the variation. References M. Ikeya (1993) New applications of electron spin resonance, dating, dosimetry and imaging, World Scientific. Y. Ono, T. Naruse, M. Ikeya, H. Kohno, and

A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control

PubMed Central

Stone, Jennifer D.; Harris, Daniel T.; Soto, Carolina M.; Chervin, Adam S.; Aggen, David H.; Roy, Edward J.; Kranz, David M.

2014-01-01

Adoptive transfer of genetically modified T cells to treat cancer has shown promise in several clinical trials. Two main strategies have been applied to redirect T cells against cancer: 1) introduction of a full-length T cell receptor (TCR) specific for a tumor-associated peptide-MHC, or 2) introduction of a chimeric antigen receptor (CAR), including an antibody fragment specific for a tumor cell surface antigen, linked intracellularly to T cell signaling domains. Each strategy has advantages and disadvantages for clinical applications. Here, we present data on the in vitro and in vivo effectiveness of a single-chain signaling receptor incorporating a TCR variable fragment as the targeting element (referred to as TCR-SCS). This receptor contained a single-chain TCR (Vβ-linker-Vα) from a high-affinity TCR called m33, linked to the intracellular signaling domains of CD28 and CD3ζ. This format avoided mispairing with endogenous TCR chains, and mediated specific T cell activity when expressed in either CD4 or CD8 T cells. TCR-SCS-transduced CD8-negative cells showed an intriguing sensitivity, compared to full-length TCRs, to higher densities of less stable pepMHC targets. T cells that expressed this peptide-specific receptor persisted in vivo, and exhibited polyfunctional responses. Growth of metastatic antigen-positive tumors was significantly inhibited by T cells that expressed this receptor, and tumor cells that escaped were antigen loss variants. TCR-SCS receptors represent an alternative targeting receptor strategy that combines the advantages of single-chain expression, avoidance of TCR chain mispairing, and targeting of intracellular antigens presented in complex with MHC proteins. PMID:25082071

Long-term reproducibility of phantom signal intensities in nonuniformity corrected STIR-MRI examinations of skeletal muscle.

PubMed

Viddeleer, Alain R; Sijens, Paul E; van Ooijen, Peter M A; Kuypers, Paul D L; Hovius, Steven E R; Oudkerk, Matthijs

2009-08-01

Nerve regeneration could be monitored by comparing MRI image intensities in time, as denervated muscles display increased signal intensity in STIR sequences. In this study long-term reproducibility of STIR image intensity was assessed under clinical conditions and the required image intensity nonuniformity correction was improved by using phantom scans obtained at multiple positions. Three-dimensional image intensity nonuniformity was investigated in phantom scans. Next, over a three-year period, 190 clinical STIR hand scans were obtained using a standardized acquisition protocol, and corrected for intensity nonuniformity by using the results of phantom scanning. The results of correction with 1, 3, and 11 phantom scans were compared. The image intensities in calibration tubes close to the hands were measured every time to determine the reproducibility of our method. With calibration, the reproducibility of STIR image intensity improved from 7.8 to 6.4%. Image intensity nonuniformity correction with 11 phantom scans gave significantly better results than correction with 1 or 3 scans. The image intensities in clinical STIR images acquired at different times can be compared directly, provided that the acquisition protocol is standardized and that nonuniformity correction is applied. Nonuniformity correction is preferably based on multiple phantom scans.

PKCθ links proximal T cell and Notch signaling through localized regulation of the actin cytoskeleton

PubMed Central

Britton, Graham J; Ambler, Rachel; Clark, Danielle J; Hill, Elaine V; Tunbridge, Helen M; McNally, Kerrie E; Burton, Bronwen R; Butterweck, Philomena; Sabatos-Peyton, Catherine; Hampton-O’Neil, Lea A; Verkade, Paul; Wülfing, Christoph; Wraith, David Cameron

2017-01-01

Notch is a critical regulator of T cell differentiation and is activated through proteolytic cleavage in response to ligand engagement. Using murine myelin-reactive CD4 T cells, we demonstrate that proximal T cell signaling modulates Notch activation by a spatiotemporally constrained mechanism. The protein kinase PKCθ is a critical mediator of signaling by the T cell antigen receptor and the principal costimulatory receptor CD28. PKCθ selectively inactivates the negative regulator of F-actin generation, Coronin 1A, at the center of the T cell interface with the antigen presenting cell (APC). This allows for effective generation of the large actin-based lamellum required for recruitment of the Notch-processing membrane metalloproteinase ADAM10. Such enhancement of Notch activation is critical for efficient T cell proliferation and Th17 differentiation. We reveal a novel mechanism that, through modulation of the cytoskeleton, controls Notch activation at the T cell:APC interface thereby linking T cell receptor and Notch signaling pathways. DOI: http://dx.doi.org/10.7554/eLife.20003.001 PMID:28112644

Sphingosine 1-phosphate (S1P)/S1P receptor 1 signaling regulates receptor activator of NF-{kappa}B ligand (RANKL) expression in rheumatoid arthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takeshita, Harunori; Kitano, Masayasu, E-mail: mkitano6@hyo-med.ac.jp; Iwasaki, Tsuyoshi

Highlights: Black-Right-Pointing-Pointer MH7A cells and CD4{sup +} T cells expressed S1P1 and RANKL. Black-Right-Pointing-Pointer S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells. Black-Right-Pointing-Pointer The effect of S1P in MH7A cells was inhibited by specific Gi/Go inhibitors. -- Abstract: Sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1P1) signaling plays an important role in synovial cell proliferation and inflammatory gene expression by rheumatoid arthritis (RA) synoviocytes. The purpose of this study is to clarify the role of S1P/S1P1 signaling in the expression of receptor activator of NF-{kappa}B ligand (RANKL) in RA synoviocytes and CD4{sup +} T cells. We demonstrated MH7Amore » cells, a human RA synovial cell line, and CD4{sup +} T cells expressed S1P1 and RANKL. Surprisingly, S1P increased RANKL expression in MH7A cells and CD4{sup +} T cells in a dose-dependent manner. Moreover, S1P enhanced RANKL expression induced by stimulation with TNF-{alpha} in MH7A cells and CD4{sup +} T cells. These effects of S1P in MH7A cells were inhibited by pretreatment with PTX, a specific Gi/Go inhibitor. These findings suggest that S1P/S1P1 signaling may play an important role in RANKL expression by MH7A cells and CD4{sup +} T cells. S1P/S1P1 signaling of RA synoviocytes is closely connected with synovial hyperplasia, inflammation, and RANKL-induced osteoclastogenesis in RA. Thus, regulation of S1P/S1P1 signaling may become a novel therapeutic target for RA.« less

Mechanism and function of Vav1 localisation in TCR signalling

PubMed Central

Ksionda, Olga; Saveliev, Alexander; Köchl, Robert; Rapley, Jonathan; Faroudi, Mustapha; Smith-Garvin, Jennifer E.; Wülfing, Christoph; Rittinger, Katrin; Carter, Tom; Tybulewicz, Victor L. J.

2012-01-01

Summary The antigen-specific binding of T cells to antigen presenting cells results in recruitment of signalling proteins to microclusters at the cell-cell interface known as the immunological synapse (IS). The Vav1 guanine nucleotide exchange factor plays a critical role in T cell antigen receptor (TCR) signalling, leading to the activation of multiple pathways. We now show that it is recruited to microclusters and to the IS in primary CD4+ and CD8+ T cells. Furthermore, we show that this recruitment depends on the SH2 and C-terminal SH3 (SH3B) domains of Vav1, and on phosphotyrosines 112 and 128 of the SLP76 adaptor protein. Biophysical measurements show that Vav1 binds directly to these residues on SLP76 and that efficient binding depends on the SH2 and SH3B domains of Vav1. Finally, we show that the same two domains are critical for the phosphorylation of Vav1 and its signalling function in TCR-induced calcium flux. We propose that Vav1 is recruited to the IS by binding to SLP76 and that this interaction is critical for the transduction of signals leading to calcium flux. PMID:22956543

Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways

PubMed Central

Lee, Jun Ho; Patel, Kalpesh; Tae, Hyun Jin; Lustig, Ana; Kim, Jie Wan; Mattson, Mark P.; Taub, Dennis D.

2014-01-01

Thymic atrophy occurs during normal aging, and is accelerated by exposure to chronic stressors that elevate glucocorticoid levelsand impair the naïve T cell output. The orexigenic hormone ghrelin was recently shown to attenuate age-associated thymic atrophy. Here, we report that ghrelin enhances the proliferation of murine CD4+ primary T cells and a CD4+ T-cell line. Ghrelin induced activation of the ERK1/2 and Akt signaling pathways, via upstream activation of phosphatidylinositol-3-kinase and protein kinase C, to enhance T-cell proliferation. Moreover, ghrelin induced expression of the cell cycle proteins cyclin D1, cyclin E, cyclin-dependent kinase 2 (CDK2) and retinoblastoma phosphorylation. Finally, ghrelin activated the above-mentioned signaling pathways and stimulated thymocyte proliferation in young and older mice in vivo. PMID:25447526

Signal intensity alteration within infrapatellar fat pad predicts knee replacement within 5 years: data from the Osteoarthritis Initiative.

PubMed

Wang, K; Ding, C; Hannon, M J; Chen, Z; Kwoh, C K; Lynch, J; Hunter, D J

2018-05-26

To investigate whether infrapatellar fat pad (IPFP) signal intensity (SI) alteration predicts the occurrence of knee replacement (KR) in knee osteoarthritis (OA) patients over 5 years. The subjects were selected from Osteoarthritis Initiative (OAI) study. Case knees (n = 127) were defined as those who received KR during 5 years follow-up visit. They were matched by gender, age and radiographic status with control knees (n = 127). We used T2-weighted MR images to measure IPFP SI alteration using a newly developed algorithm in MATLAB. The measurements were assessed at baseline (BL), T0 (the visit just before KR) and 1 year before T0 (T-1). Conditional logistic regression was used to analyse the associations between IPFP SI alterations and the risk of KR. Participants were mostly female (57%), with an average age of 63.7 years old and a mean body mass index (BMI) of 29.5 kg/m 2 . In multivariable analysis, the standard deviation (SD) of IPFP SI [sDev (IPFP)] and the ratio of high SI region volume to whole IPFP volume [Percentage (H)] measured at BL were significantly associated with increased risks of KR after adjustment for covariates. IPFP SI alterations measured at T-1 including sDev (IPFP), Percentage (H) and clustering effect of high SI [Clustering factor (H)] were significantly associated with higher risks of KR. All measurements were significantly associated with higher risks of KR at T0. IPFP SI is associated with the occurrence of KR suggesting it may play a role in end-stage knee OA. Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Loss of T-cadherin (CDH-13) regulates AKT signaling and desensitizes cells to apoptosis in melanoma.

PubMed

Bosserhoff, Anja K; Ellmann, Lisa; Quast, Annika S; Eberle, Juergen; Boyle, Glen M; Kuphal, Silke

2014-08-01

An understanding of signaling pathways is a basic requirement for the treatment of melanoma. Currently, kinases are at the center of melanoma therapies. According to our research, additional alternative molecules are equally important for development of melanoma. In this regard, cancer progression is, among other factors, driven by an altered adhesion via cadherins. For instance, the de-regulated expression of the adhesion molecule T-cadherin is found in various cancer types, including melanoma, and influences migration and invasion. T-cadherin is thought to affect cellular function largely through its signaling and not its adhesion properties because the molecule is anchored into the cell membrane by a glycosylphosphatidylinositol (GPI) moiety. However, detailed knowledge about the consequences of the loss of T-cadherin in melanoma is currently lacking. For this reason, we were interested in assessing which signaling pathways are initiated by T-cadherin. The tumor growth of subcutaneously injected T-cadherin-positive melanoma cells was diminished compared with T-cadherin-negative cells in nude mice. The difference in tumor volume was not due to decreased proliferation but rather due to increased apoptosis. After the expression of T-cadherin was induced, we detected V-AKT murine thymoma viral oncogene homolog (AKT) and FoxO3a hypophosphorylation accompanied by the downregulation of the antiapoptotic molecules BCL-2, BCL-x and Clusterin. Furthermore, we detected a diminished transcriptional activity of CREB and AP-1. We demonstrated that T-cadherin functions as a pro-apoptotic tumor suppressor that antagonizes AKT/CREB/AP-1/FoxO3a signaling, whereas NFκB, TCF/LEF and mTOR are not part of the T-cadherin signaling pathway. Notably, we found that the restoration of T-cadherin in melanoma cells causes sensitization to apoptosis induced by CD95/Fas antibody CH-11. © 2013 Wiley Periodicals, Inc.

Differential Regulation of ERK1/2 and mTORC1 Through T1R1/T1R3 in MIN6 Cells.

PubMed

Wauson, Eric M; Guerra, Marcy L; Dyachok, Julia; McGlynn, Kathleen; Giles, Jennifer; Ross, Elliott M; Cobb, Melanie H

2015-08-01

The MAPKs ERK1/2 respond to nutrients and other insulin secretagogues in pancreatic β-cells and mediate nutrient-dependent insulin gene transcription. Nutrients also stimulate the mechanistic target of rapamycin complex 1 (mTORC1) to regulate protein synthesis. We showed previously that activation of both ERK1/2 and mTORC1 in the MIN6 pancreatic β-cell-derived line by extracellular amino acids (AAs) is at least in part mediated by the heterodimeric T1R1/T1R3, a G protein-coupled receptor. We show here that AAs differentially activate these two signaling pathways in MIN6 cells. Pretreatment with pertussis toxin did not prevent the activation of either ERK1/2 or mTORC1 by AAs, indicating that G(I) is not central to either pathway. Although glucagon-like peptide 1, an agonist for a G(s-)coupled receptor, activated ERK1/2 well and mTORC1 to a small extent, AAs had no effect on cytosolic cAMP accumulation. Ca(2+) entry is required for ERK1/2 activation by AAs but is dispensable for AA activation of mTORC1. Pretreatment with UBO-QIC, a selective G(q) inhibitor, reduced the activation of ERK1/2 but had little effect on the activation of mTORC1 by AAs, suggesting a differential requirement for G(q). Inhibition of G(12/13) by the overexpression of the regulator of G protein signaling domain of p115 ρ-guanine nucleotide exchange factor had no effect on mTORC1 activation by AAs, suggesting that these G proteins are also not involved. We conclude that AAs regulate ERK1/2 and mTORC1 through distinct signaling pathways.

Differential Regulation of ERK1/2 and mTORC1 Through T1R1/T1R3 in MIN6 Cells

PubMed Central

Wauson, Eric M.; Guerra, Marcy L.; Dyachok, Julia; McGlynn, Kathleen; Giles, Jennifer; Ross, Elliott M.

2015-01-01

The MAPKs ERK1/2 respond to nutrients and other insulin secretagogues in pancreatic β-cells and mediate nutrient-dependent insulin gene transcription. Nutrients also stimulate the mechanistic target of rapamycin complex 1 (mTORC1) to regulate protein synthesis. We showed previously that activation of both ERK1/2 and mTORC1 in the MIN6 pancreatic β-cell-derived line by extracellular amino acids (AAs) is at least in part mediated by the heterodimeric T1R1/T1R3, a G protein-coupled receptor. We show here that AAs differentially activate these two signaling pathways in MIN6 cells. Pretreatment with pertussis toxin did not prevent the activation of either ERK1/2 or mTORC1 by AAs, indicating that Gi is not central to either pathway. Although glucagon-like peptide 1, an agonist for a Gs-coupled receptor, activated ERK1/2 well and mTORC1 to a small extent, AAs had no effect on cytosolic cAMP accumulation. Ca2+ entry is required for ERK1/2 activation by AAs but is dispensable for AA activation of mTORC1. Pretreatment with UBO-QIC, a selective Gq inhibitor, reduced the activation of ERK1/2 but had little effect on the activation of mTORC1 by AAs, suggesting a differential requirement for Gq. Inhibition of G12/13 by the overexpression of the regulator of G protein signaling domain of p115 ρ-guanine nucleotide exchange factor had no effect on mTORC1 activation by AAs, suggesting that these G proteins are also not involved. We conclude that AAs regulate ERK1/2 and mTORC1 through distinct signaling pathways. PMID:26168033

Quantitative signal intensity alteration in infrapatellar fat pad predict incident radiographic osteoarthritis: the Osteoarthritis Initiative.

PubMed

Wang, Kang; Ding, Changhai; Hannon, Michael J; Chen, Zhongshan; Kwoh, C Kent; Hunter, David J

2018-04-12

To determine if infrapatellar fat pad (IPFP) signal intensity (SI) measures are predictive of incident radiographic osteoarthritis (iROA) over 4 years in the OA Initiative (OAI) study. Case knees (n=355) defined by iROA were matched one-to-one by gender, age and radiographic status with control knees. T2-weighted MR images were assessed at P0 (the visit when iROA was found on radiograph), P-1 (1 year prior to P0) and baseline, and utilized to assess IPFP SI semi-automatically using MATLAB. Conditional logistic regression analyses were used to assess risk of iROA associated with IPFP SI alteration after adjustment for covariates. Participants were on average 60.2 years old, predominantly female (66.7%) and overweight (mean BMI: 28.3). Baseline IPFP measures including mean value and standard deviation of IPFP SI [Mean(IPFP), sDev(IPFP)] (HR, 95%CI: 5.2, 1.1 to 23.6 and 5.7, 2.2 to 14.5, respectively), mean value and standard deviation of IPFP high SI [Mean(H), sDev(H)] (HR, 95%CI: 3.3, 1.7 to 6.4 and 3.1, 1.3 to 7.7, respectively), median value and upper quartile value of IPFP high SI [Median(H), UQ(H)], and clustering effect of high SI [Clustering factor(H)] were associated with iROA during 4 years. All P-1 IPFP measures were associated with iROA after 12 months. P-0 IPFP SI measures were all associated with ROA. The quantitative segmentation of high signal in IPFP is confirming previous work based on semiquantitative assessment suggesting its predictive validity. The IPFP high SI alteration could be an important imaging biomarker to predict the occurrence of radiographic OA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

mTOR Complex 1 Signaling Regulates the Generation and Function of Central and Effector Foxp3+ Regulatory T Cells.

PubMed

Sun, Im-Hong; Oh, Min-Hee; Zhao, Liang; Patel, Chirag H; Arwood, Matthew L; Xu, Wei; Tam, Ada J; Blosser, Richard L; Wen, Jiayu; Powell, Jonathan D

2018-06-08

The mechanistic/mammalian target of rapamycin (mTOR) has emerged as a critical integrator of signals from the immune microenvironment capable of regulating T cell activation, differentiation, and function. The precise role of mTOR in the control of regulatory T cell (Treg) differentiation and function is complex. Pharmacologic inhibition and genetic deletion of mTOR promotes the generation of Tregs even under conditions that would normally promote generation of effector T cells. Alternatively, mTOR activity has been observed to be increased in Tregs, and the genetic deletion of the mTOR complex 1 (mTORC1)-scaffold protein Raptor inhibits Treg function. In this study, by employing both pharmacologic inhibitors and genetically altered T cells, we seek to clarify the role of mTOR in Tregs. Our studies demonstrate that inhibition of mTOR during T cell activation promotes the generation of long-lived central Tregs with a memory-like phenotype in mice. Metabolically, these central memory Tregs possess enhanced spare respiratory capacity, similar to CD8 + memory cells. Alternatively, the generation of effector Tregs (eTregs) requires mTOR function. Indeed, genetic deletion of Rptor leads to the decreased expression of ICOS and PD-1 on the eTregs. Overall, our studies define a subset of mTORC1 hi eTregs and mTORC1 lo central Tregs. Copyright © 2018 by The American Association of Immunologists, Inc.

Leucine Metabolism in T Cell Activation: mTOR Signaling and Beyond123

PubMed Central

Powell, Jonathan D; Hutson, Susan M

2016-01-01

In connection with the increasing interest in metabolic regulation of the immune response, this review discusses current advances in understanding the role of leucine and leucine metabolism in T lymphocyte (T cell) activation. T cell activation during the development of an immune response depends on metabolic reprogramming to ensure that sufficient nutrients and energy are taken up by the highly proliferating T cells. Leucine has been described as an important essential amino acid and a nutrient signal that activates complex 1 of the mammalian target of rapamycin (mTORC1), which is a critical regulator of T cell proliferation, differentiation, and function. The role of leucine in these processes is further discussed in relation to amino acid transporters, leucine-degrading enzymes, and other metabolites of leucine metabolism. A new model of T cell regulation by leucine is proposed and outlines a chain of events that leads to the activation of mTORC1 in T cells. PMID:27422517

Signal Transduction in T Cell Activation and Tolerance

DTIC Science & Technology

1993-01-01

chains and ’ chains may transduce different signals in intact T cells. These studies demonstrate that while c- deficient and c-containing TCR complexes...three independently derived pairs of CD45- and CD45+ murine T cell lymphomas, the CD45- expressing cells were consistently deficient in...D.B., Larsen, A. and Wilson, C.B. (1986) Reduced interferon-gamma mRNA levels in human neonates: Evidence for an intrinsic T cell deficiency yi 114

Intense acoustic bursts as a signal-enhancement mechanism in ultrasound-modulated optical tomography.

PubMed

Kim, Chulhong; Zemp, Roger J; Wang, Lihong V

2006-08-15

Biophotonic imaging with ultrasound-modulated optical tomography (UOT) promises ultrasonically resolved imaging in biological tissues. A key challenge in this imaging technique is a low signal-to-noise ratio (SNR). We show significant UOT signal enhancement by using intense time-gated acoustic bursts. A CCD camera captured the speckle pattern from a laser-illuminated tissue phantom. Differences in speckle contrast were observed when ultrasonic bursts were applied, compared with when no ultrasound was applied. When CCD triggering was synchronized with burst initiation, acoustic-radiation-force-induced displacements were detected. To avoid mechanical contrast in UOT images, the CCD camera acquisition was delayed several milliseconds until transient effects of acoustic radiation force attenuated to a satisfactory level. The SNR of our system was sufficiently high to provide an image pixel per acoustic burst without signal averaging. Because of the substantially improved SNR, the use of intense acoustic bursts is a promising signal enhancement strategy for UOT.

Early postnatal myelin content estimate of white matter via T1w/T2w ratio

NASA Astrophysics Data System (ADS)

Lee, Kevin; Cherel, Marie; Budin, Francois; Gilmore, John; Zaldarriaga Consing, Kirsten; Rasmussen, Jerod; Wadhwa, Pathik D.; Entringer, Sonja; Glasser, Matthew F.; Van Essen, David C.; Buss, Claudia; Styner, Martin

2015-03-01

To develop and evaluate a novel processing framework for the relative quantification of myelin content in cerebral white matter (WM) regions from brain MRI data via a computed ratio of T1 to T2 weighted intensity values. We employed high resolution (1mm3 isotropic) T1 and T2 weighted MRI from 46 (28 male, 18 female) neonate subjects (typically developing controls) scanned on a Siemens Tim Trio 3T at UC Irvine. We developed a novel, yet relatively straightforward image processing framework for WM myelin content estimation based on earlier work by Glasser, et al. We first co-register the structural MRI data to correct for motion. Then, background areas are masked out via a joint T1w and T2 foreground mask computed. Raw T1w/T2w-ratios images are computed next. For purpose of calibration across subjects, we first coarsely segment the fat-rich facial regions via an atlas co-registration. Linear intensity rescaling based on median T1w/T2w-ratio values in those facial regions yields calibrated T1w/T2wratio images. Mean values in lobar regions are evaluated using standard statistical analysis to investigate their interaction with age at scan. Several lobes have strongly positive significant interactions of age at scan with the computed T1w/T2w-ratio. Most regions do not show sex effects. A few regions show no measurable effects of change in myelin content change within the first few weeks of postnatal development, such as cingulate and CC areas, which we attribute to sample size and measurement variability. We developed and evaluated a novel way to estimate white matter myelin content for use in studies of brain white matter development.

A Robust Dynamic Heart-Rate Detection Algorithm Framework During Intense Physical Activities Using Photoplethysmographic Signals

PubMed Central

Song, Jiajia; Li, Dan; Ma, Xiaoyuan; Teng, Guowei; Wei, Jianming

2017-01-01

Dynamic accurate heart-rate (HR) estimation using a photoplethysmogram (PPG) during intense physical activities is always challenging due to corruption by motion artifacts (MAs). It is difficult to reconstruct a clean signal and extract HR from contaminated PPG. This paper proposes a robust HR-estimation algorithm framework that uses one-channel PPG and tri-axis acceleration data to reconstruct the PPG and calculate the HR based on features of the PPG and spectral analysis. Firstly, the signal is judged by the presence of MAs. Then, the spectral peaks corresponding to acceleration data are filtered from the periodogram of the PPG when MAs exist. Different signal-processing methods are applied based on the amount of remaining PPG spectral peaks. The main MA-removal algorithm (NFEEMD) includes the repeated single-notch filter and ensemble empirical mode decomposition. Finally, HR calibration is designed to ensure the accuracy of HR tracking. The NFEEMD algorithm was performed on the 23 datasets from the 2015 IEEE Signal Processing Cup Database. The average estimation errors were 1.12 BPM (12 training datasets), 2.63 BPM (10 testing datasets) and 1.87 BPM (all 23 datasets), respectively. The Pearson correlation was 0.992. The experiment results illustrate that the proposed algorithm is not only suitable for HR estimation during continuous activities, like slow running (13 training datasets), but also for intense physical activities with acceleration, like arm exercise (10 testing datasets). PMID:29068403

On the fallacy of quantitative segmentation for T1-weighted MRI

NASA Astrophysics Data System (ADS)

Plassard, Andrew J.; Harrigan, Robert L.; Newton, Allen T.; Rane, Swati; Pallavaram, Srivatsan; D'Haese, Pierre F.; Dawant, Benoit M.; Claassen, Daniel O.; Landman, Bennett A.

2016-03-01

T1-weighted magnetic resonance imaging (MRI) generates contrasts with primary sensitivity to local T1 properties (with lesser T2 and PD contributions). The observed signal intensity is determined by these local properties and the sequence parameters of the acquisition. In common practice, a range of acceptable parameters is used to ensure "similar" contrast across scanners used for any particular study (e.g., the ADNI standard MPRAGE). However, different studies may use different ranges of parameters and report the derived data as simply "T1-weighted". Physics and imaging authors pay strong heed to the specifics of the imaging sequences, but image processing authors have historically been more lax. Herein, we consider three T1-weighted sequences acquired the same underlying protocol (MPRAGE) and vendor (Philips), but "normal study-to-study variation" in parameters. We show that the gray matter/white matter/cerebrospinal fluid contrast is subtly but systemically different between these images and yields systemically different measurements of brain volume. The problem derives from the visually apparent boundary shifts, which would also be seen by a human rater. We present and evaluate two solutions to produce consistent segmentation results across imaging protocols. First, we propose to acquire multiple sequences on a subset of the data and use the multi-modal imaging as atlases to segment target images any of the available sequences. Second (if additional imaging is not available), we propose to synthesize atlases of the target imaging sequence and use the synthesized atlases in place of atlas imaging data. Both approaches significantly improve consistency of target labeling.

Regulation and function of mTOR signalling in T cell fate decision

PubMed Central

Chi, Hongbo

2012-01-01

The evolutionary conserved kinase mTOR couples cell growth and metabolism to environmental inputs in eukaryotes. T cells depend on mTOR signalling to integrate immune signals and metabolic cues for their proper maintenance and activation. Under steady-state conditions, mTOR is actively controlled by multiple inhibitory mechanisms, and this enforces normal T cell homeostasis. Antigen recognition by naïve CD4+ and CD8+ T cells triggers mTOR activation, which in turn programs their differentiation into functionally distinct lineages. This Review focuses on the signalling mechanisms of mTOR in T cell homeostatic and functional fates and therapeutic implications of targeting mTOR in T cells. PMID:22517423

Homeostatic Signals do not Drive Post-thymic T cell Maturation

PubMed Central

Houston, Evan G.; Boursalian, Tamar E.; Fink, Pamela J.

2012-01-01

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3-week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell’s responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property. PMID:22398309

Method for a detailed measurement of image intensity nonuniformity in magnetic resonance imaging.

PubMed

Wang, Deming; Doddrell, David M

2005-04-01

In magnetic resonance imaging (MRI), the MR signal intensity can vary spatially and this spatial variation is usually referred to as MR intensity nonuniformity. Although the main source of intensity nonuniformity arises from B1 inhomogeneity of the coil acting as a receiver and/or transmitter, geometric distortion also alters the MR signal intensity. It is useful on some occasions to have these two different sources be separately measured and analyzed. In this paper, we present a practical method for a detailed measurement of the MR intensity nonuniformity. This method is based on the same three-dimensional geometric phantom that was recently developed for a complete measurement of the geometric distortion in MR systems. In this paper, the contribution to the intensity nonuniformity from the geometric distortion can be estimated and thus, it provides a mechanism for estimation of the intensity nonuniformity that reflects solely the spatial characteristics arising from B1. Additionally, a comprehensive scheme for characterization of the intensity nonuniformity based on the new measurement method is proposed. To demonstrate the method, the intensity nonuniformity in a 1.5 T Sonata MR system was measured and is used to illustrate the main features of the method.

Minimisation of Signal Intensity Differences in Distortion Correction Approaches of Brain Magnetic Resonance Diffusion Tensor Imaging.

PubMed

Lee, Dong-Hoon; Lee, Do-Wan; Henry, David; Park, Hae-Jin; Han, Bong-Soo; Woo, Dong-Cheol

2018-04-12

To evaluate the effects of signal intensity differences between the b0 image and diffusion tensor imaging (DTI) in the image registration process. To correct signal intensity differences between the b0 image and DTI data, a simple image intensity compensation (SIMIC) method, which is a b0 image re-calculation process from DTI data, was applied before the image registration. The re-calculated b0 image (b0 ext ) from each diffusion direction was registered to the b0 image acquired through the MR scanning (b0 nd ) with two types of cost functions and their transformation matrices were acquired. These transformation matrices were then used to register the DTI data. For quantifications, the dice similarity coefficient (DSC) values, diffusion scalar matrix, and quantified fibre numbers and lengths were calculated. The combined SIMIC method with two cost functions showed the highest DSC value (0.802 ± 0.007). Regarding diffusion scalar values and numbers and lengths of fibres from the corpus callosum, superior longitudinal fasciculus, and cortico-spinal tract, only using normalised cross correlation (NCC) showed a specific tendency toward lower values in the brain regions. Image-based distortion correction with SIMIC for DTI data would help in image analysis by accounting for signal intensity differences as one additional option for DTI analysis. • We evaluated the effects of signal intensity differences at DTI registration. • The non-diffusion-weighted image re-calculation process from DTI data was applied. • SIMIC can minimise the signal intensity differences at DTI registration.

Mitochondria-derived hydrogen peroxide selectively enhances T cell receptor-initiated signal transduction.

PubMed

Gill, Tejpal; Levine, Alan D

2013-09-06

T cell receptor (TCR)-initiated signal transduction is reported to increase production of intracellular reactive oxygen species, such as superoxide (O2˙(-)) and hydrogen peroxide (H2O2), as second messengers. Although H2O2 can modulate signal transduction by inactivating protein phosphatases, the mechanism and the subcellular localization of intracellular H2O2 as a second messenger of the TCR are not known. The antioxidant enzyme superoxide dismutase (SOD) catalyzes the dismutation of highly reactive O2˙(-) into H2O2 and thus acts as an intracellular generator of H2O2. As charged O2˙(-) is unable to diffuse through intracellular membranes, cells express distinct SOD isoforms in the cytosol (Cu,Zn-SOD) and mitochondria (Mn-SOD), where they locally scavenge O2˙(-) leading to production of H2O2. A 2-fold organelle-specific overexpression of either SOD in Jurkat T cell lines increases intracellular production of H2O2 but does not alter the levels of intracellular H2O2 scavenging enzymes such as catalase, membrane-bound peroxiredoxin1 (Prx1), and cytosolic Prx2. We report that overexpression of Mn-SOD enhances tyrosine phosphorylation of TCR-associated membrane proximal signal transduction molecules Lck, LAT, ZAP70, PLCγ1, and SLP76 within 1 min of TCR cross-linking. This increase in mitochondrial H2O2 specifically modulates MAPK signaling through the JNK/cJun pathway, whereas overexpressing Cu,Zn-SOD had no effect on any of these TCR-mediated signaling molecules. As mitochondria translocate to the immunological synapse during TCR activation, we hypothesize this translocation provides the effective concentration of H2O2 required to selectively modulate downstream signal transduction pathways.

HIV-1 Nef limits communication between linker of activated T cells and SLP-76 to reduce formation of SLP-76-signaling microclusters following TCR stimulation.

PubMed

Abraham, Libin; Bankhead, Peter; Pan, Xiaoyu; Engel, Ulrike; Fackler, Oliver T

2012-08-15

Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1-infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef's ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76-signaling MCs.

Effects of Age, Gender and Hemispheric Location on T2 Hypointensity in the Pulvinar at 3T.

PubMed

White, Matthew L; Zhang, Yan; Helvey, Jason T; Yu, Fang; Omojola, Matthew F

2014-12-01

Pulvinar signal intensity decrease on T2-weighted images has been reported in some neurological abnormalities. We aimed to define the normal T2 signal hypointensity pattern present in the pulvinar to avoid erroneous radiological interpretation. One hundred and forty-two subjects (54 men and 88 women; age range 9-91 years) with unremarkable brain 3T MR findings were enrolled. MR images were analyzed with regard to signal intensity of the pulvinar relative to the thalamus on fluid attenuated inversion recovery images. Effects of age, gender and hemispheric location on the degree of T2 hypointensity were statistically analyzed. The statistical association was measured between the pattern of signal changes in the pulvinar region and that in the putamen and the globus pallidus. We detected a linear signal decrease in the pulvinar region with age. The male subjects had a more rapid decrease of signal with age than female subjects. The right pulvinar region had a higher chance of hypointensity compared to the left. A positive linear association was found when signal change from the pulvinar region was compared with signal in the putamen and globus pallidus. We detected a linear signal decrease with age in the pulvinar. The physiological signal features of the pulvinar also depend on gender and hemispheric lateralization. The pattern of signal change in the pulvinar is similar to but not the same as that in the putamen and globus pallidus.

T-phase and tsunami signals recorded by IMS hydrophone triplets during the 2011 Tohoku earthquake

NASA Astrophysics Data System (ADS)

Matsumoto, H.; Haralabus, G.; Zampolli, M.; Ozel, N. M.; Yamada, T.; Mark, P. K.

2016-12-01

A hydrophone station of the International Monitoring System (IMS) of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) is used to estimate the back-azimuth of T-phase signals generated by the 2011 Tohoku earthquake. Among the 6 IMS hydrophone stations required by the Treaty, 5 stations consist of two triplets, with the exception of HA1 (Australia), which has only one. The hydrophones of each triplet are suspended in the SOFAR channel and arranged to form an equilateral triangle with each side being approximately two kilometers long. The waveforms from the Tohoku earthquake were received at HA11, located on Wake Island, which is located approximately 3100 km south-east of the earthquake epicenter. The frequency range used in the array analysis was chosen to be less than 0.375 Hz, which assumed the target phase velocity to be 1.5 km/s for T-phases. The T-phase signals that originated from the seismic source however show peaks in the frequency band above one Hz. As a result of the inter-element distances of 2 km, spatial aliasing is observed in the frequency-wavenumber analysis (F-K analysis) if the entire 100 Hz bandwidth of the hydrophones is used. This spatial aliasing is significant because the distance between hydrophones in the triplet is large in comparison to the ratio between the phase velocity of T-phase signals and the frequency. To circumvent this spatial aliasing problem, a three-step processing technique used in seismic array analysis is applied: (1) high-pass filtering above 1 Hz to retrieve the T-phase, followed by (2) extraction of the envelope of this signal to highlight the T-phase contribution, and finally (3) low-pass filtering of the envelope below 0.375 Hz. The F-K analysis provides accurate back-azimuth and slowness estimations without spatial aliasing. Deconvolved waveforms are also processed to retrieve tsunami components by using a three-pole model of the frequency-amplitude-phase (FAP) response below 0.1 Hz and the measured sensor response

The XENON1T dark matter experiment

NASA Astrophysics Data System (ADS)

Aprile, E.; Aalbers, J.; Agostini, F.; Alfonsi, M.; Amaro, F. D.; Anthony, M.; Antunes, B.; Arneodo, F.; Balata, M.; Barrow, P.; Baudis, L.; Bauermeister, B.; Benabderrahmane, M. L.; Berger, T.; Breskin, A.; Breur, P. A.; Brown, A.; Brown, E.; Bruenner, S.; Bruno, G.; Budnik, R.; Bütikofer, L.; Calvén, J.; Cardoso, J. M. R.; Cervantes, M.; Chiarini, A.; Cichon, D.; Coderre, D.; Colijn, A. P.; Conrad, J.; Corrieri, R.; Cussonneau, J. P.; Decowski, M. P.; de Perio, P.; Gangi, P. Di; Giovanni, A. Di; Diglio, S.; Disdier, J.-M.; Doets, M.; Duchovni, E.; Eurin, G.; Fei, J.; Ferella, A. D.; Fieguth, A.; Franco, D.; Front, D.; Fulgione, W.; Rosso, A. Gallo; Galloway, M.; Gao, F.; Garbini, M.; Geis, C.; Giboni, K.-L.; Goetzke, L. W.; Grandi, L.; Greene, Z.; Grignon, C.; Hasterok, C.; Hogenbirk, E.; Huhmann, C.; Itay, R.; James, A.; Kaminsky, B.; Kazama, S.; Kessler, G.; Kish, A.; Landsman, H.; Lang, R. F.; Lellouch, D.; Levinson, L.; Lin, Q.; Lindemann, S.; Lindner, M.; Lombardi, F.; Lopes, J. A. M.; Maier, R.; Manfredini, A.; Maris, I.; Undagoitia, T. Marrodán; Masbou, J.; Massoli, F. V.; Masson, D.; Mayani, D.; Messina, M.; Micheneau, K.; Molinario, A.; Morå, K.; Murra, M.; Naganoma, J.; Ni, K.; Oberlack, U.; Orlandi, D.; Othegraven, R.; Pakarha, P.; Parlati, S.; Pelssers, B.; Persiani, R.; Piastra, F.; Pienaar, J.; Pizzella, V.; Piro, M.-C.; Plante, G.; Priel, N.; García, D. Ramírez; Rauch, L.; Reichard, S.; Reuter, C.; Rizzo, A.; Rosendahl, S.; Rupp, N.; Santos, J. M. F. dos; Saldanha, R.; Sartorelli, G.; Scheibelhut, M.; Schindler, S.; Schreiner, J.; Schumann, M.; Lavina, L. Scotto; Selvi, M.; Shagin, P.; Shockley, E.; Silva, M.; Simgen, H.; Sivers, M. v.; Stern, M.; Stein, A.; Tatananni, D.; Tatananni, L.; Thers, D.; Tiseni, A.; Trinchero, G.; Tunnell, C.; Upole, N.; Vargas, M.; Wack, O.; Walet, R.; Wang, H.; Wang, Z.; Wei, Y.; Weinheimer, C.; Wittweg, C.; Wulf, J.; Ye, J.; Zhang, Y.

2017-12-01

The XENON1T experiment at the Laboratori Nazionali del Gran Sasso (LNGS) is the first WIMP dark matter detector operating with a liquid xenon target mass above the ton-scale. Out of its 3.2 t liquid xenon inventory, 2.0 t constitute the active target of the dual-phase time projection chamber. The scintillation and ionization signals from particle interactions are detected with low-background photomultipliers. This article describes the XENON1T instrument and its subsystems as well as strategies to achieve an unprecedented low background level. First results on the detector response and the performance of the subsystems are also presented.

Detection of maltodextrin and its discrimination from sucrose are independent of the T1R2 + T1R3 heterodimer.

PubMed

Smith, Kimberly R; Spector, Alan C

2017-10-01

Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2 + T1R3 "sweet" taste receptor, recent evidence from T1R2- or T1R3-knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2 + T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine whether maltodextrins are 1 ) detectable when both receptor subunits are absent and 2 ) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2 + T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. Although both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose. Copyright © 2017 the American Physiological Society.

Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, Qiu-Hua; Liu, Yuan; Wu, Shan-Shan

Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus–pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our datamore » demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. - Highlights: • We explored the effects of ghrelin on serum deprivation-induced MC3T3-E1 cells apoptosis. • Both ELISA and TUNEL were used to detect the apoptosis. • The receptor of ghrelin, GHSR, was expressed in MC3T

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors.

PubMed

Kobayashi, Michihiro; Nabinger, Sarah C; Bai, Yunpeng; Yoshimoto, Momoko; Gao, Rui; Chen, Sisi; Yao, Chonghua; Dong, Yuanshu; Zhang, Lujuan; Rodriguez, Sonia; Yashiro-Ohtani, Yumi; Pear, Warren S; Carlesso, Nadia; Yoder, Mervin C; Kapur, Reuben; Kaplan, Mark H; Daniel Lacorazza, Hugo; Zhang, Zhong-Yin; Liu, Yan

2017-04-01

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors. Stem Cells 2017;35:1053-1064. © 2016 AlphaMed Press.

Non-canonical NF-κB signalling and ETS1/2 cooperatively drive C250T mutant TERT promoter activation

PubMed Central

Li, Yinghui; Zhou, Qi-Ling; Sun, Wenjie; Chandrasekharan, Prashant; Cheng, Hui Shan; Ying, Zhe; Lakshmanan, Manikandan; Raju, Anandhkumar; Tenen, Daniel G.; Cheng, Shi-Yuan; Chuang, Kai-Hsiang; Li, Jun; Prabhakar, Shyam; Li, Mengfeng; Tergaonkar, Vinay

2016-01-01

Transcriptional reactivation of TERT, the catalytic subunit of telomerase, is necessary for cancer progression in about 90% of human cancers. The recent discovery of two prevalent somatic mutations—C250T and C228T—in the TERT promoter in various cancers has provided insight into a plausible mechanism of TERT reactivation. Although the two hotspot mutations create a similar binding motif for E-twenty-six (ETS) transcription factors, we show that they are functionally distinct, in that the C250T unlike the C228T TERT promoter is driven by non-canonical NF-κB signalling. We demonstrate that binding of ETS to the mutant TERT promoter is insufficient in driving its transcription but this process requires non-canonical NF-κB signalling for stimulus responsiveness, sustained telomerase activity and hence cancer progression. Our findings highlight a previously unrecognized role of non-canonical NF-κB signalling in tumorigenesis and elucidate a fundamental mechanism for TERT reactivation in cancers, which if targeted could have immense therapeutic implications. PMID:26389665

Intensity invariance properties of auditory neurons compared to the statistics of relevant natural signals in grasshoppers.

PubMed

Clemens, Jan; Weschke, Gerroth; Vogel, Astrid; Ronacher, Bernhard

2010-04-01

The temporal pattern of amplitude modulations (AM) is often used to recognize acoustic objects. To identify objects reliably, intensity invariant representations have to be formed. We approached this problem within the auditory pathway of grasshoppers. We presented AM patterns modulated at different time scales and intensities. Metric space analysis of neuronal responses allowed us to determine how well, how invariantly, and at which time scales AM frequency is encoded. We find that in some neurons spike-count cues contribute substantially (20-60%) to the decoding of AM frequency at a single intensity. However, such cues are not robust when intensity varies. The general intensity invariance of the system is poor. However, there exists a range of AM frequencies around 83 Hz where intensity invariance of local interneurons is relatively high. In this range, natural communication signals exhibit much variation between species, suggesting an important behavioral role for this frequency band. We hypothesize, just as has been proposed for human speech, that the communication signals might have evolved to match the processing properties of the receivers. This contrasts with optimal coding theory, which postulates that neuronal systems are adapted to the statistics of the relevant signals.

Intermittent IL-7 Signaling Essential for T cell Homeostasis | Center for Cancer Research

Cancer.gov

In order for the immune system to mount an appropriate response to foreign antigens throughout a person’s life, the body must maintain a sufficient population of circulating mature, naïve T cells, a process known as T cell homeostasis. Previous studies revealed that this process depends upon signaling from the cytokine interleukin-7 (IL-7) as well as from the T cell antigen receptor (TCR). Intriguingly, signals from each pathway affect the other and lead to their alternating activation: IL-7 binding to its receptor leads to increasing expression of the TCR co-receptor CD8; sufficient CD8 expression allows TCRs to signal when bound to self-ligands, blocking IL-7 signaling; suppressed IL-7 signals lead to down-regulation of CD8 and ligand disengagement, which allows T cells to again respond to IL-7. Alfred Singer, M.D., and his colleagues in CCR’s Experimental Immunology Branch set out to understand how this intricate pathway promotes T cell survival.

Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

PubMed Central

LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

2014-01-01

Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

Genomic profiling of Sézary Syndrome identifies alterations of key T-cell signaling and differentiation genes

PubMed Central

Wang, Linghua; Ni, Xiao; Covington, Kyle R.; Yang, Betty Y.; Shiu, Jessica; Zhang, Xiang; Xi, Liu; Meng, Qingchang; Langridge, Timothy; Drummond, Jennifer; Donehower, Lawrence A.; Doddapaneni, Harshavardhan; Muzny, Donna M.; Gibbs, Richard A.; Wheeler, David A.; Duvic, Madeleine

2016-01-01

Sézary Syndrome is a rare leukemic form of cutaneous T-cell lymphoma defined as erythroderma, adenopathy, and circulating atypical T-lymphocytes. It is rarely curable with poor prognosis. Here we present a multi-platform genomic analysis of 37 Sézary Syndrome patients that implicates dysregulation of the cell cycle checkpoint and T-cell signaling. Frequent somatic alterations were identified in TP53, CARD11, CCR4, PLCG1, CDKN2A, ARID1A, RPS6KA1, and ZEB1. Activating CCR4 and CARD11 mutations were detected in nearly a third of patients. ZEB1, a transcription repressor essential for T-cell differentiation, was deleted in over half of patients. IL32 and IL2RG were over-expressed in nearly all cases. Analysis of T-cell receptor Vβ and Vα expression revealed ongoing rearrangement of the receptors after the expansion of a malignant clone in one third of subjects. Our results demonstrate profound disruption of key signaling pathways in Sézary Syndrome and suggest potential targets for novel therapies. PMID:26551670

Homeostatic signals do not drive post-thymic T cell maturation.

PubMed

Houston, Evan G; Boursalian, Tamar E; Fink, Pamela J

2012-01-01

Recent thymic emigrants, the youngest T cells in the lymphoid periphery, undergo a 3 week-long period of functional and phenotypic maturation before being incorporated into the pool of mature, naïve T cells. Previous studies indicate that this maturation requires T cell exit from the thymus and access to secondary lymphoid organs, but is MHC-independent. We now show that post-thymic T cell maturation is independent of homeostatic and costimulatory pathways, requiring neither signals delivered by IL-7 nor CD80/86. Furthermore, while CCR7/CCL19,21-regulated homing of recent thymic emigrants to the T cell zones within the secondary lymphoid organs is not required for post-thymic T cell maturation, an intact dendritic cell compartment modulates this process. It is thus clear that, unlike T cell development and homeostasis, post-thymic maturation is focused not on interrogating the T cell receptor or the cell's responsiveness to homeostatic or costimulatory signals, but on some as yet unrecognized property. Copyright © 2012 Elsevier Inc. All rights reserved.

TIM-1 signaling in B cells regulates antibody production

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, Juan; Usui, Yoshihiko; Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku-ku, Tokyo 160-0023

Highlights: {yields} TIM-1 is highly expressed on anti-IgM + anti-CD40-stimulated B cells. {yields} Anti-TIM-1 mAb enhanced proliferation and Ig production on activated B cell in vitro. {yields} TIM-1 signaling regulates Ab production by response to TI-2 and TD antigens in vivo. -- Abstract: Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. In this study, we found TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. On the other hand, TIM-1 ligand was constitutively expressedmore » on B cells and inducible on anti-CD3{sup +} anti-CD28-stimulated CD4{sup +} T cells. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). We further examined the effect of TIM-1 signaling on antibody production in vitro and in vivo. Higher levels of IgG2b and IgG3 secretion were detected in the culture supernatants of the anti-TIM-1-stimulated B cells as compared with the control IgG-stimulated B cells. When immunized with T-independent antigen TNP-Ficoll, TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly increased in the anti-TIM-1-treated mice. When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice as compared with the control IgG-treated mice. These results suggest that TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation.« less

Non-T cell activation linker (NTAL): a transmembrane adaptor protein involved in immunoreceptor signaling.

PubMed

Brdicka, Tomás; Imrich, Martin; Angelisová, Pavla; Brdicková, Nadezda; Horváth, Ondrej; Spicka, Jirí; Hilgert, Ivan; Lusková, Petra; Dráber, Petr; Novák, Petr; Engels, Niklas; Wienands, Jürgen; Simeoni, Luca; Osterreicher, Jan; Aguado, Enrique; Malissen, Marie; Schraven, Burkhart; Horejsí, Václav

2002-12-16

A key molecule necessary for activation of T lymphocytes through their antigen-specific T cell receptor (TCR) is the transmembrane adaptor protein LAT (linker for activation of T cells). Upon TCR engagement, LAT becomes rapidly tyrosine phosphorylated and then serves as a scaffold organizing a multicomponent complex that is indispensable for induction of further downstream steps of the signaling cascade. Here we describe the identification and preliminary characterization of a novel transmembrane adaptor protein that is structurally and evolutionarily related to LAT and is expressed in B lymphocytes, natural killer (NK) cells, monocytes, and mast cells but not in resting T lymphocytes. This novel transmembrane adaptor protein, termed NTAL (non-T cell activation linker) is the product of a previously identified WBSCR5 gene of so far unknown function. NTAL becomes rapidly tyrosine-phosphorylated upon cross-linking of the B cell receptor (BCR) or of high-affinity Fcgamma- and Fc epsilon -receptors of myeloid cells and then associates with the cytoplasmic signaling molecules Grb2, Sos1, Gab1, and c-Cbl. NTAL expressed in the LAT-deficient T cell line J.CaM2.5 becomes tyrosine phosphorylated and rescues activation of Erk1/2 and minimal transient elevation of cytoplasmic calcium level upon TCR/CD3 cross-linking. Thus, NTAL appears to be a structural and possibly also functional homologue of LAT in non-T cells.

TCR Signal Strength Regulates Akt Substrate Specificity To Induce Alternate Murine Th and T Regulatory Cell Differentiation Programs.

PubMed

Hawse, William F; Boggess, William C; Morel, Penelope A

2017-07-15

The Akt/mTOR pathway is a key driver of murine CD4 + T cell differentiation, and induction of regulatory T (Treg) cells results from low TCR signal strength and low Akt/mTOR signaling. However, strong TCR signals induce high Akt activity that promotes Th cell induction. Yet, it is unclear how Akt controls alternate T cell fate decisions. We find that the strength of the TCR signal results in differential Akt enzymatic activity. Surprisingly, the Akt substrate networks associated with T cell fate decisions are qualitatively different. Proteomic profiling of Akt signaling networks during Treg versus Th induction demonstrates that Akt differentially regulates RNA processing and splicing factors to drive T cell differentiation. Interestingly, heterogeneous nuclear ribonucleoprotein (hnRNP) L or hnRNP A1 are Akt substrates during Treg induction and have known roles in regulating the stability and splicing of key mRNAs that code for proteins in the canonical TCR signaling pathway, including CD3ζ and CD45. Functionally, inhibition of Akt enzymatic activity results in the dysregulation of splicing during T cell differentiation, and knockdown of hnRNP L or hnRNP A1 results in the lower induction of Treg cells. Together, this work suggests that a switch in substrate specificity coupled to the phosphorylation status of Akt may lead to alternative cell fates and demonstrates that proteins involved with alternative splicing are important factors in T cell fate decisions. Copyright © 2017 by The American Association of Immunologists, Inc.

Vav1-phospholipase C-γ1 (Vav1-PLC-γ1) pathway initiated by T cell antigen receptor (TCRγδ) activation is required to overcome inhibition by ubiquitin ligase Cbl-b during γδT cell cytotoxicity.

PubMed

Yin, Shanshan; Zhang, Jianmin; Mao, Yujia; Hu, Yu; Cui, Lianxian; Kang, Ning; He, Wei

2013-09-13

T cell antigen receptor γδ (TCRγδ) and natural killer group 2, member D (NKG2D) are two crucial receptors for γδT cell cytotoxicity. Compelling evidences suggest that γδT cell cytotoxicity is TCRγδ-dependent and can be co-stimulated by NKG2D. However, the molecular mechanism of underlying TCRγδ-dependent activation of γδT cells remains unclear. In this study we demonstrated that TCRγδ but not NKG2D engagement induced lytic granule polarization and promoted γδT cell cytotoxicity. TCRγδ activation alone was sufficient to trigger Vav1-dependent phospholipase C-γ1 signaling, resulting in lytic granule polarization and effective killing, whereas NKG2D engagement alone failed to trigger cytotoxicity-related signaling to overcome the inhibitory effect of Cbl-b; therefore, NKG2D engagement alone could not induce effective killing. However, NKG2D ligation augmented the activation of γδT cell cytotoxicity through the Vav1-phospholipase C-γ1 pathway. Vav1 overexpression or Cbl-b knockdown not only enhanced TCRγδ activation-initiated killing but also enabled NKG2D activation alone to induce γδT cell cytotoxicity. Taken together, our results suggest that the activation of γδT cell cytotoxicity requires a strong activation signal to overcome the inhibitory effect of Cbl-b. Our finding provides new insights into the molecular mechanisms underlying the initiation of γδT cell cytotoxicity and likely implications for optimizing γδT cell-based cancer immunotherapy.

The effect of inhibitory signals on the priming of drug-hapten-specific T-cells that express distinct Vβ receptors

PubMed Central

Gibson, Andrew; Faulkner, Lee; Lichtenfels, Maike; Ogese, Monday; Al-Attar, Zaid; Alfirevic, Ana; Esser, Philipp R.; Martin, Stefan F.; Pirmohamed, Munir; Park, B. Kevin; Naisbitt, Dean J.

2017-01-01

Drug hypersensitivity involves the activation of T-cells in an HLA allele-restricted manner. Since the majority of individuals who carry HLA risk alleles do not develop hypersensitivity, other parameters must control development of the drug-specific T-cell response. Thus, we have utilized a T-cell priming assay and nitroso sulfamethoxazole (SMX-NO) as a model antigen to investigate (1) the activation of specific T-cell receptor (TCR)Vβ subtypes, (2) the impact of PD-1, CTLA4 and TIM-3 co-inhibitory signalling on activation of naïve and memory T-cells and (3) the ability of Tregs to prevent responses. An expansion of the TCR repertoire was observed for nine different Vβ subtypes, while spectratyping revealed that SMX-NO-specific T-cell responses are controlled by public TCRs present in all individuals alongside private TCR repertoires specific to each individual. We proceeded to evaluate the extent to which the activation of these TCR Vβ-restricted antigen-specific T-cell responses is governed by regulatory signals. Blockade of PDL-1/CTLA4 signalling dampened activation of SMX-NO-specific naïve and memory T-cells, while blockade of TIM-3 produced no effect. PD-1, CTLA4, and TIM-3 displayed discrete expression profiles during drug-induced T-cell activation and expression of each receptor was enhanced on dividing T-cells. As these receptors are also expressed on Tregs, Treg-mediated suppression of SMX-NO-induced T-cell activation was investigated. Tregs significantly dampened the priming of T-cells. In conclusion, our findings demonstrate that distinct TCR Vβ subtypes, dysregulation of co-inhibitory signalling pathways and dysfunctional Tregs may influence predisposition to hypersensitivity. PMID:28687658

CD28 co-stimulation restores T cell responsiveness in NOD mice by overcoming deficiencies in Rac-1/p38 mitogen-activated protein kinase signaling and IL-2 and IL-4 gene transcription.

PubMed

Zhang, J; Salojin, K V; Delovitch, T L

2001-03-01

Previously, we reported that T cell hyporesponsiveness induced by TCR ligation is causal to autoimmune diabetes in NOD mice. Neonatal CD28 co-stimulation reverses T cell hyporesponsiveness and protects NOD mice from diabetes by an IL-4-mediated mechanism, indicating that a deficiency in TCR signaling may be overcome by CD28/B7-2 co-stimulation in NOD T cells. To investigate which co-stimulation-induced signaling events mediate this protection, we analyzed the activity of Ras, Rac-1, mitogen-activated protein kinases (MAPK) and several transcription factors in TCR-activated NOD T cells in the presence or absence of CD28 co-stimulation. We show that CD28 co-stimulation restores normal TCR-induced activation of Rac-1 and p38 MAPK in NOD T cells. Deficiencies in TCR-induced nuclear expression of activating protein (AP)-1 binding proteins as well as activation of AP-1 and NF-AT in the IL-2 and IL-4 P1 promoters are also corrected by CD28 co-stimulation. Thus, CD28 co-stimulation reverses NOD T cell hyporesponsiveness by restoring TCR signaling leading to the activation of AP-1 and NF-AT during IL-2 and IL-4 gene transcription. Our findings provide additional evidence that CD28 co-stimulation amplifies signals delivered by the TCR and further explain the mechanism by which CD28 co-stimulation may protect against autoimmune diabetes.

Polyunsaturated Fatty Acids Inhibit T Cell Signal Transduction by Modification of Detergent-insoluble Membrane Domains

PubMed Central

Stulnig, Thomas M.; Berger, Markus; Sigmund, Thomas; Raederstorff, Daniel; Stockinger, Hannes; Waldhäusl, Werner

1998-01-01

Polyunsaturated fatty acids (PUFAs) exert immunosuppressive effects, but the molecular alterations leading to T cell inhibition are not yet elucidated. Signal transduction seems to involve detergent-resistant membrane domains (DRMs) acting as functional rafts within the plasma membrane bilayer with Src family protein tyrosine kinases being attached to their cytoplasmic leaflet. Since DRMs include predominantly saturated fatty acyl moieties, we investigated whether PUFAs could affect T cell signaling by remodeling of DRMs. Jurkat T cells cultured in PUFA-supplemented medium showed a markedly diminished calcium response when stimulated via the transmembrane CD3 complex or glycosyl phosphatidylinositol (GPI)- anchored CD59. Immunofluorescence studies indicated that CD59 but not Src family protein tyrosine kinase Lck remained in a punctate pattern after PUFA enrichment. Analysis of DRMs revealed a marked displacement of Src family kinases (Lck, Fyn) from DRMs derived from PUFA-enriched T cells compared with controls, and the presence of Lck in DRMs strictly correlated with calcium signaling. In contrast, GPI-anchored proteins (CD59, CD48) and ganglioside GM1, both residing in the outer membrane leaflet, remained in the DRM fraction. In conclusion, PUFA enrichment selectively modifies the cytoplasmic layer of DRMs and this alteration could underlie the inhibition of T cell signal transduction by PUFAs. PMID:9813086

The phosphatase JKAP/DUSP22 inhibits T-cell receptor signalling and autoimmunity by inactivating Lck.

PubMed

Li, Ju-Pi; Yang, Chia-Yu; Chuang, Huai-Chia; Lan, Joung-Liang; Chen, Der-Yuan; Chen, Yi-Ming; Wang, Xiaohong; Chen, Alice J; Belmont, John W; Tan, Tse-Hua

2014-04-09

JNK pathway-associated phosphatase (JKAP, also known as DUSP22 or JSP-1) is a JNK activator. The in vivo role of JKAP in immune regulation remains unclear. Here we report that JKAP directly inactivates Lck by dephosphorylating tyrosine-394 residue during T-cell receptor (TCR) signalling. JKAP-knockout T cells display enhanced cell proliferation and cytokine production. JKAP-knockout mice show enhanced T-cell-mediated immune responses and are more susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, the recipient mice that are adoptively transferred with JKAP-knockout T cells show exacerbated EAE symptoms. Aged JKAP-knockout mice spontaneously develop inflammation and autoimmunity. Thus, our results indicate that JKAP is an important phosphatase that inactivates Lck in the TCR signalling turn-off stage, leading to suppression of T-cell-mediated immunity and autoimmunity.

T-lymphocyte signalling in systemic lupus erythematosus: a lipid raft perspective

PubMed Central

Jury, EC; Kabouridis, PS

2008-01-01

In the last few years it has become clear that in cells of the immune system, specialized microdomains present in the plasma membrane, called lipid rafts, have been found to play a central role in regulating signalling by immune receptors. Recent studies have looked at whether lipid rafts may be connected to the abnormalities in signalling seen in T lymphocytes isolated from patients with systemic lupus erythematosus (SLE). These early findings show that in SLE T cells, the expression and protein composition of lipid rafts is different when compared with normal T cells. These results also demonstrate changes in the function and localization of critical signalling molecules such as the LCK tyrosine kinase and the CD45 tyrosine phosphatase. PMID:15303567

Oncogenic NOTCH1 control of MYC and PI3K: challenges and opportunities for anti-NOTCH1 therapy in T-ALL

PubMed Central

Palomero, Teresa; Ferrando, Adolfo

2008-01-01

The identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias and lymphomas (T-ALL) has brought much interest in inhibiting NOTCH1 signaling as therapeutic target in this disease. Small molecule inhibitors of the γ-secretase complex, which mediates a critical proteolytic cleavage required for NOTCH1 activation, hold the promise of becoming an effective molecular therapy against relapsed and refractory T-ALL. Recent progress in the elucidation of the transcriptional regulatory networks downstream of oncogenic NOTCH1 has uncovered a central role of NOTCH1 signaling in promoting leukemic cell growth and revealed an intricate circuitry that connects NOTCH1 signaling with MYC and the PI3K-AKT signaling pathway. The identification of the downstream effector pathways controlled by NOTCH1 should pave the way for the rational design of anti-NOTCH1 therapies for the treatment of T-ALL. PMID:18765521

Intracellular signaling required for CCL25-stimulated T cell adhesion mediated by the integrin alpha4beta1.

PubMed

Parmo-Cabañas, Marisa; García-Bernal, David; García-Verdugo, Rosa; Kremer, Leonor; Márquez, Gabriel; Teixidó, Joaquin

2007-08-01

The alpha4beta1 integrin is expressed on thymocytes and mediates cell attachment to its ligands CS-1/fibronectin (CS-1/FN) and VCAM-1 in the thymus. The chemokine CCL25 is highly expressed in the thymus, where it binds to its receptor CCR9 on thymocytes promoting migration and activation. We show here that alpha4beta1 and CCR9 are coexpressed mainly on double- and single-positive thymocytes and that CCL25 strongly stimulates CD4(+)CD8(+) and CD4(+)CD8(-) adhesion to CS-1/FN and VCAM-1. CCL25 rapidly activated the GTPases Rac and Rap1 on thymocytes, and this activation was required for stimulation of adhesion, as detected using the CCR9(+)/alpha4beta1(+) human T cell line Molt-4. To study the role on CCL25-stimulated adhesion of the Rac downstream effector Wiskott-Aldrich syndrome protein family verproline-homologous protein 2 (WAVE2) as well as of Rap1-GTP-interacting proteins, regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) and Rap1-GTP-interacting adapter molecule (RIAM), we knocked down their expression and tested transfectant attachment to alpha4beta1 ligands. We found that WAVE2 and RAPL but not RIAM were required for efficient triggering by CCL25 of T cell adhesion to CS-1/FN and VCAM-1. Although Rac and Rap1 activation was required during early steps of T cell adhesion stimulated by CCL25, WAVE2 was needed for the development of actin-dependent T cell spreading subsequent to adhesion strengthening but not during initial alpha4beta1-ligand interactions. These results suggest that regulation by CCL25 of adhesion of thymocyte subpopulations mediated by alpha4beta1 could contribute to control their trafficking in the thymus during maturation, and identify Rac-WAVE2 and Rap1-RAPL as pathways whose activation is required in inside-out signaling, leading to stimulated adhesion.

Influence of signal intensity non-uniformity on brain volumetry using an atlas-based method.

PubMed

Goto, Masami; Abe, Osamu; Miyati, Tosiaki; Kabasawa, Hiroyuki; Takao, Hidemasa; Hayashi, Naoto; Kurosu, Tomomi; Iwatsubo, Takeshi; Yamashita, Fumio; Matsuda, Hiroshi; Mori, Harushi; Kunimatsu, Akira; Aoki, Shigeki; Ino, Kenji; Yano, Keiichi; Ohtomo, Kuni

2012-01-01

Many studies have reported pre-processing effects for brain volumetry; however, no study has investigated whether non-parametric non-uniform intensity normalization (N3) correction processing results in reduced system dependency when using an atlas-based method. To address this shortcoming, the present study assessed whether N3 correction processing provides reduced system dependency in atlas-based volumetry. Contiguous sagittal T1-weighted images of the brain were obtained from 21 healthy participants, by using five magnetic resonance protocols. After image preprocessing using the Statistical Parametric Mapping 5 software, we measured the structural volume of the segmented images with the WFU-PickAtlas software. We applied six different bias-correction levels (Regularization 10, Regularization 0.0001, Regularization 0, Regularization 10 with N3, Regularization 0.0001 with N3, and Regularization 0 with N3) to each set of images. The structural volume change ratio (%) was defined as the change ratio (%) = (100 × [measured volume - mean volume of five magnetic resonance protocols] / mean volume of five magnetic resonance protocols) for each bias-correction level. A low change ratio was synonymous with lower system dependency. The results showed that the images with the N3 correction had a lower change ratio compared with those without the N3 correction. The present study is the first atlas-based volumetry study to show that the precision of atlas-based volumetry improves when using N3-corrected images. Therefore, correction for signal intensity non-uniformity is strongly advised for multi-scanner or multi-site imaging trials.

Influence of Signal Intensity Non-Uniformity on Brain Volumetry Using an Atlas-Based Method

PubMed Central

Abe, Osamu; Miyati, Tosiaki; Kabasawa, Hiroyuki; Takao, Hidemasa; Hayashi, Naoto; Kurosu, Tomomi; Iwatsubo, Takeshi; Yamashita, Fumio; Matsuda, Hiroshi; Mori, Harushi; Kunimatsu, Akira; Aoki, Shigeki; Ino, Kenji; Yano, Keiichi; Ohtomo, Kuni

2012-01-01

Objective Many studies have reported pre-processing effects for brain volumetry; however, no study has investigated whether non-parametric non-uniform intensity normalization (N3) correction processing results in reduced system dependency when using an atlas-based method. To address this shortcoming, the present study assessed whether N3 correction processing provides reduced system dependency in atlas-based volumetry. Materials and Methods Contiguous sagittal T1-weighted images of the brain were obtained from 21 healthy participants, by using five magnetic resonance protocols. After image preprocessing using the Statistical Parametric Mapping 5 software, we measured the structural volume of the segmented images with the WFU-PickAtlas software. We applied six different bias-correction levels (Regularization 10, Regularization 0.0001, Regularization 0, Regularization 10 with N3, Regularization 0.0001 with N3, and Regularization 0 with N3) to each set of images. The structural volume change ratio (%) was defined as the change ratio (%) = (100 × [measured volume - mean volume of five magnetic resonance protocols] / mean volume of five magnetic resonance protocols) for each bias-correction level. Results A low change ratio was synonymous with lower system dependency. The results showed that the images with the N3 correction had a lower change ratio compared with those without the N3 correction. Conclusion The present study is the first atlas-based volumetry study to show that the precision of atlas-based volumetry improves when using N3-corrected images. Therefore, correction for signal intensity non-uniformity is strongly advised for multi-scanner or multi-site imaging trials. PMID:22778560

Therapeutic targeting of HES1 transcriptional programs in T-ALL

PubMed Central

Schnell, Stephanie A.; Ambesi-Impiombato, Alberto; Sanchez-Martin, Marta; Belver, Laura; Xu, Luyao; Qin, Yue; Kageyama, Ryoichiro

2015-01-01

Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo. PMID:25784680

RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells.

PubMed

Priatel, John J; Chen, Xiaoxi; Huang, Yu-Hsuan; Chow, Michael T; Zenewicz, Lauren A; Coughlin, Jason J; Shen, Hao; Stone, James C; Tan, Rusung; Teh, Hung Sia

2010-01-15

Ag encounter by naive CD8 T cells initiates a developmental program consisting of cellular proliferation, changes in gene expression, and the formation of effector and memory T cells. The strength and duration of TCR signaling are known to be important parameters regulating the differentiation of naive CD8 T cells, although the molecular signals arbitrating these processes remain poorly defined. The Ras-guanyl nucleotide exchange factor RasGRP1 has been shown to transduce TCR-mediated signals critically required for the maturation of developing thymocytes. To elucidate the role of RasGRP1 in CD8 T cell differentiation, in vitro and in vivo experiments were performed with 2C TCR transgenic CD8 T cells lacking RasGRP1. In this study, we report that RasGRP1 regulates the threshold of T cell activation and Ag-induced expansion, at least in part, through the regulation of IL-2 production. Moreover, RasGRP1(-/-) 2C CD8 T cells exhibit an anergic phenotype in response to cognate Ag stimulation that is partially reversible upon the addition of exogenous IL-2. By contrast, the capacity of IL-2/IL-2R interactions to mediate Ras activation and CD8 T cell expansion and differentiation appears to be largely RasGRP1-independent. Collectively, our results demonstrate that RasGRP1 plays a selective role in T cell signaling, controlling the initiation and duration of CD8 T cell immune responses.

Environmental signals modulate ToxT-dependent virulence factor expression in Vibrio cholerae.

PubMed

Schuhmacher, D A; Klose, K E

1999-03-01

The regulatory protein ToxT directly activates the transcription of virulence factors in Vibrio cholerae, including cholera toxin (CT) and the toxin-coregulated pilus (TCP). Specific environmental signals stimulate virulence factor expression by inducing the transcription of toxT. We demonstrate that transcriptional activation by the ToxT protein is also modulated by environmental signals. ToxT expressed from an inducible promoter activated high-level expression of CT and TCP in V. cholerae at 30 degrees C, but expression of CT and TCP was significantly decreased or abolished by the addition of 0.4% bile to the medium and/or an increase of the temperature to 37 degrees C. Also, expression of six ToxT-dependent TnphoA fusions was modulated by temperature and bile. Measurement of ToxT-dependent transcription of genes encoding CT and TCP by ctxAp- and tcpAp-luciferase fusions confirmed that negative regulation by 37 degrees C or bile occurs at the transcriptional level in V. cholerae. Interestingly, ToxT-dependent transcription of these same promoters in Salmonella typhimurium was relatively insensitive to regulation by temperature or bile. These data are consistent with ToxT transcriptional activity being modulated by environmental signals in V. cholerae and demonstrate an additional level of complexity governing the expression of virulence factors in this pathogen. We propose that negative regulation of ToxT-dependent transcription by environmental signals prevents the incorrect temporal and spatial expression of virulence factors during cholera pathogenesis.

Comparison of dynamic contrast-enhanced MRI parameters of breast lesions at 1.5 and 3.0 T: a pilot study

PubMed Central

Pineda, F D; Medved, M; Fan, X; Ivancevic, M K; Abe, H; Shimauchi, A; Newstead, G M

2015-01-01

Objective: To compare dynamic contrast-enhanced (DCE) MRI parameters from scans of breast lesions at 1.5 and 3.0 T. Methods: 11 patients underwent paired MRI examinations in both Philips 1.5 and 3.0 T systems (Best, Netherlands) using a standard clinical fat-suppressed, T1 weighted DCE-MRI protocol, with 70–76 s temporal resolution. Signal intensity vs time curves were fit with an empirical mathematical model to obtain semi-quantitative measures of uptake and washout rates as well as time-to-peak enhancement (TTP). Maximum percent enhancement and signal enhancement ratio (SER) were also measured for each lesion. Percent differences between parameters measured at the two field strengths were compared. Results: TTP and SER parameters measured at 1.5 and 3.0 T were similar; with mean absolute differences of 19% and 22%, respectively. Maximum percent signal enhancement was significantly higher at 3 T than at 1.5 T (p = 0.006). Qualitative assessment showed that image quality was significantly higher at 3 T (p = 0.005). Conclusion: Our results suggest that TTP and SER are more robust to field strength change than other measured kinetic parameters, and therefore measurements of these parameters can be more easily standardized than measurements of other parameters derived from DCE-MRI. Semi-quantitative measures of overall kinetic curve shape showed higher reproducibility than do discrete classification of kinetic curve early and delayed phases in a majority of the cases studied. Advances in knowledge: Qualitative measures of curve shape are not consistent across field strength even when acquisition parameters are standardized. Quantitative measures of overall kinetic curve shape, by contrast, have higher reproducibility. PMID:25785918

Regulation of T-cell receptor signalling by membrane microdomains

PubMed Central

Razzaq, Tahir M; Ozegbe, Patricia; Jury, Elizabeth C; Sembi, Phupinder; Blackwell, Nathan M; Kabouridis, Panagiotis S

2004-01-01

There is now considerable evidence suggesting that the plasma membrane of mammalian cells is compartmentalized by functional lipid raft microdomains. These structures are assemblies of specialized lipids and proteins and have been implicated in diverse biological functions. Analysis of their protein content using proteomics and other methods revealed enrichment of signalling proteins, suggesting a role for these domains in intracellular signalling. In T lymphocytes, structure/function experiments and complementary pharmacological studies have shown that raft microdomains control the localization and function of proteins which are components of signalling pathways regulated by the T-cell antigen receptor (TCR). Based on these studies, a model for TCR phosphorylation in lipid rafts is presented. However, despite substantial progress in the field, critical questions remain. For example, it is unclear if membrane rafts represent a homogeneous population and if their structure is modified upon TCR stimulation. In the future, proteomics and the parallel development of complementary analytical methods will undoubtedly contribute in further delineating the role of lipid rafts in signal transduction mechanisms. PMID:15554919

Akt signaling is critical for memory CD8+ T-cell development and tumor immune surveillance.

PubMed

Rogel, Anne; Willoughby, Jane E; Buchan, Sarah L; Leonard, Henry J; Thirdborough, Stephen M; Al-Shamkhani, Aymen

2017-02-14

Memory CD8 + T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8 + T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8 + T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8 + T cells from pdk1 K465E/K465E knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3) lo CD43 lo effector-like memory cells. Consequently, antitumor immunity by CD8 + T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8 + T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8 + T-cell responses.

Akt signaling is critical for memory CD8+ T-cell development and tumor immune surveillance

PubMed Central

Rogel, Anne; Willoughby, Jane E.; Buchan, Sarah L.; Leonard, Henry J.; Thirdborough, Stephen M.; Al-Shamkhani, Aymen

2017-01-01

Memory CD8+ T cells confer long-term immunity against tumors, and anticancer vaccines therefore should maximize their generation. Multiple memory CD8+ T-cell subsets with distinct functional and homing characteristics exist, but the signaling pathways that regulate their development are ill defined. Here we examined the role of the serine/threonine kinase Akt in the generation of protective immunity by CD8+ T cells. Akt is known to be activated by the T-cell antigen receptor and the cytokine IL-2, but its role in T-cell immunity in vivo has not been explored. Using CD8+ T cells from pdk1K465E/K465E knockin mice, we found that decreased Akt activity inhibited the survival of T cells during the effector-to-memory cell transition and abolished their differentiation into C-X-C chemokine receptor 3 (CXCR3)loCD43lo effector-like memory cells. Consequently, antitumor immunity by CD8+ T cells that display defective Akt signaling was substantially diminished during the memory phase. Reduced memory T-cell survival and altered memory cell differentiation were associated with up-regulation of the proapoptotic protein Bim and the T-box transcription factor eomesodermin, respectively. These findings suggest an important role for effector-like memory CD8+ T cells in tumor immune surveillance and identify Akt as a key signaling node in the development of protective memory CD8+ T-cell responses. PMID:28137869

Noiseless intensity amplification of repetitive signals by coherent addition using the temporal Talbot effect

PubMed Central

Maram, Reza; Van Howe, James; Li, Ming; Azaña, José

2014-01-01

Amplification of signal intensity is essential for initiating physical processes, diagnostics, sensing, communications and measurement. During traditional amplification, the signal is amplified by multiplying the signal carriers through an active gain process, requiring the use of an external power source. In addition, the signal is degraded by noise and distortions that typically accompany active gain processes. We show noiseless intensity amplification of repetitive optical pulse waveforms with gain from 2 to ~20 without using active gain. The proposed method uses a dispersion-induced temporal self-imaging (Talbot) effect to redistribute and coherently accumulate energy of the original repetitive waveforms into fewer replica waveforms. In addition, we show how our passive amplifier performs a real-time average of the wave-train to reduce its original noise fluctuation, as well as enhances the extinction ratio of pulses to stand above the noise floor. Our technique is applicable to repetitive waveforms in any spectral region or wave system. PMID:25319207

Intramuscular adipose tissue determined by T1-weighted MRI at 3T primarily reflects extramyocellular lipids.

PubMed

Akima, Hiroshi; Hioki, Maya; Yoshiko, Akito; Koike, Teruhiko; Sakakibara, Hisataka; Takahashi, Hideyuki; Oshida, Yoshiharu

2016-05-01

The purpose of this study was to assess relationships between intramuscular adipose tissue (IntraMAT) content determined by MRI and intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) determined by (1)H magnetic resonance spectroscopy ((1)H MRS) or echo intensity determined by B-mode ultrasonography of human skeletal muscles. Thirty young and elderly men and women were included. T1-weighted MRI was taken from the right mid-thigh to measure IntraMAT content of the vastus lateralis (VL) and biceps femoris (BF) using a histogram shape-based thresholding technique. IMCL and EMCL were measured from the VL and BF at the right mid-thigh using (1)H MRS. Ultrasonographic images were taken from the VL and BF of the right mid-thigh to measure echo intensity based on gray-scale level for quantitative analysis. There was a significant correlation between IntraMAT content by MRI and EMCL of the VL and BF (VL, r=0.506, P<0.01; BF, r=0.591, P<0.001) and between echo intensity and EMCL of the VL and BF (VL, r=0.485, P<0.05; BF, r=0.648, P<0.01). IntraMAT content was also significantly correlated with echo intensity of the VL and BF (VL, r=0.404, P<0.05; BF, r=0.493, P<0.01). Our study suggests that IntraMAT content determined by T1-weighted MRI at 3T primarily reflects extramyocellular lipids, not intramyocellular lipids, in human skeletal muscles. Copyright © 2016 Elsevier Inc. All rights reserved.

Non-contrast T1-mapping detects acute myocardial edema with high diagnostic accuracy: a comparison to T2-weighted cardiovascular magnetic resonance

PubMed Central

2012-01-01

Background T2w-CMR is used widely to assess myocardial edema. Quantitative T1-mapping is also sensitive to changes in free water content. We hypothesized that T1-mapping would have a higher diagnostic performance in detecting acute edema than dark-blood and bright-blood T2w-CMR. Methods We investigated 21 controls (55 ± 13 years) and 21 patients (61 ± 10 years) with Takotsubo cardiomyopathy or acute regional myocardial edema without infarction. CMR performed within 7 days included cine, T1-mapping using ShMOLLI, dark-blood T2-STIR, bright-blood ACUT2E and LGE imaging. We analyzed wall motion, myocardial T1 values and T2 signal intensity (SI) ratio relative to both skeletal muscle and remote myocardium. Results All patients had acute cardiac symptoms, increased Troponin I (0.15-36.80 ug/L) and acute wall motion abnormalities but no LGE. T1 was increased in patient segments with abnormal and normal wall motion compared to controls (1113 ± 94 ms, 1029 ± 59 ms and 944 ± 17 ms, respectively; p < 0.001). T2 SI ratio using STIR and ACUT2E was also increased in patient segments with abnormal and normal wall motion compared to controls (all p < 0.02). Receiver operator characteristics analysis showed that T1-mapping had a significantly larger area-under-the-curve (AUC = 0.94) compared to T2-weighted methods, whether the reference ROI was skeletal muscle or remote myocardium (AUC = 0.58-0.89; p < 0.03). A T1 value of greater than 990 ms most optimally differentiated segments affected by edema from normal segments at 1.5 T, with a sensitivity and specificity of 92 %. Conclusions Non-contrast T1-mapping using ShMOLLI is a novel method for objectively detecting myocardial edema with a high diagnostic performance. T1-mapping may serve as a complementary technique to T2-weighted imaging for assessing myocardial edema in ischemic and non-ischemic heart disease, such as quantifying area-at-risk and diagnosing

Signal transduction in primary human T lymphocytes in altered gravity - results of the MASER-12 suborbital space flight mission.

PubMed

Tauber, Svantje; Hauschild, Swantje; Crescio, Claudia; Secchi, Christian; Paulsen, Katrin; Pantaleo, Antonella; Saba, Angela; Buttron, Isabell; Thiel, Cora Sandra; Cogoli, Augusto; Pippia, Proto; Ullrich, Oliver

2013-05-07

We investigated the influence of altered gravity on key proteins of T cell activation during the MASER-12 ballistic suborbital rocket mission of the European Space Agency (ESA) and the Swedish Space Cooperation (SSC) at ESRANGE Space Center (Kiruna, Sweden). We quantified components of the T cell receptor, the membrane proximal signaling, MAPK-signaling, IL-2R, histone modifications and the cytoskeleton in non-activated and in ConA/CD28-activated primary human T lymphocytes. The hypergravity phase during the launch resulted in a downregulation of the IL-2 and CD3 receptor and reduction of tyrosine phosphorylation, p44/42-MAPK phosphorylation and histone H3 acetylation, whereas LAT phosphorylation was increased. Compared to the baseline situation at the point of entry into the microgravity phase, CD3 and IL-2 receptor expression at the surface of non-activated T cells were reduced after 6 min microgravity. Importantly, p44/42-MAPK-phosphorylation was also reduced after 6 min microgravity compared to the 1g ground controls, but also in direct comparison between the in-flight μg and the 1g group. In activated T cells, the reduced CD3 and IL-2 receptor expression at the baseline situation recovered significantly during in-flight 1g conditions, but not during microgravity conditions. Beta-tubulin increased significantly after onset of microgravity until the end of the microgravity phase, but not in the in-flight 1g condition. This study suggests that key proteins of T cell signal modules are not severely disturbed in microgravity. Instead, it can be supposed that the strong T cell inhibiting signal occurs downstream from membrane proximal signaling, such as at the transcriptional level as described recently. However, the MASER-12 experiment could identify signal molecules, which are sensitive to altered gravity, and indicates that gravity is obviously not only a requirement for transcriptional processes as described before, but also for specific phosphorylation

HIV-1 Nef and Vpu Interfere with L-Selectin (CD62L) Cell Surface Expression To Inhibit Adhesion and Signaling in Infected CD4+ T Lymphocytes

PubMed Central

Vassena, Lia; Giuliani, Erica; Koppensteiner, Herwig; Bolduan, Sebastian; Schindler, Michael

2015-01-01

ABSTRACT Leukocyte recirculation between blood and lymphoid tissues is required for the generation and maintenance of immune responses against pathogens and is crucially controlled by the L-selectin (CD62L) leukocyte homing receptor. CD62L has adhesion and signaling functions and initiates the capture and rolling on the vascular endothelium of cells entering peripheral lymph nodes. This study reveals that CD62L is strongly downregulated on primary CD4+ T lymphocytes upon infection with human immunodeficiency virus type 1 (HIV-1). Reduced cell surface CD62L expression was attributable to the Nef and Vpu viral proteins and not due to increased shedding via matrix metalloproteases. Both Nef and Vpu associated with and sequestered CD62L in perinuclear compartments, thereby impeding CD62L transport to the plasma membrane. In addition, Nef decreased total CD62L protein levels. Importantly, infection with wild-type, but not Nef- and Vpu-deficient, HIV-1 inhibited the capacity of primary CD4+ T lymphocytes to adhere to immobilized fibronectin in response to CD62L ligation. Moreover, HIV-1 infection impaired the signaling pathways and costimulatory signals triggered in primary CD4+ T cells by CD62L ligation. We propose that HIV-1 dysregulates CD62L expression to interfere with the trafficking and activation of infected T cells. Altogether, this novel HIV-1 function could contribute to virus dissemination and evasion of host immune responses. IMPORTANCE L-selectin (CD62L) is an adhesion molecule that mediates the first steps of leukocyte homing to peripheral lymph nodes, thus crucially controlling the initiation and maintenance of immune responses to pathogens. Here, we report that CD62L is downmodulated on the surfaces of HIV-1-infected T cells through the activities of two viral proteins, Nef and Vpu, that prevent newly synthesized CD62L molecules from reaching the plasma membrane. We provide evidence that CD62L downregulation on HIV-1-infected primary T cells results in

Changes in Expression of Signal Transduction Proteins in T Lymphocytes of Patients with Leprosy

PubMed Central

Zea, Arnold H.; Ochoa, Maria T.; Ghosh, Paritosh; Longo, Dan L.; Alvord, W. Gregory; Valderrama, Liliana; Falabella, Rafael; Harvey, Linda K.; Saravia, Nancy; Moreno, Luis H.; Ochoa, Augusto C.

1998-01-01

Advanced stages of mycobacterial diseases such as leprosy and tuberculosis are characterized by a loss of T-cell function. The basis of this T-cell dysfunction is not well understood. The present report demonstrates major alterations in the expression of signal transduction molecules in T cells of leprosy patients. These alterations were most frequently observed in lepromatous leprosy (LL) patients. Of 29 LL patients, 69% had decreased T-cell receptor ζ-chain expression, 48% had decreased p56lck tyrosine kinase, and 63% had a loss of nuclear transcription factor NF-κB p65. An electrophoretic mobility shift assay with the gamma interferon core promoter region revealed a loss of the Th1 DNA-binding pattern in LL patients. In contrast, tuberculoid leprosy patients had only minor signal transduction alterations. These novel findings might improve our understanding of the T-cell dysfunction observed in leprosy and other infectious diseases and consequently might lead to better immunologic evaluation of patients. PMID:9453602

Thylakoid redox signals are integrated into organellar-gene-expression-dependent retrograde signaling in the prors1-1 mutant

PubMed Central

Tadini, Luca; Romani, Isidora; Pribil, Mathias; Jahns, Peter; Leister, Dario; Pesaresi, Paolo

2012-01-01

Perturbations in organellar gene expression (OGE) and the thylakoid redox state (TRS) activate retrograde signaling pathways that adaptively modify nuclear gene expression (NGE), according to developmental and metabolic needs. The prors1-1 mutation in Arabidopsis down-regulates the expression of the nuclear gene Prolyl-tRNA Synthetase1 (PRORS1) which acts in both plastids and mitochondria, thereby impairing protein synthesis in both organelles and triggering OGE-dependent retrograde signaling. Because the mutation also affects thylakoid electron transport, TRS-dependent signals may likewise have an impact on the changes in NGE observed in this genotype. In this study, we have investigated whether signals related to TRS are actually integrated into the OGE-dependent retrograde signaling pathway. To this end, the chaos mutation (for chlorophyll a/b binding protein harvesting-organelle specific), which shows a partial loss of PSII antennae proteins and thus a reduction in PSII light absorption capability, was introduced into the prors1-1 mutant background. The resulting double mutant displayed a prors1-1-like reduction in plastid translation rate and a chaos-like decrease in PSII antenna size, whereas the hyper-reduction of the thylakoid electron transport chain, caused by the prors1-1 mutation, was alleviated, as determined by monitoring chlorophyll (Chl) fluorescence and thylakoid phosphorylation. Interestingly, a substantial fraction of the nucleus-encoded photosynthesis genes down-regulated in the prors1-1 mutant are expressed at nearly wild-type rates in prors1-1 chaos leaves, and this recovery is reflected in the steady-state levels of their protein products in the chloroplast. We therefore conclude that signals related to photosynthetic electron transport and TRS, and indirectly to carbohydrate metabolism and energy balance, are indeed fed into the OGE-dependent retrograde pathway to modulate NGE and adjust the abundance of chloroplast proteins. PMID:23293642

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8+ T-cell immune responses in tuberculosis infection

PubMed Central

Wang, Yang; Zhong, Huiling; Xie, Xiaodan; Chen, Crystal Y.; Huang, Dan; Shen, Ling; Zhang, Hui; Chen, Zheng W.; Zeng, Gucheng

2015-01-01

Molecular mechanisms for T-cell immune responses modulated by T cell-inhibitory molecules during tuberculosis (TB) infection remain unclear. Here, we show that active human TB infection up-regulates CD244 and CD244 signaling-associated molecules in CD8+ T cells and that blockade of CD244 signaling enhances production of IFN-γ and TNF-α. CD244 expression/signaling in TB correlates with high levels of a long noncoding RNA (lncRNA)-BC050410 [named as lncRNA-AS-GSTT1(1-72) or lncRNA-CD244] in the CD244+CD8+ T-cell subpopulation. CD244 signaling drives lncRNA-CD244 expression via sustaining a permissive chromatin state in the lncRNA-CD244 locus. By recruiting polycomb protein enhancer of zeste homolog 2 (EZH2) to infg/tnfa promoters, lncRNA-CD244 mediates H3K27 trimethylation at infg/tnfa loci toward repressive chromatin states and inhibits IFN-γ/TNF-α expression in CD8+ T cells. Such inhibition can be reversed by knock down of lncRNA-CD244. Interestingly, adoptive transfer of lncRNA-CD244–depressed CD8+ T cells to Mycobacterium tuberculosis (MTB)-infected mice reduced MTB infection and TB pathology compared with lncRNA-CD244–expressed controls. Thus, this work uncovers previously unidentified mechanisms in which T cell-inhibitory signaling and lncRNAs regulate T-cell responses and host defense against TB infection. PMID:26150504

A pathway of costimulation that prevents anergy in CD28- T cells: B7- independent costimulation of CD1-restricted T cells

PubMed Central

1995-01-01

A class of molecules that is expressed on antigen presenting cells, exemplified by CD80 (B7), has been found to provide a necessary costimulatory signal for T cell activation and proliferation. CD28 and CTLA4 are the B7 counterreceptors and are expressed on the majority of human CD4+ T cells and many CD8+ T cells. The signal these molecules mediate is distinguished from other costimulatory signals by the finding that T cell recognition of antigen results in a prolonged state of T cell unresponsiveness or anergy, unless these costimulatory molecules are engaged. However, nearly half of the CD8+ and CD4-CD8- T cells lack CD28, and the costimulatory signals required for the activation of such cells are unknown. To understand the pathways of activation used by CD28- T cells, we have examined the costimulatory requirements of antigen-specific CD4-CD8- TCR(+)-alpha/beta circulating T cells that lack the expression of CD28. We have characterized two T cell lines, DN1 and DN6, that recognize a mycobacterial antigen, and are restricted not by major histocompatibility complex class I or II, but by CD1b or CD1c, two members of a family of major histocompatibility complex-related molecules that have been recently implicated in a distinct pathway for antigen presentation. Comparison of antigen-specific cytolytic responses of the DN1 and DN6 T cell lines against antigen-pulsed CD1+ monocytes or CD1+ B lymphoblastoid cell lines (B-LCL) demonstrated that these T cells recognized antigen presented by both types of cells. However, T cell proliferation occurred only when antigen was presented by CD1+ monocytes, indicating that the CD1+ monocytes expressed a costimulatory molecule that the B- LCL transfectants lacked. This hypothesis was confirmed by demonstrating that the T cells became anergic when incubated with the CD1(+)-transfected B-LCL in the presence of antigen, but not in the absence of antigen. The required costimulatory signal occurred by a CD28-independent mechanism since

Integrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signal.

PubMed

Fuentealba, Luis C; Eivers, Edward; Ikeda, Atsushi; Hurtado, Cecilia; Kuroda, Hiroki; Pera, Edgar M; De Robertis, Edward M

2007-11-30

BMP receptors determine the intensity of BMP signals via Smad1 C-terminal phosphorylations. Here we show that a finely controlled cell biological pathway terminates this activity. The duration of the activated pSmad1(Cter) signal was regulated by sequential Smad1 linker region phosphorylations at conserved MAPK and GSK3 sites required for its polyubiquitinylation and transport to the centrosome. Proteasomal degradation of activated Smad1 and total polyubiquitinated proteins took place in the centrosome. Inhibitors of the Erk, p38, and JNK MAPKs, as well as GSK3 inhibitors, prolonged the duration of a pulse of BMP7. Wnt signaling decreased pSmad1(GSK3) antigen levels and redistributed it from the centrosome to cytoplasmic LRP6 signalosomes. In Xenopus embryos, it was found that Wnts induce epidermis and that this required an active BMP-Smad pathway. Epistatic experiments suggested that the dorsoventral (BMP) and anteroposterior (Wnt/GSK3) patterning gradients are integrated at the level of Smad1 phosphorylations during embryonic pattern formation.

Calcineurin-Crz1 Signaling in Lower Eukaryotes

PubMed Central

2014-01-01

Calcium ions are ubiquitous intracellular messengers. An increase in the cytosolic Ca2+ concentration activates many proteins, including calmodulin and the Ca2+/calmodulin-dependent protein phosphatase calcineurin. The phosphatase is conserved from yeast to humans (except in plants), and many target proteins of calcineurin have been identified. The most prominent and best-investigated targets, however, are the transcription factors NFAT (nuclear factor of activated T cells) in mammals and Crz1 (calcineurin-responsive zinc finger 1) in yeast. In recent years, many orthologues of Crz1 have been identified and characterized in various species of fungi, amoebae, and other lower eukaryotes. It has been shown that the functions of calcineurin-Crz1 signaling, ranging from ion homeostasis through cell wall biogenesis to the building of filamentous structures, are conserved in the different organisms. Furthermore, frequency-modulated gene expression through Crz1 has been discovered as a striking new mechanism by which cells can coordinate their response to a signal. In this review, I focus on the latest findings concerning calcineurin-Crz1 signaling in fungi, amoebae and other lower eukaryotes. I discuss the potential of Crz1 and its orthologues as putative drug targets, and I also discuss possible parallels with calcineurin-NFAT signaling in mammals. PMID:24681686

B and T Lymphocyte Attenuator Down-regulation by HIV-1 Depends on Type I Interferon and Contributes to T-Cell Hyperactivation

PubMed Central

Zhang, Zheng; Xu, Xiangsheng; Lu, Jiyun; Zhang, Shuye; Gu, Lanlan; Fu, Junliang; Jin, Lei; Li, Haiying; Zhao, Min; Zhang, Jiyuan; Wu, Hao; Su, Lishan; Fu, Yang-Xin

2011-01-01

Background. Nonspecific T-cell hyperactivation is the main driving force for human immunodeficiency virus (HIV)–1 disease progression, but the reasons why the excess immune response is not properly shut off are poorly defined. Methods. Eighty-five HIV-1–infected individuals were enrolled to characterize B and T lymphocyte attenuator (BTLA) expression and function. Infection and blockade assays were used to dissect the factors that influenced BTLA signaling in vitro. Results. BTLA expression on overall CD4+ and CD8+ T cells was progressively decreased in HIV-1 infection, which was directly correlated with disease progression and CD4+ T-cell differentiation and activation. BTLA+CD4+ T cells from HIV-1–infected patients also displayed an altered immune status, which was indicated by reduced expression of naive markers but increased activation and exhaustion markers. Cross-linking of BTLA can substantially decrease CD4+ T-cell activation in vitro. This responsiveness of CD4+ T cells to BTLA-mediated inhibitory signaling was further found to be impaired in HIV-1–infected patients. Furthermore, HIV-1 NL4-3 down-regulated BTLA expression on CD4+ T cells dependent on plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α. Blockade of IFN-α or depletion of pDCs prevents HIV-1-induced BTLA down-regulation. Conclusions. HIV-1 infection potentially impairs BTLA-mediated signaling dependent on pDC-derived IFN-α, which may contribute to broad T-cell hyperactivation induced by chronic HIV-1 infection. PMID:21592997

Inhibition of IRAK1/4 sensitizes T cell acute lymphoblastic leukemia to chemotherapies

PubMed Central