Evolution of Intrameniscal Signal-Intensity Alterations Detected on MRI Over 24 Months in Patients With Traumatic Anterior Cruciate Ligament Tear.

PubMed

Guimaraes, Julio Brandao; Facchetti, Luca; Schwaiger, Benedikt J; Gersing, Alexandra S; Majumdar, Sharmila; Ma, Benjamin C; Li, Xiaojuan; Link, Thomas M

2017-02-01

The objective of our study was to assess the prevalence and evolution of intrameniscal signal-intensity alteration in subjects with an anterior cruciate ligament (ACL) tear over 24 months and compare clinical outcome and changes of cartilage between subjects with and those without this meniscal abnormality. Fifty-seven subjects with an ACL tear were screened for intrameniscal signal-intensity alteration. Morphologic and compositional MRI was performed before ACL reconstruction and 12 and 24 months after ACL reconstruction. Twelve subjects with an intrameniscal signal-intensity alteration and 12 subjects without any meniscal abnormality on MRI were identified. Clinical outcome was measured using the Knee Injury and Osteoarthritis Outcome Score (KOOS), and T1ρ and T2 maps of the cartilage were obtained. In 10 of 12 subjects (83%) the meniscal signal-intensity abnormality identified on baseline MRI was located at the posterior horn of the medial meniscus. None of these subjects presented with a meniscal tear over 24 months of follow-up. At 12 months after the ACL tear, the intrameniscal signal-intensity alteration detected on baseline MRI had completely resolved in seven of 12 subjects (58%), showed a signal-intensity decrease in four (33%), and remained stable in one subject (8%). Of the 10 subjects who underwent MRI at 24 months, the meniscal signal-intensity alteration had completely resolved in eight (80%), and the signal intensity had decreased in the other two subjects. Changes in the KOOS and cartilage T1ρ and T2 values from baseline and 24 months did not differ significantly between subjects with and those without intrameniscal signal-intensity alteration (p > 0.05). High intrameniscal signal-intensity alterations are a common finding in subjects with an ACL tear and have a benign course over 24 months after surgical repair of the ACL tear.

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.

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.

Mis-segmentation in voxel-based morphometry due to a signal intensity change in the putamen.

PubMed

Goto, Masami; Abe, Osamu; Miyati, Tosiaki; Aoki, Shigeki; Gomi, Tsutomu; Takeda, Tohoru

2017-12-01

The aims of this study were to demonstrate an association between changes in the signal intensity of the putamen on three-dimensional T1-weighted magnetic resonance images (3D-T1WI) and mis-segmentation, using the voxel-based morphometry (VBM) 8 toolbox. The sagittal 3D-T1WIs of 22 healthy volunteers were obtained for VBM analysis using the 1.5-T MR scanner. We prepared five levels of 3D-T1WI signal intensity (baseline, same level, background level, low level, and high level) in regions of interest containing the putamen. Groups of smoothed, spatially normalized tissue images were compared to the baseline group using a paired t test. The baseline was compared to the other four levels. In all comparisons, significant volume changes were observed around and outside the area that included the signal intensity change. The present study demonstrated an association between a change in the signal intensity of the putamen on 3D-T1WI and changed volume in segmented tissue images.

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.

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.

Asymptomatic Carotid T1-High-Intense Plaque as a Risk Factor for a Subsequent Cerebrovascular Ischemic Event.

PubMed

Kurosaki, Yoshitaka; Yoshida, Kazumichi; Fukuda, Hitoshi; Handa, Akira; Chin, Masaki; Yamagata, Sen

2017-01-01

Intraplaque hemorrhage, detected as a high-signal intensity on carotid MRI, is also strongly associated with ischemic events in symptomatic patients. However, in asymptomatic patients, the relationship of the T1-high intense plaque and the subsequent stroke is not clear. The aim of this study is to test the hypothesis that asymptomatic carotid T1-high intense plaque is a risk factor for a subsequent cerebrovascular ischemic event. Of the 1,353 consecutive patients, who underwent head and carotid MRI as part of their annual medical check-up, the imaging quality of 13 was poor and 150 did not present for follow-up examination, thus leaving 1,190 subjects for evaluation. Of the 1,190 patients, 96 patients had findings of high-signal intensity on carotid MRI and 1,094 patients did not. Cerebrovascular events were retrospectively evaluated. During a mean follow-up period of 53 months, 4 patients with high-signal intensities on carotid MRI (4%) and 3 with no findings (0.3%) had a cerebrovascular ischemic event, with the occurrences significantly higher in the high-signal-intensity group. (p < 0.01) Cox regression analysis indicated that the presence of the high-intense plaque on carotid MRI (hazard ratio [HR] 4.2; 95% CI 1.0-17.1; p = 0.04), age (HR 1.1; 95% CI 1.0-1.2; p = 0.003), and diabetes mellitus (HR 7.2; 95% CI 1.8-27.4; p = 0.004) were associated with the occurrence of subsequent ischemic cerebrovascular events. Asymptomatic carotid T1-high-intense plaque might be a potential high-risk factor for a subsequent cerebrovascular ischemic event. © 2017 S. Karger AG, Basel.

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.

[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

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.

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

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

Statistical analysis of measured free-space laser signal intensity over a 2.33 km optical path.

PubMed

Tunick, Arnold

2007-10-17

Experimental research is conducted to determine the characteristic behavior of high frequency laser signal intensity data collected over a 2.33 km optical path. Results focus mainly on calculated power spectra and frequency distributions. In addition, a model is developed to calculate optical turbulence intensity (C(n)/2) as a function of receiving and transmitting aperture diameter, log-amplitude variance, and path length. Initial comparisons of calculated to measured C(n)/2 data are favorable. It is anticipated that this kind of signal data analysis will benefit laser communication systems development and testing at the U.S. Army Research Laboratory (ARL) and elsewhere.

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.

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

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

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

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.

MR of Toxoplasma encephalitis: Signal characteristics on T2-weighted images and pathologic correlation

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

Brightbill, T.C.; Hensley, G.T.; Ruiz, A.

1996-05-01

Our goal was to determine if there are any T2-weighted MR signal characteristics of Toxoplasma encephalitis that might be useful in diagnosis and/or in gauging the effectiveness of medical therapy. We retrospectively analyzed the MR, CT, thallium-201 SPECT brain scans, and medical records of 27 patients with medically proven (26) and biopsy proven (1) Toxoplasma encephalitis, supplemented by autopsy findings in 4 additional patients, 2 of whom had postmortem MR correlation. The neuropathologic literature was also reviewed. Among the 27 patients, we discovered three distinct imaging patterns. Ten (37%) patients had predominantly T2-weighted hyperintense lesions and had been on medicalmore » therapy an average of 3 days (excluding one outlier). Ten (37%) patients had T2-weighted isointense lesions and had received medical therapy an average of 61 days. Seven (26%) patients had lesions with mixed signal on T2-weighted images and bad been on treatment an average of 6 days. Analysis of autopsy material from the four additional patients revealed the presence of organizing abscesses in three and necrotizing encephalitis in one, while the patient who had a brain biopsy demonstrated both types of pathologic lesions. In both cases having postmortem MRI, organizing abscesses appeared isointense to hypointense on T2-weighted images. There is a definite variation in the appearance of lesions of Toxoplasma encephalitis on T2-weighted images that precludes a definitive diagnosis based on signal characteristics alone. Pathologically, our data suggest that T2-weighted hyperintensity correlates with necrotizing encephalitis and T2-weighted isointensity with organizing abscesses. Furthermore, in patients on medical therapy the T2-weighted MR appearance may be a transition from hyperintensity to isointensity as a function of a positive response to antibiotic treatment, indicating that the signal change might be used to gauge the effectiveness of medical therapy. 15 refs., 6 figs.« less

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.

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.

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.

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.

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.

Estimation of T2* Relaxation Time of Breast Cancer: Correlation with Clinical, Imaging and Pathological Features

PubMed Central

Seo, Mirinae; Jahng, Geon-Ho; Sohn, Yu-Mee; Rhee, Sun Jung; Oh, Jang-Hoon; Won, Kyu-Yeoun

2017-01-01

Objective The purpose of this study was to estimate the T2* relaxation time in breast cancer, and to evaluate the association between the T2* value with clinical-imaging-pathological features of breast cancer. Materials and Methods Between January 2011 and July 2013, 107 consecutive women with 107 breast cancers underwent multi-echo T2*-weighted imaging on a 3T clinical magnetic resonance imaging system. The Student's t test and one-way analysis of variance were used to compare the T2* values of cancer for different groups, based on the clinical-imaging-pathological features. In addition, multiple linear regression analysis was performed to find independent predictive factors associated with the T2* values. Results Of the 107 breast cancers, 92 were invasive and 15 were ductal carcinoma in situ (DCIS). The mean T2* value of invasive cancers was significantly longer than that of DCIS (p = 0.029). Signal intensity on T2-weighted imaging (T2WI) and histologic grade of invasive breast cancers showed significant correlation with T2* relaxation time in univariate and multivariate analysis. Breast cancer groups with higher signal intensity on T2WI showed longer T2* relaxation time (p = 0.005). Cancer groups with higher histologic grade showed longer T2* relaxation time (p = 0.017). Conclusion The T2* value is significantly longer in invasive cancer than in DCIS. In invasive cancers, T2* relaxation time is significantly longer in higher histologic grades and high signal intensity on T2WI. Based on these preliminary data, quantitative T2* mapping has the potential to be useful in the characterization of breast cancer. PMID:28096732

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.

[The use of the T2-weighted turbo-spin-echo sequence in studying the neurocranium. A comparison with the conventional T2-weighted spin-echo sequence].

PubMed

Siewert, C; Hosten, N; Felix, R

1994-07-01

T2-weighted spin-echo imaging is the standard screening procedure in MR imaging of the neurocranium. We evaluated fast spin-echo T2-weighted imaging (TT2) of the neurocranium in comparison to conventional spin-echo T2-weighted imaging (T2). Signal-to-noise and contrast-to-noise ratio of normal brain tissues (basal ganglia, grey and white matter, CSF fluid) and different pathologies were calculated. Signal-to-noise ratio and contrast-to-noise ratio were significantly higher in TT2 than in T2 (with the exception of gray-to-white matter contrast). Tissues with increased content of water protons (mobile protons) showed the highest contrast to surrounding tissues. The increased signal intensity of fat must be given due attention in fatty lesions. Because the contrast-to-noise ratio between white matter and basal ganglia is less in TT2, Parkinson patients have to be examined by conventional T2. If these limitations are taken into account, fast spin-echo T2-weighted imaging is well appropriate for MR imaging of the neurocranium, resulting in heavy T2-weighting achieved in a short acquisition time.

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...

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

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.

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.

Resolution of abnormal cardiac MRI T2 signal following immune suppression for cardiac sarcoidosis.

PubMed

Crouser, Elliott D; Ruden, Emily; Julian, Mark W; Raman, Subha V

2016-08-01

Cardiac MR (CMR) with late gadolinium enhancement is commonly used to detect cardiac damage in the setting of cardiac sarcoidosis. The addition of T2 mapping to CMR was recently shown to enhance cardiac sarcoidosis detection and correlates with increased cardiac arrhythmia risk. This study was conducted to determine if CMR T2 abnormalities and related arrhythmias are reversible following immune suppression therapy. A retrospective study of subjects with cardiac sarcoidosis with abnormal T2 signal on baseline CMR and a follow-up CMR study at least 4 months later was conducted at The Ohio State University from 2011 to 2015. Immune suppression treated participants had a significant reduction in peak myocardial T2 value (70.0±5.5 vs 59.2±6.1 ms, pretreatment vs post-treatment; p=0.017), and 83% of immune suppression treated subjects had objective improvement in cardiac arrhythmias. Two subjects who had received inadequate immune suppression treatment experienced progression of cardiac sarcoidosis. This report indicates that abnormal CMR T2 signal represents an acute inflammatory manifestation of cardiac sarcoidosis that is potentially reversible with adequate immune suppression therapy. Copyright © 2016 American Federation for Medical Research.

β-Arrestin-2-Dependent Signaling Promotes CCR4-mediated Chemotaxis of Murine T-Helper Type 2 Cells.

PubMed

Lin, Rui; Choi, Yeon Ho; Zidar, David A; Walker, Julia K L

2018-06-01

Allergic asthma is a complex inflammatory disease that leads to significant healthcare costs and reduction in quality of life. Although many cell types are implicated in the pathogenesis of asthma, CD4 + T-helper cell type 2 (Th2) cells are centrally involved. We previously reported that the asthma phenotype is virtually absent in ovalbumin-sensitized and -challenged mice that lack global expression of β-arrestin (β-arr)-2 and that CD4 + T cells from these mice displayed significantly reduced CCL22-mediated chemotaxis. Because CCL22-mediated activation of CCR4 plays a role in Th2 cell regulation in asthmatic inflammation, we hypothesized that CCR4-mediated migration of CD4 + Th2 cells to the lung in asthma may use β-arr-dependent signaling. To test this hypothesis, we assessed the effect of various signaling inhibitors on CCL22-induced chemotaxis using in vitro-polarized primary CD4 + Th2 cells from β-arr2-knockout and wild-type mice. Our results show, for the first time, that CCL22-induced, CCR4-mediated Th2 cell chemotaxis is dependent, in part, on a β-arr2-dependent signaling pathway. In addition, we show that this chemotactic signaling mechanism involves activation of P-p38 and Rho-associated protein kinase. These findings point to a proinflammatory role for β-arr2-dependent signaling and support β-arr2 as a novel therapeutic target in asthma.

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

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

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.

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.

What is the most suitable MR signal index for quantitative evaluation of placental function using Half-Fourier acquisition single-shot turbo spin-echo compared with T2-relaxation time?

PubMed

Kameyama, Kyoko Nakao; Kido, Aki; Himoto, Yuki; Moribata, Yusaku; Minamiguchi, Sachiko; Konishi, Ikuo; Togashi, Kaori

2018-06-01

Background Half-Fourier acquisition single-shot turbo spin-echo (HASTE) imaging is now widely used for placental and fetal imaging because of its rapidity and low sensitivity to fetal movement. If placental dysfunction is also predicted by quantitative value obtained from HASTE image, then it might be beneficial for evaluating placental wellbeing. Purpose To ascertain the most suitable magnetic resonance (MR) signal indexes reflecting placental function using HASTE imaging. Material and Methods This retrospective study included 37 consequent patients who had given informed consent to MR imaging (MRI) examinations. All had undergone MRI examinations between February 2014 and June 2015. First, the correlation between T2-relaxation time of normal placenta and gestational age (GA) was examined. Second, correlation between signal intensity ratios (SIRs) using HASTE imaging and placental T2-relaxation time were assessed. The SIRs were calculated using placental signal intensity (SI) relative to the SI of the amniotic fluid, fetal ocular globes, gastric fluid, bladder, maternal psoas major muscles, and abdominal subcutaneous adipose tissue. Results Among the 37 patients, the correlation between T2-relaxation time of the 25 normal placentas and GA showed a moderately strong correlation (Spearman rho = -0.447, P = 0.0250). The most significant correlation with placental T2-relaxation time was observed with the placental SIR relative to the maternal psoas major muscles (SIR pl./psoas muscle ) (Spearman rho = -0.531, P = 0.0007). Conclusion This study revealed that SIR pl./psoas muscle showed the best correlation to placental T2-relaxation time. Results show that SIR pl./psoas muscle might be optimal as a clinically available quantitative index of placental function.

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.

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

Chemical-exchange-sensitive MRI of amide, amine and NOE at 9.4 T versus 15.2 T.

PubMed

Chung, Julius Juhyun; Choi, Wonmin; Jin, Tao; Lee, Jung Hee; Kim, Seong-Gi

2017-09-01

Chemical exchange (CE)-sensitive MRI benefits greatly from stronger magnetic fields; however, field effects on CE-sensitive imaging have not yet been studied well in vivo. We have compared CE-sensitive Z-spectra and maps obtained at the fields of 9.4 T and 15.2 T in phantoms and rats with off-resonance chemical-exchange-sensitive spin lock (CESL), which is similar to conventional chemical exchange saturation transfer. At higher fields, the background peak at water resonance has less spread and the exchange rate relative to chemical shift decreases, thus CESL intensity is dependent on B 0 . For the in vivo amide and nuclear Overhauser enhancement (NOE) composite resonances of rat brains, intensities were similar for both magnetic fields, but effective amide proton transfer and NOE values obtained with three-point quantification or a curve fitting method were larger at 15.2 T due to the reduced spread of attenuation at the direct water resonance. When using intermediate exchange-sensitive irradiation parameters, the amine proton signal was 65% higher at 15.2 T than at 9.4 T due to a reduced ratio of exchange rate to chemical shift. In summary, increasing magnetic field provides enhancements to CE-sensitive signals in the intermediate exchange regime and reduces contamination from background signals in the slow exchange regime. Consequently, ultrahigh magnetic field is advantageous for CE-sensitive MRI, especially for amine and hydroxyl protons. Copyright © 2017 John Wiley & Sons, Ltd.

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

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

Spatio-temporal propagation of Ca2+ signals by cyclic ADP-ribose in 3T3 cells stimulated via purinergic P2Y receptors

PubMed Central

Bruzzone, Santina; Kunerth, Svenja; Zocchi, Elena; De Flora, Antonio; Guse, Andreas H.

2003-01-01

The role of cyclic ADP-ribose in the amplification of subcellular and global Ca2+ signaling upon stimulation of P2Y purinergic receptors was studied in 3T3 fibroblasts. Either (1) 3T3 fibroblasts (CD38− cells), (2) 3T3 fibroblasts preloaded by incubation with extracellular cyclic ADP-ribose (cADPR), (3) 3T3 fibroblasts microinjected with ryanodine, or (4) 3T3 fibroblasts transfected to express the ADP-ribosyl cyclase CD38 (CD38+ cells) were used. Both preincubation with cADPR and CD38 expression resulted in comparable intracellular amounts of cyclic ADP-ribose (42.3 ± 5.2 and 50.5 ± 8.0 pmol/mg protein). P2Y receptor stimulation of CD38− cells yielded a small increase of intracellular Ca2+ concentration and a much higher Ca2+ signal in CD38-transfected cells, in cADPR-preloaded cells, or in cells microinjected with ryanodine. Confocal Ca2+ imaging revealed that stimulation of ryanodine receptors by cADPR or ryanodine amplified localized pacemaker Ca2+ signals with properties resembling Ca2+ quarks and triggered the propagation of such localized signals from the plasma membrane toward the internal environment, thereby initiating a global Ca2+ wave. PMID:14623867

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

Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells.

PubMed

Carmenate, Tania; Ortíz, Yaquelín; Enamorado, Michel; García-Martínez, Karina; Avellanet, Janet; Moreno, Ernesto; Graça, Luis; León, Kalet

2018-05-15

IL-2 is critical for peripheral tolerance mediated by regulatory T (Treg) cells, which represent an obstacle for effective cancer immunotherapy. Although IL-2 is important for effector (E) T cell function, it has been hypothesized that therapies blocking IL-2 signals weaken Treg cell activity, promoting immune responses. This hypothesis has been partially tested using anti-IL-2 or anti-IL-2R Abs with antitumor effects that cannot be exclusively attributed to lack of IL-2 signaling in vivo. In this work, we pursued an alternative strategy to block IL-2 signaling in vivo, taking advantage of the trimeric structure of the IL-2R. We designed an IL-2 mutant that conserves the capacity to bind to the αβ-chains of the IL-2R but not to the γ c -chain, thus having a reduced signaling capacity. We show our IL-2 mutein inhibits IL-2 Treg cell-dependent differentiation and expansion. Moreover, treatment with IL-2 mutein reduces Treg cell numbers and impairs tumor growth in mice. A mathematical model was used to better understand the effect of the mutein on Treg and E T cells, suggesting suitable strategies to improve its design. Our results show that it is enough to transiently inhibit IL-2 signaling to bias E and Treg cell balance in vivo toward immunity. Copyright © 2018 by The American Association of Immunologists, Inc.

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.

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

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.

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

Production of N-acetylgalactosaminyl-transferase 2 (GalNAc-T2) fused with secretory signal Igκ in insect cells.

PubMed

Horynová, Milada; Takahashi, Kazuo; Hall, Stacy; Renfrow, Matthew B; Novak, Jan; Raška, Milan

2012-02-01

The human UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyl-transferase 2 (GalNAc-T2) is one of the key enzymes that initiate synthesis of hinge-region O-linked glycans of human immunoglobulin A1 (IgA1). We designed secreted soluble form of human GalNAc-T2 as a fusion protein containing mouse immunoglobulin light chain kappa secretory signal and expressed it using baculovirus and mammalian expression vectors. The recombinant protein was secreted by insect cells Sf9 and human HEK 293T cells in the culture medium. The protein was purified from the media using affinity Ni-NTA chromatography followed by stabilization of purified protein in 50mM Tris-HCl buffer at pH 7.4. Although the purity of recombinant GalNAc-T2 was comparable in both expression systems, the yield was higher in Sf9 insect expression system (2.5mg of GalNAc-T2 protein per 1L culture medium). The purified soluble recombinant GalNAc-T2 had an estimated molecular mass of 65.8kDa and its amino-acid sequence was confirmed by mass-spectrometric analysis. The enzymatic activity of Sf9-produced recombinant GalNAc-T2 was determined by the quantification of enzyme-mediated attachment of GalNAc to synthetic IgA1 hinge-region peptide as the acceptor and UDP-GalNAc as the donor. In conclusion, murine immunoglobulin kappa secretory signal was used for production of secreted enzymatically active GalNAc-T2 in insect baculovirus expression system. Copyright © 2011 Elsevier Inc. All rights reserved.

Signal-to-noise ratio, T2 , and T2* for hyperpolarized helium-3 MRI of the human lung at three magnetic field strengths.

PubMed

Komlosi, Peter; Altes, Talissa A; Qing, Kun; Mooney, Karen E; Miller, G Wilson; Mata, Jaime F; de Lange, Eduard E; Tobias, William A; Cates, Gordon D; Mugler, John P

2017-10-01

To evaluate T 2 , T2*, and signal-to-noise ratio (SNR) for hyperpolarized helium-3 ( 3 He) MRI of the human lung at three magnetic field strengths ranging from 0.43T to 1.5T. Sixteen healthy volunteers were imaged using a commercial whole body scanner at 0.43T, 0.79T, and 1.5T. Whole-lung T 2 values were calculated from a Carr-Purcell-Meiboom-Gill spin-echo-train acquisition. T2* maps and SNR were determined from dual-echo and single-echo gradient-echo images, respectively. Mean whole-lung SNR values were normalized by ventilated lung volume and administered 3 He dose. As expected, T 2 and T2* values demonstrated a significant inverse relationship to field strength. Hyperpolarized 3 He images acquired at all three field strengths had comparable SNR values and thus appeared visually very similar. Nonetheless, the relatively small SNR differences among field strengths were statistically significant. Hyperpolarized 3 He images of the human lung with similar image quality were obtained at three field strengths ranging from 0.43T and 1.5T. The decrease in susceptibility effects at lower fields that are reflected in longer T 2 and T2* values may be advantageous for optimizing pulse sequences inherently sensitive to such effects. The three-fold increase in T2* at lower field strength would allow lower receiver bandwidths, providing a concomitant decrease in noise and relative increase in SNR. Magn Reson Med 78:1458-1463, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

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.

Evaluation of median nerve T2 signal changes in patients with surgically treated carpal tunnel syndrome.

PubMed

Samanci, Yavuz; Karagöz, Yeşim; Yaman, Mehmet; Atçı, İbrahim Burak; Emre, Ufuk; Kılıçkesmez, Nuri Özgür; Çelik, Suat Erol

2016-11-01

To determine the accuracy of median nerve T2 evaluation and its relation with Boston Questionnaire (BQ) and nerve conduction studies (NCSs) in pre-operative and post-operative carpal tunnel syndrome (CTS) patients in comparison with healthy volunteers. Twenty-three CTS patients and 24 healthy volunteers underwent NCSs, median nerve T2 evaluation and self-administered BQ. Pre-operative and 1st year post-operative median nerve T2 values and cross-sectional areas (CSAs) were compared both within pre-operative and post-operative CTS groups, and with healthy volunteers. The relationship between MRI findings and BQ and NCSs was analyzed. The ROC curve analysis was used for determining the accuracy. The comparison of pre-operative and post-operative T2 values and CSAs revealed statistically significant improvements in the post-operative patient group (p<0.001 for all parameters). There were positive correlations between T2 values at all levels and BQ values, and positive and negative correlations were also found regarding T2 values and NCS findings in CTS patients. The receiver operating characteristic curve analysis for defined cut-off levels of median nerve T2 values in hands with severe CTS yielded excellent accuracy at all levels. However, this accuracy could not be demonstrated in hands with mild CTS. This study is the first to analyze T2 values in both pre-operative and post-operative CTS patients. The presence of increased T2 values in CTS patients compared to controls and excellent accuracy in hands with severe CTS indicates T2 signal changes related to CTS pathophysiology and possible utilization of T2 signal evaluation in hands with severe CTS. Copyright © 2016 Elsevier B.V. All rights reserved.

Acute pancreatitis with gradient echo T2*-weighted magnetic resonance imaging

PubMed Central

Tang, Meng Yue; Chen, Tian Wu; Huang, Xiao Hua; Li, Xing Hui; Wang, Si Yue; Liu, Nian

2016-01-01

Background To study gradient recalled echo (GRE) T2*-weighted imaging (T2*WI) for normal pancreas and acute pancreatitis (AP). Methods Fifty-one patients without any pancreatic disorders (control group) and 117 patients with AP were recruited. T2* values derived from T2*WI of the pancreas were measured for the two groups. The severity of AP was graded by the magnetic resonance severity index (MRSI) and the Acute Physiology and Chronic Healthy Evaluation II (APACHE II) scoring system. Logistic regression was used to analyze the relationship between the T2* values and AP severity. The usefulness of the T2* value for diagnosing AP and the relationship between the T2* values and the severity of AP were analyzed. Results On GRE-T2*WI, the normal pancreas showed a well-marinated and consistently homogeneous isointensity. Edematous AP, as well as the non-necrotic area in necrotizing AP, showed ill-defined but homogeneous signal intensity. AP with pancreatic hemorrhage showed a decreased T2* value and a signal loss on the signal decay curve. The T2* value of pancreas in the AP group was higher than that of the control group (t=−8.20, P<0.05). The T2* value tended to increase along with the increase in MRSI scores but not with the APACHE II scores (P>0.05). AP was associated with a one standard deviation increment in the T2* value (OR =1.37; 95% CI: 1.216–1.532). Conclusions T2*WI demonstrates a few characteristics of the normal pancreas and AP, which could potentially be helpful for detecting hemorrhage, and contributes to diagnosing AP and its severity. PMID:27190768

Effect of Intensive Statin Therapy on Coronary High-Intensity Plaques Detected by Noncontrast T1-Weighted Imaging: The AQUAMARINE Pilot Study.

PubMed

Noguchi, Teruo; Tanaka, Atsushi; Kawasaki, Tomohiro; Goto, Yoichi; Morita, Yoshiaki; Asaumi, Yasuhide; Nakao, Kazuhiro; Fujiwara, Reiko; Nishimura, Kunihiro; Miyamoto, Yoshihiro; Ishihara, Masaharu; Ogawa, Hisao; Koga, Nobuhiko; Narula, Jagat; Yasuda, Satoshi

2015-07-21

Coronary high-intensity plaques detected by noncontrast T1-weighted imaging may represent plaque instability. High-intensity plaques can be quantitatively assessed by a plaque-to-myocardium signal-intensity ratio (PMR). This pilot, hypothesis-generating study sought to investigate whether intensive statin therapy would lower PMR. Prospective serial noncontrast T1-weighted magnetic resonance imaging and computed tomography angiography were performed in 48 patients with coronary artery disease at baseline and after 12 months of intensive pitavastatin treatment with a target low-density lipoprotein cholesterol level <80 mg/dl. The control group consisted of coronary artery disease patients not treated with statins that were matched by propensity scoring (n = 48). The primary endpoint was the 12-month change in PMR. Changes in computed tomography angiography parameters and high-sensitivity C-reactive protein levels were analyzed. In the statin group, 12 months of statin therapy significantly improved low-density lipoprotein cholesterol levels (125 to 70 mg/dl; p < 0.001), PMR (1.38 to 1.11, an 18.9% reduction; p < 0.001), low-attenuation plaque volume, and the percentage of total atheroma volume on computed tomography. In the control group, the PMR increased significantly (from 1.22 to 1.49, a 19.2% increase; p < 0.001). Changes in PMR were correlated with changes in low-density lipoprotein cholesterol (r = 0.533; p < 0.001), high-sensitivity C-reactive protein (r = 0.347; p < 0.001), percentage of atheroma volume (r = 0.477; p < 0.001), and percentage of low-attenuation plaque volume (r = 0.416; p < 0.001). Statin treatment significantly reduced the PMR of high-intensity plaques. Noncontrast T1-weighted magnetic resonance imaging could become a useful technique for repeated quantitative assessment of plaque composition. (Attempts at Plaque Vulnerability Quantification with Magnetic Resonance Imaging Using Noncontrast T1-weighted Technique [AQUAMARINE

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.

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.

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

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

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.

Sympathetic neural signaling via the β2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function.

PubMed

Estrada, Leonardo D; Ağaç, Didem; Farrar, J David

2016-08-01

Postganglionic sympathetic neurons innervate secondary lymphoid organs and secrete norepinephrine (NE) as the primary neurotransmitter. NE binds and signals through five distinct members of the adrenergic receptor family. In this study, we show elevated expression of the β2-adrenergic receptor (ADRB2) on primary human CD8(+) effector memory T cells. Treatment of both human and murine CD8(+) T cells with NE decreased IFN-γ and TNF-α secretion and suppressed their cytolytic capacity in response to T-cell receptor (TCR) activation. The effects of NE were specifically reversed by β2-specific antagonists. Adrb2(-/-) CD8(+) T cells were completely resistant to the effects of NE. Further, the ADRB2-specific pharmacological ligand, albuterol, significantly suppressed effector functions in both human and mouse CD8(+) T cells. While both TCR activation and stimulation with IL-12 + IL-18 were able to induce inflammatory cytokine secretion, NE failed to suppress IFN-γ secretion in response to IL-12 + IL18. Finally, the long-acting ADRB2-specific agonist, salmeterol, markedly reduced the cytokine secretion capacity of CD8(+) T cells in response to infection with vesicular stomatitis virus. This study reveals a novel intrinsic role for ADRB2 signaling in CD8(+) T-cell function and underscores the novel role this pathway plays in adaptive T-cell responses to infection. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Effect of biological characteristics of different types of uterine fibroids, as assessed with T2-weighted magnetic resonance imaging, on ultrasound-guided high-intensity focused ultrasound ablation.

PubMed

Zhao, Wen-Peng; Chen, Jin-Yun; Chen, Wen-Zhi

2015-02-01

The aims of this study were to assess the effects of the biological characteristics of different types of uterine fibroids, as assessed with T2-weighted magnetic resonance imaging (MRI), on ultrasound-guided high-intensity focused ultrasound (USgHIFU) ablation. Thirty-five patients with 39 symptomatic uterine fibroids who underwent myomectomy or hysterectomy were enrolled. Before surgery, the uterine fibroids were subdivided into hypo-intense, iso-intense, heterogeneous hyper-intense and homogeneous hyper-intense categories based on signal intensity on T2-weighted MRI. Tissue density and moisture content were determined in post-operative samples and normal uterine tissue, the isolated uterine fibroids were subjected to USgHIFU, and the extent of ablation was measured using triphenyltetrazolium chloride. Hematoxylin and eosin staining and sirius red staining were undertaken to investigate the organizational structure of the uterine fibroids. Estrogen and progesterone receptor expression was assayed via immunohistochemical staining. The mean diameter of uterine fibroids was 6.9 ± 2.8 cm. For all uterine fibroids, the average density and moisture content were 10.7 ± 0.7 mg/mL and 75.7 ± 2.4%, respectively; and for the homogeneous hyper-intense fibroids, 10.3 ± 0.5 mg/mL and 76.6 ± 2.3%. The latter subgroup had lower density and higher moisture content compared with the other subgroups. After USgHIFU treatment, the extent of ablation of the hyper-intense fibroids was 102.7 ± 42.1 mm(2), which was significantly less than those of the hypo-intense and heterogeneous hyper-intense fibroids. Hematoxylin and eosin staining and sirius red staining revealed that the homogeneous hyper-intense fibroids had sparse collagen fibers and abundant cells. Immunohistochemistry results revealed that estrogen and progesterone receptors were highly expressed in the homogeneous hyper-intense fibroids. This study revealed that lower density, higher moisture content, sparse collagen

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.

Feasibility of in vivo three-dimensional T 2* mapping using dicarboxy-PROXYL and CW-EPR-based single-point imaging.

PubMed

Kubota, Harue; Komarov, Denis A; Yasui, Hironobu; Matsumoto, Shingo; Inanami, Osamu; Kirilyuk, Igor A; Khramtsov, Valery V; Hirata, Hiroshi

2017-06-01

The aim of this study was to demonstrate the feasibility of in vivo three-dimensional (3D) relaxation time T 2 * mapping of a dicarboxy-PROXYL radical using continuous-wave electron paramagnetic resonance (CW-EPR) imaging. Isotopically substituted dicarboxy-PROXYL radicals, 3,4-dicarboxy-2,2,5,5-tetra( 2 H 3 )methylpyrrolidin-(3,4- 2 H 2 )-(1- 15 N)-1-oxyl ( 2 H, 15 N-DCP) and 3,4-dicarboxy-2,2,5,5-tetra( 2 H 3 )methylpyrrolidin-(3,4- 2 H 2 )-1-oxyl ( 2 H-DCP), were used in the study. A clonogenic cell survival assay was performed with the 2 H-DCP radical using squamous cell carcinoma (SCC VII) cells. The time course of EPR signal intensities of intravenously injected 2 H, 15 N-DCP and 2 H-DCP radicals were determined in tumor-bearing hind legs of mice (C3H/HeJ, male, n = 5). CW-EPR-based single-point imaging (SPI) was performed for 3D T 2 * mapping. 2 H-DCP radical did not exhibit cytotoxicity at concentrations below 10 mM. The in vivo half-life of 2 H, 15 N-DCP in tumor tissues was 24.7 ± 2.9 min (mean ± standard deviation [SD], n = 5). The in vivo time course of the EPR signal intensity of the 2 H, 15 N-DCP radical showed a plateau of 10.2 ± 1.2 min (mean ± SD) where the EPR signal intensity remained at more than 90% of the maximum intensity. During the plateau, in vivo 3D T 2 * maps with 2 H, 15 N-DCP were obtained from tumor-bearing hind legs, with a total acquisition time of 7.5 min. EPR signals of 2 H, 15 N-DCP persisted long enough after bolus intravenous injection to conduct in vivo 3D T 2 * mapping with CW-EPR-based SPI.

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.

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.

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

Protein kinase D2 is a digital amplifier of T cell receptor–stimulated diacylglycerol signaling in naïve CD8+ T cells

PubMed Central

Navarro, María N.; Feijoo-Carnero, Carmen; Arandilla, Alba Gonzalez; Trost, Matthias; Cantrell, Doreen A.

2016-01-01

Protein kinase D2 (PKD2) is a serine and threonine kinase that is activated in T cells by diacylglycerol and protein kinase C in response to stimulation of the T cell receptor (TCR) by antigen. We quantified the activation of PKD2 at the single-cell level and found that this kinase acts as a sensitive digital amplifier of TCR engagement, enabling CD8+ T cells to match the production of inflammatory cytokines to the quality and quantity of TCR ligands. There was a digital response pattern of PKD2 activation in response to TCR engagement, such that increasing the concentration and potency of TCR ligands increased the number of cells that exhibited activated PKD2. However, for each cell that responded to TCR stimulation, the entire cellular pool of PKD2 (~400,000 molecules) was activated. Moreover, PKD2 acted as an amplification checkpoint for antigen-stimulated digital cytokine responses and translated the differential strength of TCR signaling to determine the number of naïve CD8+ T cells that became effector cells. Together, these results provide insights into PKD family kinases and how they act digitally to amplify signaling networks controlled by the TCR. PMID:25336615

A comparison study between 3D T2-weighted SPACE and conventional 2D T2-weighted turbo spin echo in assessment of carotid plaque.

PubMed

Lv, Peng; Dai, Yuanyuan; Lin, Jiang; Zhang, Weisheng; Liu, Hao; Liu, Hui; Tang, Xiao

2017-03-01

The aim of this study was to compare 3D T2-weighted sampling perfection with application optimized contrast using different flip angle evolutions (T2w SPACE) with conventional 2D T2w turbo-spin echo (TSE) in plaque imaging of carotid artery. 45 patients underwent 3.0-T MRI for carotid arteries imaging. MR sequences included T2w SPACE, T2w TSE, Time of flight (TOF) and T1-weighted (T1w) TSE. The signal intensity of intra-plaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), and loose matrix (LM) were measured and their contrast ratios (CRs) against adjacent muscle were calculated. CRs from T2w SPACE and T2w TSE were compared to each other. CRs of LM, LRNC, and IPH measured on T2w SPACE were 1.74-3.04 (2.44), 0.98-1.66 (1.39), and 1.91-2.93 (2.51), respectively. CRs of LM, LRNC, and IPH on T2w TSE were 1.97-3.41 (2.44), 1.18-1.73 (1.43), and 2.26-3.75 (2.26), respectively. There was no significant difference of CR of the carotid plaques between T2w SPACE and T2w TSE (p = 0.455). Markedly significant differences of CRs were found between LM and LRNC (p < 0.001), and between LRNC and IPH (p < 0.001) on T2w SPACE and T2w TSE. T2w SPACE was comparable with conventional T2w TSE in characterization of carotid plaque.

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

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...

Dynamic T2-mapping during magnetic resonance guided high intensity focused ultrasound ablation of bone marrow

NASA Astrophysics Data System (ADS)

Waspe, Adam C.; Looi, Thomas; Mougenot, Charles; Amaral, Joao; Temple, Michael; Sivaloganathan, Siv; Drake, James M.

2012-11-01

Focal bone tumor treatments include amputation, limb-sparing surgical excision with bone reconstruction, and high-dose external-beam radiation therapy. Magnetic resonance guided high intensity focused ultrasound (MR-HIFU) is an effective non-invasive thermotherapy for palliative management of bone metastases pain. MR thermometry (MRT) measures the proton resonance frequency shift (PRFS) of water molecules and produces accurate (<1°C) and dynamic (<5s) thermal maps in soft tissues. PRFS-MRT is ineffective in fatty tissues such as yellow bone marrow and, since accurate temperature measurements are required in the bone to ensure adequate thermal dose, MR-HIFU is not indicated for primary bone tumor treatments. Magnetic relaxation times are sensitive to lipid temperature and we hypothesize that bone marrow temperature can be determined accurately by measuring changes in T2, since T2 increases linearly in fat during heating. T2-mapping using dual echo times during a dynamic turbo spin-echo pulse sequence enabled rapid measurement of T2. Calibration of T2-based thermal maps involved heating the marrow in a bovine femur and simultaneously measuring T2 and temperature with a thermocouple. A positive T2 temperature dependence in bone marrow of 20 ms/°C was observed. Dynamic T2-mapping should enable accurate temperature monitoring during MR-HIFU treatment of bone marrow and shows promise for improving the safety and reducing the invasiveness of pediatric bone tumor treatments.

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.

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.

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

[Traffic-related PM2.5 regulates IL-2 releasing in Jurkat T cells by calcium signaling pathway].

PubMed

Tong, Guoqiang; Zhang, Zhihong; Han, Jianbiao; Qiu, Yong; Xu, Jianjun

2013-09-01

To explore the effects of traffic-related PM2.5 on interleukin-2 (IL-2) in Jurkat T cells and the regulatory action of calcium signaling pathway. The cells were exposed to 100 microg/ml of PM2.5 for 3, 6 and 24 h. Normal saline group, blank filter group, calcium chelating agent EGTA group and the calcineurin antagonist cyclosporine A (CSA) group were as parallel control. The level of IL-2 was detected by ELISA kits, the mRNA expression of CaN, NFAT were determined by QRT-PCR. The nuclear distribution of NFAT was observed by immunofluorescence microscopy. The level of IL-2 in Jurkat T cells exposed to 100 microg/ml PM2.5 was significantly lower than parallel groups, but higher than PM2.5 + CSA group and PM2.5 + EGTA group (P < 0.05). With the increase of time, the releasing level of IL-2 appeared reducing trend in 100 microg/ml of PM2.5 group. The mRNA expression level of NFAT and CaN were higher than parallel groups, PM2.5 + CSA group and PM2.5 + EGTA group (P < 0.05). PM2.5 can induce NFAT protein with dephosphorylation and be activated, and NFAT protein can shift into nuclear. The level of IL-2 was negatively associated with the expression level of NFAT and CaN gene (P < 0.05). Traffic-related PM2.5 may inhibit the releasing of IL-2, Ca(2+)-CaN-NFAT signal pathway may involve in the regulation of IL-2.

Decreased SAP expression in T cells from patients with SLE contributes to early signaling abnormalities and reduced IL-2 production

PubMed Central

Karampetsou, Maria P.; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C.; Tsokos, George C.

2016-01-01

T cells from patients with systemic lupus erythematosus (SLE) display a number of functions including increased early signaling events following engagement of the T cell receptor (TCR). Signaling lymphocytic activation molecule family (SLAMF) cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating immune response. Here we present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and 3 men with SLE independently of disease activity. In SLE T cells the SAP protein is also subject to increased degradation by a caspase-3. Forced expression of SAP in SLE T cells simultaneously heightened IL-2 production, calcium (Ca2+) responses and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR antibodies, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. PMID:27183584

Physiological noise in murine solid tumours using T2*-weighted gradient-echo imaging: a marker of tumour acute hypoxia?

PubMed

Baudelet, Christine; Ansiaux, Réginald; Jordan, Bénédicte F; Havaux, Xavier; Macq, Benoit; Gallez, Bernard

2004-08-07

T2*-weighted gradient-echo magnetic resonance imaging (T2*-weighted GRE MRI) was used to investigate spontaneous fluctuations in tumour vasculature non-invasively. FSa fibrosarcomas, implanted intramuscularly (i.m.) in the legs of mice, were imaged at 4.7 T, over a 30 min or 1 h sampling period. On a voxel-by-voxel basis, time courses of signal intensity were analysed using a power spectrum density (PSD) analysis to isolate voxels for which signal changes did not originate from Gaussian white noise or linear drift. Under baseline conditions, the tumours exhibited spontaneous signal fluctuations showing spatial and temporal heterogeneity over the tumour. Statistically significant fluctuations occurred at frequencies ranging from 1 cycle/3 min to 1 cycle/h. The fluctuations were independent of the scanner instabilities. Two categories of signal fluctuations were reported: (i) true fluctuations (TFV), i.e., sequential signal increase and decrease, and (ii) profound drop in signal intensity with no apparent signal recovery (SDV). No temporal correlation between tumour and contralateral muscle fluctuations was observed. Furthermore, treatments aimed at decreasing perfusion-limited hypoxia, such as carbogen combined with nicotinamide and flunarizine, decreased the incidence of tumour T2*-weighted GRE fluctuations. We also tracked dynamic changes in T2* using multiple GRE imaging. Fluctuations of T2* were observed; however, fluctuation maps using PSD analysis could not be generated reliably. An echo-time dependency of the signal fluctuations was observed, which is typical to physiological noise. Finally, at the end of T2*-weighted GRE MRI acquisition, a dynamic contrast-enhanced MRI was performed to characterize the microenvironment in which tumour signal fluctuations occurred in terms of vessel functionality, vascularity and microvascular permeability. Our data showed that TFV were predominantly located in regions with functional vessels, whereas SDV occurred in regions

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

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.

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.

Notch/Delta signaling constrains reengineering of pro-T cells by PU.1

PubMed Central

Franco, Christopher B.; Scripture-Adams, Deirdre D.; Proekt, Irina; Taghon, Tom; Weiss, Angela H.; Yui, Mary A.; Adams, Stephanie L.; Diamond, Rochelle A.; Rothenberg, Ellen V.

2006-01-01

PU.1 is essential for early stages of mouse T cell development but antagonizes it if expressed constitutively. Two separable mechanisms are involved: attenuation and diversion. Dysregulated PU.1 expression inhibits pro-T cell survival, proliferation, and passage through β-selection by blocking essential T cell transcription factors, signaling molecules, and Rag gene expression, which expression of a rearranged T cell antigen receptor transgene cannot rescue. However, Bcl2 transgenic cells are protected from this attenuation and may even undergo β-selection, as shown by PU.1 transduction of defined subsets of Bcl2 transgenic fetal thymocytes with differentiation in OP9-DL1 and OP9 control cultures. The outcome of PU.1 expression in these cells depends on Notch/Delta signaling. PU.1 can efficiently divert thymocytes toward a myeloid-like state with multigene regulatory changes, but Notch/Delta signaling vetoes diversion. Gene expression analysis distinguishes sets of critical T lineage regulatory genes with different combinatorial responses to PU.1 and Notch/Delta signals, suggesting particular importance for inhibition of E proteins, Myb, and/or Gfi1 (growth factor independence 1) in diversion. However, Notch signaling only protects against diversion of cells that have undergone T lineage specification after Thy-1 and CD25 up-regulation. The results imply that in T cell precursors, Notch/Delta signaling normally acts to modulate and channel PU.1 transcriptional activities during the stages from T lineage specification until commitment. PMID:16880393

Infiltrating T cells promote renal cell carcinoma (RCC) progression via altering the estrogen receptor β-DAB2IP signals.

PubMed

Yeh, Chiuan-Ren; Ou, Zheng-Yu; Xiao, Guang-Qian; Guancial, Elizabeth; Yeh, Shuyuan

2015-12-29

Previous studies indicated the T cells, one of the most common types of immune cells existing in the microenvironment of renal cell carcinoma (RCC), may influence the progression of RCC. The potential linkage of T cells and the estrogen receptor beta (ERβ), a key player to impact RCC progression, however, remains unclear. Our results demonstrate that RCC cells can recruit more T cells than non-malignant kidney cells. Using an in vitro matrigel invasion system, we found infiltrating T cells could promote RCC cells invasion via increasing ERβ expression and transcriptional activity. Mechanism dissection suggested that co-culturing T cells with RCC cells released more T cell attraction factors, including IFN-γ, CCL3 and CCL5, suggesting a positive regulatory feed-back mechanism. Meanwhile, infiltrating T cells may also promote RCC cell invasion via increased ERβ and decreased DAB2IP expressions, and knocking down DAB2IP can then reverse the T cells-promoted RCC cell invasion. Together, our results suggest that infiltrating T cells may promote RCC cell invasion via increasing the RCC cell ERβ expression to inhibit the tumor suppressor DAB2IP signals. Further mechanism dissection showed that co-culturing T cells with RCC cells could produce more IGF-1 and FGF-7, which may enhance the ERβ transcriptional activity. The newly identified relationship between infiltrating T cells/ERβ/DAB2IP signals may provide a novel therapeutic target in the development of agents against RCC.

"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.

ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

PubMed Central

Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

2015-01-01

Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

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.

Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4.IL-2.

PubMed

Condie, R; Herring, A; Koh, W S; Lee, M; Kaminski, N E

1996-05-31

Cannabinoid receptors negatively regulate adenylate cyclase through a pertussis toxin-sensitive GTP-binding protein. In the present studies, signaling via the adenylate cyclase/cAMP pathway was investigated in the murine thymoma-derived T-cell line, EL4.IL-2. Northern analysis of EL4.IL-2 cells identified the presence of 4-kilobase CB2 but not CB1 receptor-subtype mRNA transcripts. Southern analysis of genomic DNA digests for the CB2 receptor demonstrated identical banding patterns for EL4.IL-2 cells and mouse-derived DNA, both of which were dissimilar to DNA isolated from rat. Treatment of EL4.IL-2 cells with either cannabinol or Delta9-THC disrupted the adenylate cyclase signaling cascade by inhibiting forskolin-stimulated cAMP accumulation which consequently led to a decrease in protein kinase A activity and the binding of transcription factors to a CRE consensus sequence. Likewise, an inhibition of phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced interleukin 2 (IL-2) protein secretion, which correlated to decreased IL-2 gene transcription, was induced by both cannabinol and Delta9-THC. Further, cannabinoid treatment also decreased PMA/ionomycin-induced nuclear factor binding to the AP-1 proximal site of the IL-2 promoter. Conversely, forskolin enhanced PMA/ionomycin-induced AP-1 binding. These findings suggest that inhibition of signal transduction via the adenylate cyclase/cAMP pathway induces T-cell dysfunction which leads to a diminution in IL-2 gene transcription.

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.

Decreased SAP Expression in T Cells from Patients with Systemic Lupus Erythematosus Contributes to Early Signaling Abnormalities and Reduced IL-2 Production.

PubMed

Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Terhorst, Cox; Kyttaris, Vasileios C; Tsokos, George C

2016-06-15

T cells from patients with systemic lupus erythematosus (SLE) display a number of abnormalities, including increased early signaling events following engagement of the TCR. Signaling lymphocytic activation molecule family cell surface receptors and the X-chromosome-defined signaling lymphocytic activation molecule-associated protein (SAP) adaptor are important in the development of several immunocyte lineages and modulating the immune response. We present evidence that SAP protein levels are decreased in T cells and in their main subsets isolated from 32 women and three men with SLE, independent of disease activity. In SLE T cells, SAP protein is also subject to increased degradation by caspase-3. Forced expression of SAP in SLE T cells normalized IL-2 production, calcium (Ca(2+)) responses, and tyrosine phosphorylation of a number of proteins. Exposure of normal T cells to SLE serum IgG, known to contain anti-CD3/TCR Abs, resulted in SAP downregulation. We conclude that SLE T cells display reduced levels of the adaptor protein SAP, probably as a result of continuous T cell activation and degradation by caspase-3. Restoration of SAP levels in SLE T cells corrects the overexcitable lupus T cell phenotype. Copyright © 2016 by The American Association of Immunologists, Inc.

Fluoxetine suppresses calcium signaling in human T lymphocytes through depletion of intracellular calcium stores.

PubMed

Gobin, V; De Bock, M; Broeckx, B J G; Kiselinova, M; De Spiegelaere, W; Vandekerckhove, L; Van Steendam, K; Leybaert, L; Deforce, D

2015-09-01

Selective serotonin reuptake inhibitors, such as fluoxetine, have recently been shown to exert anti-inflammatory and immunosuppressive effects. Although the effects on cytokine secretion, proliferation and viability of T lymphocytes have been extensively characterized, little is known about the mechanism behind these effects. It is well known that Ca(2+) signaling is an important step in the signaling transduction pathway following T cell receptor activation. Therefore, we investigated if fluoxetine interferes with Ca(2+) signaling in Jurkat T lymphocytes. Fluoxetine was found to suppress Ca(2+) signaling in response to T cell receptor activation. Moreover, fluoxetine was found to deplete intracellular Ca(2+) stores, thereby leaving less Ca(2+) available for release upon IP3- and ryanodine-receptor activation. The Ca(2+)-modifying effects of fluoxetine are not related to its capability to block the serotonin transporter, as even a large excess of 5HT did not abolish the effects. In conclusion, these data show that fluoxetine decreases IP3- and ryanodine-receptor mediated Ca(2+) release in Jurkat T lymphocytes, an effect likely to be at the basis of the observed immunosuppression. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

The attentional blink is not affected by backward masking of T2, T2-mask SOA, or level of T2 impoverishment.

PubMed

Jannati, Ali; Spalek, Thomas M; Lagroix, Hayley E P; Di Lollo, Vincent

2012-02-01

Identification of the second of two targets (T2) is impaired when presented shortly after the first (T1). This attentional blink (AB) is thought to arise from a delay in T2 processing during which T2 is vulnerable to masking. Conventional studies have measured T2 accuracy which is constrained by the 100% ceiling. We avoided this problem by using a dynamic threshold-tracking procedure that is inherently free from ceiling constraints. In two experiments we examined how AB magnitude is affected by three masking-related factors: (a) presence/absence of T2 mask, (b) T2-mask stimulus onset asynchrony (SOA), and (c) level of T2 impoverishment (signal-to-noise ratio [SNR]). In Experiment 1, overall accuracy decreased with T2-mask SOA. The magnitude of the AB, however, was invariant with SOA and with mask presence/absence. Experiment 2 further showed that the AB was invariant with T2 SNR. The relationship among mask presence/absence, SOA, and T2 SNR and the AB is encompassed in a qualitative model.

T2 hyperintense signal in patients with temporal lobe epilepsy with MRI signs of hippocampal sclerosis and in patients with temporal lobe epilepsy with normal MRI.

PubMed

Kubota, Bruno Yukio; Coan, Ana Carolina; Yasuda, Clarissa Lin; Cendes, Fernando

2015-05-01

Increased MRI T2 signal is commonly present not only in the hippocampus but also in other temporal structures of patients with temporal lobe epilepsy (TLE), and it is associated with histological abnormalities related to the epileptogenic lesion. This study aimed to verify the distribution of T2 increased signal in temporal lobe structures and its correlations with clinical characteristics of TLE patients with (TLE-HS) or without (TLE-NL) MRI signs of hippocampal sclerosis. We selected 203 consecutive patients: 124 with TLE-HS and 79 with TLE-NL. Healthy controls (N=59) were used as a comparison group/comparative group. T2 multiecho images obtained via a 3-T MRI were evaluated with in-house software. T2 signal decays were computed from five original echoes in regions of interest in the hippocampus, amygdala, and white matter of the anterior temporal lobe. Values higher than 2 standard deviations from the mean of controls were considered as abnormal. T2 signal increase was observed in the hippocampus in 78% of patients with TLE-HS and in 17% of patients with TLE-NL; in the amygdala in 13% of patients with TLE-HS and in 14% of patients with TLE-NL; and in the temporal lobe white matter in 22% of patients with TLE-HS and in 8% of patients with TLE-NL. Group analysis demonstrated a significant difference in the distribution of the T2 relaxation times of the hippocampus (ANOVA, p<0.0001), amygdala (p=0.003), and temporal lobe white matter (p<0.0001) ipsilateral to the epileptogenic zone for patients with TLE-HS compared with controls but only for the amygdala (p=0.029) and temporal lobe white matter (ANOVA, p=0.025) for patients with TLE-NL compared with controls. The average signal from the hippocampus ipsilateral to the epileptogenic zone was significantly higher in patients with no family history of epilepsy (two-sample T-test, p=0.005). Increased T2 signal occurs in different temporal structures of patients with TLE-HS and in patients with TLE-NL. The hippocampal

A dynamic dual role of IL-2 signaling in the two-step differentiation process of adaptive regulatory T cells.

PubMed

Guo, Zhiyong; Khattar, Mithun; Schroder, Paul M; Miyahara, Yoshihiro; Wang, Guohua; He, Xiaoshung; Chen, Wenhao; Stepkowski, Stanislaw M

2013-04-01

The molecular mechanism of the extrathymic generation of adaptive, or inducible, CD4(+)Foxp3(+) regulatory T cells (iTregs) remains incompletely defined. We show that exposure of splenic CD4(+)CD25(+)Foxp3(-) cells to IL-2, but not other common γ-chain cytokines, resulted in Stat5 phosphorylation and induced Foxp3 expression in ∼10% of the cells. Thus, IL-2/Stat5 signaling may be critical for Foxp3 induction in peripheral CD4(+)CD25(+)Foxp3(-) iTreg precursors. In this study, to further define the role of IL-2 in the formation of iTreg precursors as well as their subsequent Foxp3 expression, we designed a two-step iTreg differentiation model. During the initial "conditioning" step, CD4(+)CD25(-)Foxp3(-) naive T cells were activated by TCR stimulation. Inhibition of IL-2 signaling via Jak3-Stat5 was required during this step to generate CD4(+)CD25(+)Foxp3(-) cells containing iTreg precursors. During the subsequent Foxp3-induction step driven by cytokines, IL-2 was the most potent cytokine to induce Foxp3 expression in these iTreg precursors. This two-step method generated a large number of iTregs with relatively stable expression of Foxp3, which were able to prevent CD4(+)CD45RB(high) cell-mediated colitis in Rag1(-/-) mice. In consideration of this information, whereas initial inhibition of IL-2 signaling upon T cell priming generates iTreg precursors, subsequent activation of IL-2 signaling in these precursors induces the expression of Foxp3. These findings advance the understanding of iTreg differentiation and may facilitate the therapeutic use of iTregs in immune disorders.

Motion corrected DWI with integrated T2-mapping for simultaneous estimation of ADC, T2-relaxation and perfusion in prostate cancer.

PubMed

Skorpil, M; Brynolfsson, P; Engström, M

2017-06-01

Multiparametric magnetic resonance imaging (MRI) and PI-RADS (Prostate Imaging - Reporting and Data System) has become the standard to determine a probability score for a lesion being a clinically significant prostate cancer. T2-weighted and diffusion-weighted imaging (DWI) are essential in PI-RADS, depending partly on visual assessment of signal intensity, while dynamic-contrast enhanced imaging is less important. To decrease inter-rater variability and further standardize image evaluation, complementary objective measures are in need. We here demonstrate a sequence enabling simultaneous quantification of apparent diffusion coefficient (ADC) and T2-relaxation, as well as calculation of the perfusion fraction f from low b-value intravoxel incoherent motion data. Expandable wait pulses were added to a FOCUS DW SE-EPI sequence, allowing the effective echo time to change at run time. To calculate both ADC and f, b-values 200s/mm 2 and 600s/mm 2 were chosen, and for T2-estimation 6 echo times between 64.9ms and 114.9ms were used. Three patients with prostate cancer were examined and all had significantly decreased ADC and T2-values, while f was significantly increased in 2 of 3 tumors. T2 maps obtained in phantom measurements and in a healthy volunteer were compared to T2 maps from a SE sequence with consecutive scans, showing good agreement. In addition, a motion correction procedure was implemented to reduce the effects of prostate motion, which improved T2-estimation. This sequence could potentially enable more objective tumor grading, and decrease the inter-rater variability in the PI-RADS classification. Copyright © 2017 Elsevier Inc. All rights reserved.

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

TCR signaling by conventional CD4+ T cells is required for optimal maintenance of peripheral regulatory T cell numbers.

PubMed

Leichner, Theresa M; Satake, Atsushi; Kambayashi, Taku

2016-06-01

To maintain immune tolerance, regulatory T cell (Treg) numbers must be closely indexed to the number of conventional T cells (Tconvs) so that an adequate Treg:Tconv ratio can be maintained. Two factors important in this process are the cytokine interleukin-2 (IL-2) and T cell receptor (TCR) stimulation by major histocompatibility complex class II (MHC-II). Here, we report that in addition to TCR stimulation of Tregs themselves, the maintenance of Tregs also requires TCR signaling by Tconvs. We found that Tconvs produce IL-2 in response to self-peptide-MHC-II complexes and that Tconvs possessing more highly self-reactive TCRs express more IL-2 at baseline. Furthermore, selective disruption of TCR signaling in Tconvs led to a trend toward decreased expression of IL-2 and attenuated their ability to maintain Treg numbers. These data suggest that in order to maintain an adequate Treg:Tconv ratio, Tregs are continuously indexed to self-peptide-MHC-II-induced TCR signaling of Tconvs. These results have implications in attempts to modulate immune tolerance, as Treg numbers adjust to the self-reactivity, and ultimately IL-2 production by the T cells around them.

Exploiting multicompartment effects in triple-echo steady-state T2 mapping for fat fraction quantification.

PubMed

Liu, Dian; Steingoetter, Andreas; Curcic, Jelena; Kozerke, Sebastian

2018-01-01

To investigate and exploit the effect of intravoxel off-resonance compartments in the triple-echo steady-state (TESS) sequence without fat suppression for T 2 mapping and to leverage the results for fat fraction quantification. In multicompartment tissue, where at least one compartment is excited off-resonance, the total signal exhibits periodic modulations as a function of echo time (TE). Simulated multicompartment TESS signals were synthesized at various TEs. Fat emulsion phantoms were prepared and scanned at the same TE combinations using TESS. In vivo knee data were obtained with TESS to validate the simulations. The multicompartment effect was exploited for fat fraction quantification in the stomach by acquiring TESS signals at two TE combinations. Simulated and measured multicompartment signal intensities were in good agreement. Multicompartment effects caused erroneous T 2 offsets, even at low water-fat ratios. The choice of TE caused T 2 variations of as much as 28% in cartilage. The feasibility of fat fraction quantification to monitor the decrease of fat content in the stomach during digestion is demonstrated. Intravoxel off-resonance compartments are a confounding factor for T 2 quantification using TESS, causing errors that are dependent on the TE. At the same time, off-resonance effects may allow for efficient fat fraction mapping using steady-state imaging. Magn Reson Med 79:423-429, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Gaining insight into the T _2^*-T2 relationship in surface NMR free-induction decay measurements

NASA Astrophysics Data System (ADS)

Grombacher, Denys; Auken, Esben

2018-05-01

One of the primary shortcomings of the surface nuclear magnetic resonance (NMR) free-induction decay (FID) measurement is the uncertainty surrounding which mechanism controls the signal's time dependence. Ideally, the FID-estimated relaxation time T_2^* that describes the signal's decay carries an intimate link to the geometry of the pore space. In this limit the parameter T_2^* is closely linked to a related parameter T2, which is more closely linked to pore-geometry. If T_2^* ˜eq {T_2} the FID can provide valuable insight into relative pore-size and can be used to make quantitative permeability estimates. However, given only FID measurements it is difficult to determine whether T_2^* is linked to pore geometry or whether it has been strongly influenced by background magnetic field inhomogeneity. If the link between an observed T_2^* and the underlying T2 could be further constrained the utility of the standard surface NMR FID measurement would be greatly improved. We hypothesize that an approach employing an updated surface NMR forward model that solves the full Bloch equations with appropriately weighted relaxation terms can be used to help constrain the T_2^*-T2 relationship. Weighting the relaxation terms requires estimating the poorly constrained parameters T2 and T1; to deal with this uncertainty we propose to conduct a parameter search involving multiple inversions that employ a suite of forward models each describing a distinct but plausible T_2^*-T2 relationship. We hypothesize that forward models given poor T2 estimates will produce poor data fits when using the complex-inversion, while forward models given reliable T2 estimates will produce satisfactory data fits. By examining the data fits produced by the suite of plausible forward models, the likely T_2^*-T2 can be constrained by identifying the range of T2 estimates that produce reliable data fits. Synthetic and field results are presented to investigate the feasibility of the proposed technique.

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.

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

Measuring hepatic functional reserve using T1 mapping of Gd-EOB-DTPA enhanced 3T MR imaging: A preliminary study comparing with 99mTc GSA scintigraphy and signal intensity based parameters.

PubMed

Nakagawa, Masataka; Namimoto, Tomohiro; Shimizu, Kie; Morita, Kosuke; Sakamoto, Fumi; Oda, Seitaro; Nakaura, Takeshi; Utsunomiya, Daisuke; Shiraishi, Shinya; Yamashita, Yasuyuki

2017-07-01

To determine the utility of liver T1-mapping on gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) enhanced magnetic resonance (MR) imaging for the measurement of liver functional reserve compared with the signal intensity (SI) based parameters, technetium-99m-galactosyl serum albumin ( 99m Tc-GSA) scintigraphy and indocyanine green (ICG) clearance. This retrospective study included 111 patients (Child-Pugh-A 90; -B 21) performed with both Gd-EOB-DTPA enhanced liver MR imaging and 99m Tc-GSA (76 patients with ICG). Receiver operating characteristic (ROC) curve analysis was performed to compare diagnostic performances of T1-relaxation-time parameters [pre-(T1pre) and post-contrast (T1hb) Gd-EOB-DTPA], SI based parameters [relative enhancement (RE), liver-to-muscle-ratio (LMR), liver-to-spleen-ratio (LSR)] and 99m Tc-GSA scintigraphy blood clearance index (HH15)] for Child-Pugh classification. Pearson's correlation was used for comparisons among T1-relaxation-time parameters, SI-based parameters, HH15 and ICG. A significant difference was obtained for Child-Pugh classification with T1hb, ΔT1, all SI based parameters and HH15. T1hb had the highest AUC followed by RE, LMR, LSR, ΔT1, HH15 and T1pre. The correlation coefficients with HH15 were T1pre 0.22, T1hb 0.53, ΔT1 -0.38 of T1 relaxation parameters; RE -0.44, LMR -0.45, LSR -0.43 of SI-based parameters. T1hb was highest for correlation with HH15. The correlation coefficients with ICG were T1pre 0.29, T1hb 0.64, ΔT1 -0.42 of T1 relaxation parameters; RE -0.50, LMR -0.61, LSR -0.58 of SI-based parameters; 0.64 of HH15. Both T1hb and HH15 were highest for correlation with ICG. T1 relaxation time at post-contrast of Gd-EOB-DTPA (T1hb) was strongly correlated with ICG clearance and moderately correlated HH15 with 99m Tc-GSA. T1hb has the potential to provide robust parameter of liver functional reserve. Copyright © 2017 Elsevier B.V. All rights reserved.

WE-G-BRD-09: Prediction of Local Control/Failure by Using Feature Histogram Selection in Follow-Up T2-Weighted MR Image in Spinal Tumors After Stereotactic Body Radiation Therapy

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

Zhou, J; Harb, J; Jawad, M

2014-06-15

Purpose: In follow-up T2-weighted MR images of spinal tumor patients treated with stereotactic body radiation therapy (SBRT), high intensity features embedded in dark surroundings may suggest a local failure (LF). We investigated image intensity histogram in imaging features to predict LF and local control (LC). Methods: Sixty-seven spinal tumors were treated with SBRT at our institution with scheduled follow-up MR T2-weighted (TR 3200–6600ms; TE 75-132ms) imaging. The LF group included 10 tumors with 8.7 months median follow-up, while the LC group had 11 tumors with 24.1 months median follow-up. The follow-up images were fused to the planning CT. Image intensitymore » histograms of the GTV were calculated. Voxels in greater than 90% (V90), 80% (V80), and peak (Vpeak) of the histogram were grouped into sub-ROIs to determine the best feature histogram. The intensity of each sub-ROI was evaluated using the mean T2-weighted signal ratio (intensity in sub-ROI / intensity in normal vertebrae). An ROC curve in predicting LF for each sub-ROI was calculated to determine the best feature histogram parameter for LF prediction. Results: Mean T2-weighted signal ratio in the LF group was significantly higher than that in the LC group for all sub-ROIs (1.1±0.4 vs. 0.7±0.2, 1.2±0.4 vs. 0.8±0.2, 1.4±0.5 vs. 0.8±0.2, for V90, V80, and Vpeak, p=0.02, 0.02, and 0.002, respectively). The corresponding areas-under-curve (AUC) of ROC were 0.78, 0.80, and 0.87, p=0.02, 0.03, 0.004, respectively. No correlation was found between T2-weighted signal ratio in Vpeak and follow-up time (Pearson's ρ=0.15). Conclusion: Increased T2-weighted signal can be used to identify local failure while decreased signal indicates local control after spinal SBRT. By choosing the best histogram parameter (here the Vpeak), the AUC of the ROC can be substantially improved, which implies reliable prediction of LC and LF. These results are being further studied and validated with large multi

Potential of fluid-attenuated inversion recovery (FLAIR) in identification of temporomandibular joint effusion compared with T2-weighted images.

PubMed

Imoto, Kenichi; Otonari-Yamamoto, Mika; Nishikawa, Keiichi; Sano, Tsukasa; Yamamoto, Aya

2011-08-01

The purpose of this study was to determine the potential of fluid-attenuated inversion recovery (FLAIR) sequence images in the identification of joint effusion (JE) compared with T2-weighted images. A total of 31 joints (28 patients) with JE were investigated by magnetic resonance imaging (MRI). Regions of interest were placed over JE, cerebrospinal fluid (CSF), and gray matter (GM) on T2-weighted and FLAIR images and their signal intensities compared. The signal intensity ratios (SIRs) of JE and CSF were calculated with GM as the reference point. The Pearson product-moment correlation coefficient was used for the statistical analysis. The SIR of JE showed a strong correlation between T2-weighted and FLAIR images. However, no correlation was observed for CSF. The average suppression ratio for JE was lower than that for CSF. MRI using FLAIR sequences revealed that JE was not just water content, but a fluid accumulation containing elements such as protein. Further studies are needed, and FLAIR sequences could be useful for the diagnosis of pain and symptoms of the temporomandibular joint (TMJ). Copyright © 2011 Mosby, Inc. All rights reserved.

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.

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.

Comparing consistency of R2* and T2*-weighted BOLD analysis of resting state fetal fMRI

NASA Astrophysics Data System (ADS)

Seshamani, Sharmishtaa; Blazejewska, Anna I.; Gatenby, Christopher; Mckown, Susan; Caucutt, Jason; Dighe, Manjiri; Studholme, Colin

2015-03-01

Understanding when and how resting state brain functional activity begins in the human brain is an increasing area of interest in both basic neuroscience and in the clinical evaluation of the brain during pregnancy and after premature birth. Although fMRI studies have been carried out on pregnant women since the 1990's, reliable mapping of brain function in utero is an extremely challenging problem due to the unconstrained fetal head motion. Recent studies have employed scrubbing to exclude parts of the time series and whole subjects from studies in order to control the confounds of motion. Fundamentally, even after correction of the location of signals due to motion, signal intensity variations are a fundamental limitation, due to coil sensitivity and spin history effects. An alternative technique is to use a more parametric MRI signal derived from multiple echoes that provides a level of independence from basic MRI signal variation. Here we examine the use of R2* mapping combined with slice based multi echo geometric distortion correction for in-utero studies. The challenges for R2* mapping arise from the relatively low signal strength of in-utero data. In this paper we focus on comparing activation detection in-utero using T2W and R2* approaches. We make use a subset of studies with relatively limited motion to compare the activation patterns without the additional confound of significant motion. Results at different gestational ages indicate comparable agreement in many activation patterns when limited motion is present, and the detection of some additional networks in the R2* data, not seen in the T2W results.

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

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.

Notch ligands Delta1 and Jagged1 transmit distinct signals to T-cell precursors

PubMed Central

Lehar, Sophie M.; Dooley, James; Farr, Andrew G.; Bevan, Michael J.

2009-01-01

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and γδ T-cell lineages. PMID:15486060

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.

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.

The effect of Liuwei Dihuang decoction on PI3K/Akt signaling pathway in liver of type 2 diabetes mellitus (T2DM) rats with insulin resistance.

PubMed

Dai, Bing; Wu, Qinxuan; Zeng, Chengxi; Zhang, Jiani; Cao, Luting; Xiao, Zizeng; Yang, Menglin

2016-11-04

Liuwei Dihaung decoction (LWDHT) is a well-known classic traditional Chinese medicine formula, consists of six herbs including Rehmannia glutinosa Libosch.(family: Scrophulariaceae), Cornus officinalis Sieb.(family: Cornaceae), Dioscorea opposite Thunb.(family: Dioscoreaceae), Alisma orientale(G. Samuelsson) Juz (family: Alismataceae), Poria cocos (Schw.) Wolf (family: Polyporaceae) and Paeonia suffruticosa Andrews (family: Paeoniaceae). It has been used in the treatment of many types of diseases with signs of deficiency of Yin in the kidneys in China clinically. This study is aimed at investigating the effect of Liuwei dihuang decoction on PI3K/Akt signaling pathway in liver of T2DM rats with insulin resistance. T2DM model was induced in male Sprague-Dawley (SD) rats by high sugar and high fat diets combined with small dose of streptozocin (STZ) injection. The successful T2DM rats were randomly allocated three group--vehicle group, positive control group and Liuwei Dihuang decoction group. After 12-weeks treatment with distilled water, rosiglitazone and LWDHT by intragastric administration respectively, the rats were put to death in batches. The variance of fasting blood glucose (FBG) and fasting insulin (FINS) in serum were determined, the pathological changes of each rats' liver were observed by hematoxylin-eosin (HE) staining, the expression of insulin receptor substrate 2(IRS2), phosphatidylinositol 3-kinase (PI3K) and protein kinas B (Akt) involving the canonical PI3K/Akt signaling pathway were detected by Real-time fluorescent quantitative PCR (RT-PCR), and the expression level of IRS2, PI3K, Akt protein and phosphorylated IRS2, PI3K, Akt protein were evaluated by Western Blot. All the data were analyzed by SPSS 17.0. Four weeks of treatment with LWDHT could significantly decrease the level of FBG and FINS in serum, improve the cellular morphology of liver, kidney, pancreas tissue, and the expression of IRS2, PI3K, Akt mRNA and phosphorylated IRS2, PI3K, Akt

Effect of Wnt-1 inducible signaling pathway protein-2 (WISP-2/CCN5), a downstream protein of Wnt signaling, on adipocyte differentiation

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

Inadera, Hidekuni; Shimomura, Akiko; Tachibana, Shinjiro

2009-02-20

Wnt signaling negatively regulates adipocyte differentiation, and ectopic expression of Wnt-1 in 3T3-L1 cells induces several downstream molecules of Wnt signaling, including Wnt-1 inducible signaling pathway protein (WISP)-2. In this study, we examined the role of WISP-2 in the process of adipocyte differentiation using an in vitro cell culture system. In the differentiation of 3T3-L1 cells, WISP-2 expression was observed in growing cells and declined thereafter. In the mitotic clonal expansion phase of adipocyte differentiation, WISP-2 expression was transiently down-regulated concurrently with up-regulation of CCAAT/enhancer-binding protein {delta} expression. Treatment of 3T3-L1 cells in the differentiation medium with lithium, an activatormore » of Wnt signaling, inhibited the differentiation process with concomitant induction of WISP-2. Treatment of differentiated cells with lithium induced de-differentiation as evidenced by profound reduction of peroxisome proliferator-activator receptor {gamma} expression and concomitant induction of WISP-2. However, de-differentiation of differentiated cells induced by tumor necrosis factor-{alpha} did not induce WISP-2 expression. To directly examine the effect of WISP-2 on adipocyte differentiation, 3T3-L1 cells were infected with a retrovirus carrying WISP-2. Although forced expression of WISP-2 inhibited preadipocyte proliferation, it had no effect on adipocyte differentiation. Thus, although WISP-2 is a downstream protein of Wnt signaling, the role of WISP-2 on adipocyte differentiation may be marginal, at least in this in vitro culture model.« less

A new linear least squares method for T1 estimation from SPGR signals with multiple TRs

NASA Astrophysics Data System (ADS)

Chang, Lin-Ching; Koay, Cheng Guan; Basser, Peter J.; Pierpaoli, Carlo

2009-02-01

The longitudinal relaxation time, T1, can be estimated from two or more spoiled gradient recalled echo x (SPGR) images with two or more flip angles and one or more repetition times (TRs). The function relating signal intensity and the parameters are nonlinear; T1 maps can be computed from SPGR signals using nonlinear least squares regression. A widely-used linear method transforms the nonlinear model by assuming a fixed TR in SPGR images. This constraint is not desirable since multiple TRs are a clinically practical way to reduce the total acquisition time, to satisfy the required resolution, and/or to combine SPGR data acquired at different times. A new linear least squares method is proposed using the first order Taylor expansion. Monte Carlo simulations of SPGR experiments are used to evaluate the accuracy and precision of the estimated T1 from the proposed linear and the nonlinear methods. We show that the new linear least squares method provides T1 estimates comparable in both precision and accuracy to those from the nonlinear method, allowing multiple TRs and reducing computation time significantly.

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

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.

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

Revised PROPELLER for T2-weighted imaging of the prostate at 3 Tesla: impact on lesion detection and PI-RADS classification.

PubMed

Meier-Schroers, Michael; Marx, Christian; Schmeel, Frederic Carsten; Wolter, Karsten; Gieseke, Jürgen; Block, Wolfgang; Sprinkart, Alois Martin; Traeber, Frank; Willinek, Winfried; Schild, Hans Heinz; Kukuk, Guido Matthias

2018-01-01

To evaluate revised PROPELLER (RevPROP) for T2-weighted imaging (T2WI) of the prostate as a substitute for turbo spin echo (TSE). Three-Tesla MR images of 50 patients with 55 cancer-suspicious lesions were prospectively evaluated. Findings were correlated with histopathology after MRI-guided biopsy. T2 RevPROP, T2 TSE, diffusion-weighted imaging, dynamic contrast enhancement, and MR-spectroscopy were acquired. RevPROP was compared to TSE concerning PI-RADS scores, lesion size, lesion signal-intensity, lesion contrast, artefacts, and image quality. There were 41 carcinomas in 55 cancer-suspicious lesions. RevPROP detected 41 of 41 carcinomas (100%) and 54 of 55 lesions (98.2%). TSE detected 39 of 41 carcinomas (95.1%) and 51 of 55 lesions (92.7%). RevPROP showed fewer artefacts and higher image quality (each p < 0.001). No differences were observed between single and overall PI-RADS scores based on RevPROP or TSE (p = 0.106 and p = 0.107). Lesion size was not different (p = 0.105). T2-signal intensity of lesions was higher and T2-contrast of lesions was lower on RevPROP (each p < 0.001). For prostate cancer detection RevPROP is superior to TSE with respect to motion robustness, image quality and detection rates of lesions. Therefore, RevPROP might be used as a substitute for T2WI. • Revised PROPELLER can be used as a substitute for T2-weighted prostate imaging. • Revised PROPELLER detected more carcinomas and more suspicious lesions than TSE. • Revised PROPELLER showed fewer artefacts and better image quality compared to TSE. • There were no significant differences in PI-RADS scores between revised PROPELLER and TSE. • The lower T2-contrast of revised PROPELLER did not impair its diagnostic quality.

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.

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

Phosphoproteomics analyses show subnetwork systems in T-cell receptor signaling.

PubMed

Hatano, Atsushi; Matsumoto, Masaki; Nakayama, Keiichi I

2016-10-01

A key issue in the study of signal transduction is how multiple signaling pathways are systematically integrated into the cell. We have now performed multiple phosphoproteomics analyses focused on the dynamics of the T-cell receptor (TCR) signaling network and its subsystem mediated by the Ca 2+ signaling pathway. Integration of these phosphoproteomics data sets and extraction of components of the TCR signaling network dependent on Ca 2+ signaling showed unexpected phosphorylation kinetics for candidate substrates of the Ca 2+ -dependent phosphatase calcineurin (CN) during TCR stimulation. Detailed characterization of the TCR-induced phosphorylation of a novel CN substrate, Itpkb, showed that phosphorylation of this protein is regulated by both CN and the mitogen-activated protein kinase Erk in a competitive manner. Phosphorylation of additional CN substrates was also found to be regulated by Erk and CN in a similar manner. The combination of multiple phosphoproteomics approaches thus showed two major subsystems mediated by Erk and CN in the TCR signaling network, with these subsystems regulating the phosphorylation of a group of proteins in a competitive manner. © 2016 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

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

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.

Possible involvement of transient receptor potential ankyrin 1 in Ca2+ signaling via T-type Ca2+ channel in mouse sensory neurons.

PubMed

Nishizawa, Yuki; Takahashi, Kenji; Oguma, Naoko; Tominaga, Makoto; Ohta, Toshio

2018-05-01

T-type Ca 2+ channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T-type Ca 2+ channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca 2+ concentration ([Ca 2+ ] i ), which were suppressed by selective T-type Ca 2+ channel blockers. RT-PCR showed that mouse sensory neurons expressed all subtypes of T-type Ca 2+ channel. The magnitude of 15K-induced [Ca 2+ ] i increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1 -/- mouse sensory neurons. TRPA1 blockers diminished the [Ca 2+ ] i responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl-induced [Ca 2+ ] i increases even in AITC-sensitive neurons. TRPV1 blockers did not inhibit the 15K-induced [Ca 2+ ] i increase regardless of the sensitivity to capsaicin. [Ca 2+ ] i responses to TRPA1 agonist were enhanced by co-application with 15K. These pharmacological data suggest the possibility of functional interaction between T-type Ca 2+ channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca 2+ , we hypothesize that Ca 2+ entered via T-type Ca 2+ channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T-type Ca 2+ channel may be a potential target for TRPA1-related pain. © 2017 Wiley Periodicals, Inc.

GRE T2∗-Weighted MRI: Principles and Clinical Applications

PubMed Central

Tang, Meng Yue; Chen, Tian Wu; Zhang, Xiao Ming; Huang, Xiao Hua

2014-01-01

The sequence of a multiecho gradient recalled echo (GRE) T2*-weighted imaging (T2*WI) is a relatively new magnetic resonance imaging (MRI) technique. In contrast to T2 relaxation, which acquires a spin echo signal, T2* relaxation acquires a gradient echo signal. The sequence of a GRE T2*WI requires high uniformity of the magnetic field. GRE T2*WI can detect the smallest changes in uniformity in the magnetic field and can improve the rate of small lesion detection. In addition, the T2* value can indirectly reflect changes in tissue biochemical components. Moreover, it can be used for the early diagnosis and quantitative diagnosis of some diseases. This paper reviews the principles and clinical applications as well as the advantages and disadvantages of GRE T2*WI. PMID:24987676

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

The adapter protein SLP-76 mediates "outside-in" integrin signaling and function in T cells.

PubMed

Baker, R G; Hsu, C J; Lee, D; Jordan, M S; Maltzman, J S; Hammer, D A; Baumgart, T; Koretzky, G A

2009-10-01

The adapter protein SH2 domain-containing leukocyte protein of 76 kDa (SLP-76) is an essential mediator of signaling from the T-cell antigen receptor (TCR). We report here that SLP-76 also mediates signaling downstream of integrins in T cells and that SLP-76-deficient T cells fail to support adhesion to integrin ligands. In response to both TCR and integrin stimulation, SLP-76 relocalizes to surface microclusters that colocalize with phosphorylated signaling proteins. Disruption of SLP-76 recruitment to the protein named LAT (linker for activation of T cells) inhibits SLP-76 clustering downstream of the TCR but not downstream of integrins. Conversely, an SLP-76 mutant unable to bind ADAP (adhesion and degranulation-promoting adapter protein) forms clusters following TCR but not integrin engagement and fails to support T-cell adhesion to integrin ligands. These findings demonstrate that SLP-76 relocalizes to integrin-initiated signaling complexes by a mechanism different from that employed during TCR signaling and that SLP-76 relocalization corresponds to SLP-76-dependent integrin function in T cells.

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.

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.

Effects of RF profile on precision of quantitative T2 mapping using dual-echo steady-state acquisition.

PubMed

Wu, Pei-Hsin; Cheng, Cheng-Chieh; Wu, Ming-Long; Chao, Tzu-Cheng; Chung, Hsiao-Wen; Huang, Teng-Yi

2014-01-01

The dual echo steady-state (DESS) sequence has been shown successful in achieving fast T2 mapping with good precision. Under-estimation of T2, however, becomes increasingly prominent as the flip angle decreases. In 3D DESS imaging, therefore, the derived T2 values would become a function of the slice location in the presence of non-ideal slice profile of the excitation RF pulse. Furthermore, the pattern of slice-dependent variation in T2 estimates is dependent on the RF pulse waveform. Multi-slice 2D DESS imaging provides better inter-slice consistency, but the signal intensity is subject to integrated effects of within-slice distribution of the actual flip angle. Consequently, T2 measured using 2D DESS is prone to inaccuracy even at the designated flip angle of 90°. In this study, both phantom and human experiments demonstrate the above phenomena in good agreement with model prediction. © 2013.

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

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...

An alternative mode of CD43 signal transduction activates pro-survival pathways of T lymphocytes.

PubMed

Bravo-Adame, Maria Elena; Vera-Estrella, Rosario; Barkla, Bronwyn J; Martínez-Campos, Cecilia; Flores-Alcantar, Angel; Ocelotl-Oviedo, Jose Pablo; Pedraza-Alva, Gustavo; Rosenstein, Yvonne

2017-01-01

CD43 is one of the most abundant co-stimulatory molecules on a T-cell surface; it transduces activation signals through its cytoplasmic domain, contributing to modulation of the outcome of T-cell responses. The aim of this study was to uncover new signalling pathways regulated by this sialomucin. Analysis of changes in protein abundance allowed us to identify pyruvate kinase isozyme M2 (PKM2), an enzyme of the glycolytic pathway, as an element potentially participating in the signalling cascade resulting from the engagement of CD43 and the T-cell receptor (TCR). We found that the glycolytic activity of this enzyme was not significantly increased in response to TCR+CD43 co-stimulation, but that PKM2 was tyrosine phosphorylated, suggesting that it was performing moonlight functions. We report that phosphorylation of both Y 105 of PKM2 and of Y 705 of signal transducer and activator of transcription 3 was induced in response to TCR+CD43 co-stimulation, resulting in activation of the mitogen-activated protein kinase kinase 5/extracellular signal-regulated kinase 5 (MEK5/ERK5) pathway. ERK5 and the cAMP response element binding protein (CREB) were activated, and c-Myc and nuclear factor-κB (p65) nuclear localization, as well as Bad phosphorylation, were augmented. Consistent with this, expression of human CD43 in a murine T-cell hybridoma favoured cell survival. Altogether, our data highlight novel signalling pathways for the CD43 molecule in T lymphocytes, and underscore a role for CD43 in promoting cell survival through non-glycolytic functions of metabolic enzymes. © 2016 John Wiley & Sons Ltd.

Inelastic Single Pion Signal Study in T2K νe Appearance using Modified Decay Electron Cut

NASA Astrophysics Data System (ADS)

Iwamoto, Konosuke; T2K Collaboration

2015-04-01

The T2K long-baseline neutrino experiment uses sophisticated selection criteria to identify the neutrino oscillation signals among the events reconstructed in the Super-Kamiokande (SK) detector for νe and νμ appearance and disappearance analyses. In current analyses, charged-current quasi-elastic (CCQE) events are used as the signal reaction in the SK detector because the energy can be precisely reconstructed. This talk presents an approach to increase the statistics of the oscillation analysis by including non-CCQE events with one Michel electron and reconstruct them as the inelastic single pion productions. The increase in statistics, backgrounds to this new process and energy reconstruction implications will be presented with this increased event sample.

T2-weighted images are superior to other MR image types for the determination of diffuse intrinsic pontine glioma intratumoral heterogeneity.

PubMed

Harward, Stephen; Harrison Farber, S; Malinzak, Michael; Becher, Oren; Thompson, Eric M

2018-03-01

Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SD Tumor ) normalized to the genu of the corpus callosum (SD Corpus Callosum ). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. MR images from 18 patients with DIPG were evaluated. The mean survival ± standard deviation was 13.8 ± 13.7 months. T2-weighted images had the highest HI (mean ± SD, 5.1 ± 2.5) followed by contrast-enhanced T1-weighted images (3.7 ± 1.5), FLAIR images (3.0 ± 1.1), and ADC maps (1.6 ± 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p < 0.01) and ADC (p < 0.0001). Following radiotherapy, T2-weighted and contrast-enhanced T1-weighted image HI values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with

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

Suboptimal T-cell receptor signaling compromises protein translation, ribosome biogenesis, and proliferation of mouse CD8 T cells.

PubMed

Tan, Thomas C J; Knight, John; Sbarrato, Thomas; Dudek, Kate; Willis, Anne E; Zamoyska, Rose

2017-07-25

Global transcriptomic and proteomic analyses of T cells have been rich sources of unbiased data for understanding T-cell activation. Lack of full concordance of these datasets has illustrated that important facets of T-cell activation are controlled at the level of translation. We undertook translatome analysis of CD8 T-cell activation, combining polysome profiling and microarray analysis. We revealed that altering T-cell receptor stimulation influenced recruitment of mRNAs to heavy polysomes and translation of subsets of genes. A major pathway that was compromised, when TCR signaling was suboptimal, was linked to ribosome biogenesis, a rate-limiting factor in both cell growth and proliferation. Defective TCR signaling affected transcription and processing of ribosomal RNA precursors, as well as the translation of specific ribosomal proteins and translation factors. Mechanistically, IL-2 production was compromised in weakly stimulated T cells, affecting the abundance of Myc protein, a known regulator of ribosome biogenesis. Consequently, weakly activated T cells showed impaired production of ribosomes and a failure to maintain proliferative capacity after stimulation. We demonstrate that primary T cells respond to various environmental cues by regulating ribosome biogenesis and mRNA translation at multiple levels to sustain proliferation and differentiation.

Multicomponent T2 relaxation studies of the avian egg.

PubMed

Mitsouras, Dimitris; Mulkern, Robert V; Maier, Stephan E

2016-05-01

To investigate the tissue-like multiexponential T2 signal decays in avian eggs. Transverse relaxation studies of raw, soft-boiled and hard-boiled eggs were performed at 3 Tesla using a three-dimensional Carr-Purcell-Meiboom-Gill imaging sequence. Signal decays over a TE range of 11 to 354 ms were fitted assuming single- and multicomponent signal decays with up to three separately decaying components. Fat saturation was used to facilitate spectral assignment of observed decay components. Egg white, yolk and the centrally located latebra all demonstrate nonmonoexponential T2 decays. Specifically, egg white exhibits two-component decays with intermediate and long T2 times. Meanwhile, yolk and latebra are generally best characterized with triexponential decays, with short, intermediate and very long T2 decay times. Fat saturation revealed that the intermediate component of yolk could be attributed to lipids. Cooking of the egg profoundly altered the decay curves. Avian egg T2 decay curves cover a wide range of decay times. Observed T2 components in yolk and latebra as short as 10 ms, may prove valuable for testing clinical sequences designed to measure short T2 components, such as myelin-associated water in the brain. Thus we propose that the egg can be a versatile and widely available MR transverse relaxation phantom. © 2015 Wiley Periodicals, Inc.

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

Intensity Accents in French 2 Year Olds' Speech.

ERIC Educational Resources Information Center

Allen, George D.

The acoustic features and functions of accentuation in French are discussed, and features of accentuation in the speech of French 2-year-olds are explored. The four major acoustic features used to signal accentual distinctions are fundamental frequency of voicing, duration of segments and syllables, intensity of segments and syllables, and…

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

Determination of the Association Between T2-weighted MRI and Gleason Sub-pattern: A Proof of Principle Study.

PubMed

Downes, Michelle R; Gibson, Eli; Sykes, Jenna; Haider, Masoom; van der Kwast, Theo H; Ward, Aaron

2016-11-01

The study aimed to determine the relationship between T2-weighted magnetic resonance imaging (MRI) signal and histologic sub-patterns in prostate cancer areas with different Gleason grades. MR images of prostates (n = 25) were obtained prior to radical prostatectomy. These were processed as whole-mount specimens with tumors and the peripheral zone was annotated digitally by two pathologists. Gleason grade 3 was the most prevalent grade and was subdivided into packed, intermediate, and sparse based on gland-to-stroma ratio. Large cribriform, intraductal carcinoma, and small cribriform glands (grade 4 group) were separately annotated but grouped together for statistical analysis. The log MRI signal intensity for each contoured region (n = 809) was measured, and pairwise comparisons were performed using the open-source software R version 3.0.1. Packed grade 3 sub-pattern has a significantly lower MRI intensity than the grade 4 group (P < 0.00001). Sparse grade 3 has a significantly higher MRI intensity than the packed grade 3 sub-pattern (P < 0.0001). No significant difference in MRI intensity was observed between the Gleason grade 4 group and the sparse sub-pattern grade 3 group (P = 0.54). In multivariable analysis adjusting for peripheral zone, the P values maintained significance (packed grade 3 group vs grade 4 group, P < 0.001; and sparse grade 3 sub-pattern vs packed grade 3 sub-pattern, P < 0.001). This study demonstrated that T2-weighted MRI signal is dependent on histologic sub-patterns within Gleason grades 3 and 4 cancers, which may have implications for directed biopsy sampling and patient management. Copyright © 2016 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells

PubMed Central

2017-01-01

ABSTRACT Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein–Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8+ T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a−/− CD8+ T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a−/− CD8+ T cells responded equivalently to wild-type CD8+ T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8+ T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8+ T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8+ T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas. PMID:28344876

2B4-SAP signaling is required for the priming of naive CD8+ T cells by antigen-expressing B cells and B lymphoma cells.

PubMed

Huang, Yu-Hsuan; Tsai, Kevin; Tan, Sara Y; Kang, Sohyeong; Ford, Mandy L; Harder, Kenneth W; Priatel, John J

2017-01-01

Mutations in SH2D1A gene that encodes SAP (SLAM-associated protein) result in X-linked lymphoproliferative disease (XLP), a rare primary immunodeficiency disease defined by exquisite sensitivity to the B-lymphotropic Epstein-Barr virus (EBV) and B cell lymphomas. However, the precise mechanism of how the loss of SAP function contributes to extreme vulnerability to EBV and the development of B cell lymphomas remains unclear. Here, we investigate the hypothesis that SAP is critical for CD8 + T cell immune surveillance of antigen (Ag)-expressing B cells or B lymphoma cells under conditions of defined T cell receptor (TCR) signaling. Sh2d1a - / - CD8 + T cells exhibited greatly diminished proliferation relative to wild type when Ag-presenting-B cells or -B lymphoma cells served as the primary Ag-presenting cell (APC). By contrast, Sh2d1a - / - CD8 + T cells responded equivalently to wild-type CD8 + T cells when B cell-depleted splenocytes, melanoma cells or breast carcinoma cells performed Ag presentation. Through application of signaling lymphocyte activation molecule (SLAM) family receptor blocking antibodies or SLAM family receptor-deficient CD8 + T cells and APCs, we found that CD48 engagement on the B cell surface by 2B4 is crucial for initiating SAP-dependent signaling required for the Ag-driven CD8 + T cell proliferation and differentiation. Altogether, a pivotal role for SAP in promoting the expansion and differentiation of B cell-primed viral-specific naive CD8 + T cells may explain the selective immune deficiency of XLP patients to EBV and B cell lymphomas.

In vitro and in vivo effects of zinc on cytokine signalling in human T cells.

PubMed

Varin, Audrey; Larbi, Anis; Dedoussis, George V; Kanoni, Stavroula; Jajte, Jolanta; Rink, Lothar; Monti, Daniela; Malavolta, Marco; Marcellini, Fiorella; Mocchegiani, Eugenio; Herbein, Georges; Fulop, Tamas

2008-05-01

Aging is associated with changes in the immune response which are collectively called immunosenescence. The changes mainly affect the adaptive immune response and especially the T cell-mediated cellular immune response. There are a few data indicating that the cytokine signalling in T cells is altered with aging. Zinc has been specifically shown to have potent immunomodulatory effects. The aim of the present work was to study the IL-2 and IL-6 cytokine signalling and activation induced cell death (AICD) in T cells of elderly subjects of various ages and from various European countries. These experiments were performed in the frame of European Community financed project called ZINCAGE "Nutritional zinc, oxidative stress and immunosenescence: biochemical, genetic and lifestyle implications for healthy ageing", assembling 17 laboratories from 8 countries through Europe. The study was carried out in a total of 312 French and a group of 201 (26 from Italy, 63 from France, 57 from Greece, 24 from Poland and 30 from Germany) healthy non-institutionalized men and women older than 60 years of age, with available dietary data. Human peripheral blood mononuclear cells (PBMC) were obtained from heparinized blood and were stimulated in vitro by IL-2 or IL-6 for various periods and the phosphorylation of STAT3 and STAT5 was measured by FACScan. The activation induced cell death (AICD) was measured after anti-CD3 and CD28 restimulation for 48h by using the Annexin:FITC Apoptosis Kit. We found that there is an IL-2 signalling defect with aging up to 90 years of age which cannot be modulated by zinc. In contrast at 90 years and over the zinc could reverse the negative signalling effect of IL-2. There is also a signalling defect for STAT3 and STAT5 activation in T cells under IL-6 stimulation with aging and the zinc supplementation could potentiate only the STAT5 activation in the age-group 90 years and over. Studying signalling in PBL from different countries we detected less

3T deep gray matter T2 hypointensity correlates with disability over time in stable relapsing-remitting multiple sclerosis: a 3-year pilot study.

PubMed

Zhang, Y; Metz, L M; Yong, V W; Mitchell, J R

2010-10-15

Abnormally decreased deep gray matter (GM) signal intensity on T2-weighted MRI (T2 hypointensity) is associated with brain atrophy and disability progression in patients with multiple sclerosis (MS) and is believed to represent excessive iron deposition. We investigated the time course of deep GM T2 hypointensity and its relationship with disability at 3T in 8 stable relapsing-remitting (RR) MS patients treated with minocycline over 3years. MRI and disability measurements were compared at baseline, 6, 12, 24, and 36months. Grand mean deep GM T2 hypointensity was negatively correlated with EDSS over time (r=-0.94, P=0.02). This correlation was strongest in the head of caudate (r=-0.95, P=0.01) and putamen (r=-0.89, P=0.04). Additionally, baseline grand mean deep GM T2 hypointensity appears to predict third year EDSS (r=-0.72, P=0.04). These results suggest that iron associated deep GM injury correlates with patient disability in stable RRMS. Measurements of deep GM T2 hypointensity at high field MRI may prove to be useful in monitoring individuals with MS. Further studies are required to confirm these results in a large sample and to determine if T2 hypointensity changes in clinically active MS patients. Copyright 2010 Elsevier B.V. All rights reserved.

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

CD2 and CD3 associate independently with CD5 and differentially regulate signaling through CD5 in Jurkat T cells.

PubMed

Carmo, A M; Castro, M A; Arosa, F A

1999-10-15

In T lymphocytes, the CD2 and CD5 glycoproteins are believed to be involved in the regulation of signals elicited by the TCR/CD3 complex. Here we show that CD2 and CD3 independently associate with CD5 in human PBMC and Jurkat cells. CD5 coprecipitates with CD2 in CD3-deficient cells and, conversely, coprecipitates with CD3 in cells devoid of CD2. In unstimulated CD2+ CD3+ Jurkat cells, CD5 associates equivalently with CD2 and CD3 and is as efficiently phosphorylated in CD2 as in CD3 immune complexes. However, upon activation the involvement of CD5 is the opposite in the CD2 and CD3 pathways. CD5 becomes rapidly tyrosine phosphorylated after CD3 stimulation, but is dephosphorylated upon CD2 cross-linking. These opposing effects correlate with the decrease in the activity of the SH2 domain-containing protein phosphatase 1 (SHP-1) following CD3 activation vs an enhanced activity of the phosphatase after CD2 triggering. The failure of CD5 to become phosphorylated on tyrosine residues in the CD2 pathway has no parallel with the lack of use of zeta-chains in CD2 signaling; contrasting with comparable levels of association of CD2 or CD3 with CD5, zeta associates with CD2 only residually and is nevertheless slightly phosphorylated after CD2 stimulation. The modulation of CD5 phosphorylation may thus represent a level of regulation controlled by CD2 in signal transduction mechanisms in human T lymphocytes.

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

MR signal-fat-fraction analysis and T2* weighted imaging measure BAT reliably on humans without cold exposure.

PubMed

Holstila, Milja; Pesola, Marko; Saari, Teemu; Koskensalo, Kalle; Raiko, Juho; Borra, Ronald J H; Nuutila, Pirjo; Parkkola, Riitta; Virtanen, Kirsi A

2017-05-01

Brown adipose tissue (BAT) is compositionally distinct from white adipose tissue (WAT) in terms of triglyceride and water content. In adult humans, the most significant BAT depot is localized in the supraclavicular area. Our aim is to differentiate brown adipose tissue from white adipose tissue using fat T2* relaxation time mapping and signal-fat-fraction (SFF) analysis based on a commercially available modified 2-point-Dixon (mDixon) water-fat separation method. We hypothesize that magnetic resonance (MR) imaging can reliably measure BAT regardless of the cold-induced metabolic activation, with BAT having a significantly higher water and iron content compared to WAT. The supraclavicular area of 13 volunteers was studied on 3T PET-MRI scanner using T2* relaxation time and SFF mapping both during cold exposure and at ambient temperature; and 18 F-FDG PET during cold exposure. Volumes of interest (VOIs) were defined semiautomatically in the supraclavicular fat depot, subcutaneous WAT and muscle. The supraclavicular fat depot (assumed to contain BAT) had a significantly lower SFF and fat T2* relaxation time compared to subcutaneous WAT. Cold exposure did not significantly affect MR-based measurements. SFF and T2* values measured during cold exposure and at ambient temperature correlated inversely with the glucose uptake measured by 18 F-FDG PET. Human BAT can be reliably and safely assessed using MRI without cold activation and PET-related radiation exposure. Copyright © 2017 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

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

Tyrosine Kinase 2-mediated Signal Transduction in T Lymphocytes Is Blocked by Pharmacological Stabilization of Its Pseudokinase Domain*

PubMed Central

Tokarski, John S.; Zupa-Fernandez, Adriana; Tredup, Jeffrey A.; Pike, Kristen; Chang, ChiehYing; Xie, Dianlin; Cheng, Lihong; Pedicord, Donna; Muckelbauer, Jodi; Johnson, Stephen R.; Wu, Sophie; Edavettal, Suzanne C.; Hong, Yang; Witmer, Mark R.; Elkin, Lisa L.; Blat, Yuval; Pitts, William J.; Weinstein, David S.; Burke, James R.

2015-01-01

Inhibition of signal transduction downstream of the IL-23 receptor represents an intriguing approach to the treatment of autoimmunity. Using a chemogenomics approach marrying kinome-wide inhibitory profiles of a compound library with the cellular activity against an IL-23-stimulated transcriptional response in T lymphocytes, a class of inhibitors was identified that bind to and stabilize the pseudokinase domain of the Janus kinase tyrosine kinase 2 (Tyk2), resulting in blockade of receptor-mediated activation of the adjacent catalytic domain. These Tyk2 pseudokinase domain stabilizers were also shown to inhibit Tyk2-dependent signaling through the Type I interferon receptor but not Tyk2-independent signaling and transcriptional cellular assays, including stimulation through the receptors for IL-2 (JAK1- and JAK3-dependent) and thrombopoietin (JAK2-dependent), demonstrating the high functional selectivity of this approach. A crystal structure of the pseudokinase domain liganded with a representative example showed the compound bound to a site analogous to the ATP-binding site in catalytic kinases with features consistent with high ligand selectivity. The results support a model where the pseudokinase domain regulates activation of the catalytic domain by forming receptor-regulated inhibitory interactions. Tyk2 pseudokinase stabilizers, therefore, represent a novel approach to the design of potent and selective agents for the treatment of autoimmunity. PMID:25762719

MRI signal distribution within the intervertebral disc as a biomarker of adolescent idiopathic scoliosis and spondylolisthesis.

PubMed

Gervais, Julien; Périé, Delphine; Parent, Stefan; Labelle, Hubert; Aubin, Carl-Eric

2012-12-03

Early stages of scoliosis and spondylolisthesis entail changes in the intervertebral disc (IVD) structure and biochemistry. The current clinical use of MR T2-weighted images is limited to visual inspection. Our hypothesis is that the distribution of the MRI signal intensity within the IVD in T2-weighted images depends on the spinal pathology and on its severity. Therefore, this study aims to develop the AMRSID (analysis of MR signal intensity distribution) method to analyze the 3D distribution of the MR signal intensity within the IVD and to evaluate their sensitivity to scoliosis and spondylolisthesis and their severities. This study was realized on 79 adolescents who underwent a MRI acquisition (sagittal T2-weighted images) before their orthopedic or surgical treatment. Five groups were considered: low severity scoliosis (Cobb angle ≤50°), high severity scoliosis (Cobb angles >50°), low severity spondylolisthesis (Meyerding grades I and II), high severity spondylolisthesis (Meyerding grades III, IV and V) and control. The distribution of the MRI signal intensity within the IVD was analyzed using the descriptive statistics of histograms normalized by either cerebrospinal fluid or bone signal intensity, weighted centers and volume ratios. Differences between pathology and severity groups were assessed using one- and two-way ANOVAs. There were significant (p < 0.05) variations of indices between scoliosis, spondylolithesis and control groups and between low and high severity groups. The cerebrospinal fluid normalization was able to detect differences between healthy and pathologic IVDs whereas the bone normalization, which reflects both bone and IVD health, detected more differences between the severities of these pathologies. This study proves for the first time that changes in the intervertebral disc, non visible to the naked eye on sagittal T2-weighted MR images of the spine, can be detected from specific indices describing the distribution of the MR

Coagulative interstitial laser-induced thermotherapy of benign prostatic hyperplasia: online imaging with a T2-weighted fast spin-echo MR sequence--experience in six patients.

PubMed

Mueller-Lisse, U G; Thoma, M; Faber, S; Heuck, A F; Muschter, R; Schneede, P; Weninger, E; Hofstetter, A G; Reiser, M F

1999-02-01

To determine if hypointense lesions clearly outline on T2-weighted fast spin-echo (SE) magnetic resonance (MR) images obtained during coagulative interstitial laser-induced thermotherapy (LITT) of a prostate with benign hyperplasia. In six patients with benign prostatic hyperplasia (BPH), 12 LITT treatments were followed online with repetitive axial T2-weighted fast SE imaging (repetition time, 3,700 msec; echo time, 138 msec; acquisition time, 19 seconds). Development, time course, correlation with interstitial tissue temperature, and diameters of hypointense lesions around the laser diffusor tip were investigated. Lesion diameters on T2-weighted images acquired during LITT were compared with diameters of final lesions on T2-weighted images and unperfused lesions on enhanced T1-weighted SE images obtained at the end of therapy. Hypointense lesions developed within 20-40 seconds of LITT. Average correlation coefficients between interstitial temperature development and signal intensity development were 0.92 during LITT and 0.90 after LITT. Regression slopes were significantly steeper during LITT (0.67% signal intensity change per degree Celsius) than after LITT (0.47% per degree Celsius; P = .038). Lesions remained visible after LITT for all procedures. Average maximum diameters of lesions were 1-3 mm larger during LITT than after LITT (P = .0006-.019). Repetitive T2-weighted fast SE MR imaging during interstitial coagulative LITT of BPH demonstrates the development of permanent hypointense prostate lesions. However, posttherapeutic lesion diameters tend to be overestimated during LITT.

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

Direct Assessment of Wall Shear Stress by Signal Intensity Gradient from Time-of-Flight Magnetic Resonance Angiography

PubMed Central

Lee, Sang Hyuk; Ryu, Han Uk; Park, Se-Hyoung; Chung, Gyung-Ho; Cho, Young I.

2017-01-01

The aim of the study was to calculate the arterial wall signal intensity gradient (SIG) from time-of-flight MR angiography (TOF-MRA) and represent arterial wall shear stress. We developed a new algorithm that uses signal intensity (SI) of a TOF-MRA to directly calculate the signal intensity gradient (SIG). The results from our phantom study showed that the TOF-MRA SIG could be used to distinguish the magnitude of blood flow rate as high (mean SIG ± SD, 2.2 ± 0.4 SI/mm for 12.5 ± 2.3 L/min) and low (0.9 ± 0.3 SI/mm for 8.5 ± 2.6 L/min) in vessels (p < 0.001). Additionally, we found that the TOF-MRA SIG values were highly correlated with various flow rates (β = 0.96, p < 0.001). Remarkably, the correlation coefficient between the WSS obtained from the computational fluid dynamics (CFD) analysis and the TOF-MRA SIG was greater than 0.8 in each section at the carotid artery (p < 0.001 for all β values). This new technique using TOF-MRA could enable the rapid calculation of the TOF-MRA SIG and thereby the WSS. Thus, the TOF-MRA SIG can provide clinicians with an accurate and efficient screening method for making rapid decisions on the risk of vascular disease for a patient in clinical practice. PMID:28900625

Direct Assessment of Wall Shear Stress by Signal Intensity Gradient from Time-of-Flight Magnetic Resonance Angiography.

PubMed

Han, Kap-Soo; Lee, Sang Hyuk; Ryu, Han Uk; Park, Se-Hyoung; Chung, Gyung-Ho; Cho, Young I; Jeong, Seul-Ki

2017-01-01

The aim of the study was to calculate the arterial wall signal intensity gradient (SIG) from time-of-flight MR angiography (TOF-MRA) and represent arterial wall shear stress. We developed a new algorithm that uses signal intensity (SI) of a TOF-MRA to directly calculate the signal intensity gradient (SIG). The results from our phantom study showed that the TOF-MRA SIG could be used to distinguish the magnitude of blood flow rate as high (mean SIG ± SD, 2.2 ± 0.4 SI/mm for 12.5 ± 2.3 L/min) and low (0.9 ± 0.3 SI/mm for 8.5 ± 2.6 L/min) in vessels ( p < 0.001). Additionally, we found that the TOF-MRA SIG values were highly correlated with various flow rates ( β = 0.96, p < 0.001). Remarkably, the correlation coefficient between the WSS obtained from the computational fluid dynamics (CFD) analysis and the TOF-MRA SIG was greater than 0.8 in each section at the carotid artery ( p < 0.001 for all β values). This new technique using TOF-MRA could enable the rapid calculation of the TOF-MRA SIG and thereby the WSS. Thus, the TOF-MRA SIG can provide clinicians with an accurate and efficient screening method for making rapid decisions on the risk of vascular disease for a patient in clinical practice.

Multipoint Binding of the SLP-76 SH2 Domain to ADAP Is Critical for Oligomerization of SLP-76 Signaling Complexes in Stimulated T Cells

PubMed Central

Coussens, Nathan P.; Hayashi, Ryo; Brown, Patrick H.; Balagopalan, Lakshmi; Balbo, Andrea; Akpan, Itoro; Houtman, Jon C. D.; Barr, Valarie A.; Schuck, Peter; Appella, Ettore

2013-01-01

The adapter molecules SLP-76 and LAT play central roles in T cell activation by recruiting enzymes and other adapters into multiprotein complexes that coordinate highly regulated signal transduction pathways. While many of the associated proteins have been characterized, less is known concerning the mechanisms of assembly for these dynamic and potentially heterogeneous signaling complexes. Following T cell receptor (TCR) stimulation, SLP-76 is found in structures called microclusters, which contain many signaling complexes. Previous studies showed that a mutation to the SLP-76 C-terminal SH2 domain nearly abolished SLP-76 microclusters, suggesting that the SH2 domain facilitates incorporation of signaling complexes into microclusters. S. C. Bunnell, A. L. Singer, D. I. Hong, B. H. Jacque, M. S. Jordan, M. C. Seminario, V. A. Barr, G. A. Koretzky, and L. E. Samelson, Mol. Cell. Biol., 26:7155–7166, 2006). Using biophysical methods, we demonstrate that the adapter, ADAP, contains three binding sites for SLP-76, and that multipoint binding to ADAP fragments oligomerizes the SLP-76 SH2 domain in vitro. These results were complemented with confocal imaging and functional studies of cells expressing ADAP with various mutations. Our results demonstrate that all three binding sites are critical for SLP-76 microcluster assembly, but any combination of two sites will partially induce microclusters. These data support a model whereby multipoint binding of SLP-76 to ADAP facilitates the assembly of SLP-76 microclusters. This model has implications for the regulation of SLP-76 and LAT microclusters and, as a result, T cell signaling. PMID:23979596

Multipoint binding of the SLP-76 SH2 domain to ADAP is critical for oligomerization of SLP-76 signaling complexes in stimulated T cells.

PubMed

Coussens, Nathan P; Hayashi, Ryo; Brown, Patrick H; Balagopalan, Lakshmi; Balbo, Andrea; Akpan, Itoro; Houtman, Jon C D; Barr, Valarie A; Schuck, Peter; Appella, Ettore; Samelson, Lawrence E

2013-11-01

The adapter molecules SLP-76 and LAT play central roles in T cell activation by recruiting enzymes and other adapters into multiprotein complexes that coordinate highly regulated signal transduction pathways. While many of the associated proteins have been characterized, less is known concerning the mechanisms of assembly for these dynamic and potentially heterogeneous signaling complexes. Following T cell receptor (TCR) stimulation, SLP-76 is found in structures called microclusters, which contain many signaling complexes. Previous studies showed that a mutation to the SLP-76 C-terminal SH2 domain nearly abolished SLP-76 microclusters, suggesting that the SH2 domain facilitates incorporation of signaling complexes into microclusters. S. C. Bunnell, A. L. Singer, D. I. Hong, B. H. Jacque, M. S. Jordan, M. C. Seminario, V. A. Barr, G. A. Koretzky, and L. E. Samelson, Mol. Cell. Biol., 26:7155-7166, 2006). Using biophysical methods, we demonstrate that the adapter, ADAP, contains three binding sites for SLP-76, and that multipoint binding to ADAP fragments oligomerizes the SLP-76 SH2 domain in vitro. These results were complemented with confocal imaging and functional studies of cells expressing ADAP with various mutations. Our results demonstrate that all three binding sites are critical for SLP-76 microcluster assembly, but any combination of two sites will partially induce microclusters. These data support a model whereby multipoint binding of SLP-76 to ADAP facilitates the assembly of SLP-76 microclusters. This model has implications for the regulation of SLP-76 and LAT microclusters and, as a result, T cell signaling.

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.

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.

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.

Exercise intensity, redox homeostasis and inflammation in type 2 diabetes mellitus.

PubMed

Mallard, Alistair R; Hollekim-Strand, Siri Marte; Coombes, Jeff S; Ingul, Charlotte B

2017-10-01

To compare 12 weeks of exercise training at two intensities on oxidative stress, antioxidants and inflammatory biomarkers in patients with type 2 diabetes (T2D). Randomized trial. Thirty-six participants with T2D were randomized to complete either 12 weeks of treadmill based high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT), followed by 40 weeks of home-based training at the same intensities. Plasma inflammation, oxidative stress and antioxidant biomarkers (total F2-isoprostanes, protein carbonyls, total antioxidant capacity, glutathione peroxidase activity, interleukin-10, interleukin-6, interleukin-8 and TNF-α) were measured at baseline, 12-weeks and 1-year. There were no significant changes (p>0.05) in oxidative stress and inflammation biomarkers from baseline to 12-weeks in either intervention. A decrease in total antioxidant capacity in the MICT group from baseline to 1-year by 0.05mmol/L (p=0.05) was observed. There was a significant difference (p<0.05) when groups were separated by sex with females in the MICT group having a 22.1% (p<0.05) decrease in protein carbonyls from baseline to 1-year. HIIT and MICT had no acute effect on oxidative stress and inflammatory biomarkers in patients with T2D. Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

Therapeutic targeting of NOTCH1 signaling in T-ALL

PubMed Central

Palomero, Teresa; Ferrando, Adolfo

2010-01-01

The recent identification of activating mutations in NOTCH1 in the majority of T-cell acute lymphoblastic leukemias (T-ALL) has brought major interest towards targeting the NOTCH signaling pathway in this disease. Small molecule γ-secretase inhibitors (GSIs) which block a critical proteolytic step required for NOTCH1 activation can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL. PMID:19778842

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.

Multi-Component T2 Relaxation Studies of the Avian Egg

PubMed Central

Mitsouras, Dimitris; Mulkern, Robert V.; Maier, Stephan E.

2015-01-01

Purpose To investigate the tissue-like multiexponential T2 signal decays in avian eggs. Methods Transverse relaxation studies of raw, soft-boiled and hard-boiled eggs were performed at 3 Tesla using a 3D Carr-Purcell-Meiboom-Gill (CPMG) imaging sequence. Signal decays over a TE range of 11 to 354 ms were fitted assuming single- and multi-component signal decays with up to three separately decaying components. Fat saturation was used to facilitate spectral assignment of observed decay components. Results Egg white, yolk and the centrally located latebra all demonstrate nonmonoexponential T2 decays. Specifically, egg white exhibits two-component decays with intermediate and long T2 times. Meanwhile, yolk and latebra are generally best characterized with triexponential decays, with short, intermediate and very long T2 decay times. Fat saturation revealed that the intermediate component of yolk could be attributed to lipids. Cooking of the egg profoundly altered the decay curves. Conclusion Avian egg T2 decay curves cover a wide range of decay times. Observed T2 components in yolk and latebra as short as 10 ms, may prove valuable for testing clinical sequences designed to measure short T2 components, such as myelin-associated water in the brain. Thus we propose that the egg can be a versatile and widely available MR transverse relaxation phantom. PMID:26037128

Ablation of SLP-76 signaling after T cell priming generates memory CD4 T cells impaired in steady-state and cytokine-driven homeostasis.

PubMed

Bushar, Nicholas D; Corbo, Evann; Schmidt, Michelle; Maltzman, Jonathan S; Farber, Donna L

2010-01-12

The intracellular signaling mechanisms regulating the generation and long-term persistence of memory T cells in vivo remain unclear. In this study, we used mouse models with conditional deletion of the key T cell receptor (TCR)-coupled adaptor molecule SH2-domain-containing phosphoprotein of 76 kDa (SLP-76), to analyze signaling mechanisms for memory CD4 T cell generation, maintenance, and homeostasis. We found that ablation of SLP-76 expression after T cell priming did not inhibit generation of phenotypic effector or memory CD4 T cells; however, the resultant SLP-76-deficient memory CD4 T cells could not produce recall cytokines in response to TCR-mediated stimulation and showed decreased persistence in vivo. In addition, SLP-76-deficient memory CD4 T cells exhibited reduced steady-state homeostasis and were impaired in their ability to homeostatically expand in vivo in response to the gamma(c) cytokine IL-7, despite intact proximal signaling through the IL-7R-coupled JAK3/STAT5 pathway. Direct in vivo deletion of SLP-76 in polyclonal memory CD4 T cells likewise led to impaired steady-state homeostasis as well as impaired homeostatic responses to IL-7. Our findings demonstrate a dominant role for SLP-76-dependent TCR signals in regulating turnover and perpetuation of memory CD4 T cells and their responses to homeostatic cytokines, with implications for the selective survival of memory CD4 T cells following pathogen exposure, vaccination, and aging.

Signal transduction in primary human T lymphocytes in altered gravity during parabolic flight and clinostat experiments.

PubMed

Tauber, Svantje; Hauschild, Swantje; Paulsen, Katrin; Gutewort, Annett; Raig, Christiane; Hürlimann, Eva; Biskup, Josefine; Philpot, Claudia; Lier, Hartwin; Engelmann, Frank; Pantaleo, Antonella; Cogoli, Augusto; Pippia, Proto; Layer, Liliana E; Thiel, Cora S; Ullrich, Oliver

2015-01-01

Several limiting factors for human health and performance in microgravity have been clearly identified arising from the immune system, and substantial research activities are required in order to provide the basic information for appropriate integrated risk management. The gravity-sensitive nature of cells of the immune system renders them an ideal biological model in search for general gravity-sensitive mechanisms and to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to life on Earth. We investigated the influence of altered gravity in parabolic flight and 2D clinostat experiments on key proteins of activation and signaling in primary T lymphocytes. We quantified components of the signaling cascade 1.) in non-activated T lymphocytes to assess the "basal status" of the cascade and 2.) in the process of activation to assess the signal transduction. We found a rapid decrease of CD3 and IL-2R surface expression and reduced p-LAT after 20 seconds of altered gravity in non-activated primary T lymphocytes during parabolic flight. Furthermore, we observed decreased CD3 surface expression, reduced ZAP-70 abundance and increased histone H3-acetylation in activated T lymphocytes after 5 minutes of clinorotation and a transient downregulation of CD3 and stable downregulation of IL-2R during 60 minutes of clinorotation. CD3 and IL-2R are downregulated in primary T lymphocytes in altered gravity. We assume that a gravity condition around 1g is required for the expression of key surface receptors and appropriate regulation of signal molecules in T lymphocytes. © 2015 S. Karger AG, Basel.

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.

Increasing JAK/STAT Signaling Function of Infant CD4+ T Cells during the First Year of Life

PubMed Central

dela Peña-Ponce, Myra Grace; Rodriguez-Nieves, Jennifer; Bernhardt, Janice; Tuck, Ryan; Choudhary, Neelima; Mengual, Michael; Mollan, Katie R.; Hudgens, Michael G.; Peter-Wohl, Sigal; De Paris, Kristina

2017-01-01

Most infant deaths occur in the first year of life. Yet, our knowledge of immune development during this period is scarce and derived from cord blood (CB) only. To more effectively combat pediatric diseases, a deeper understanding of the kinetics and the factors that regulate the maturation of immune functions in early life is needed. Increased disease susceptibility of infants is generally attributed to T helper 2-biased immune responses. The differentiation of CD4+ T cells along a specific T helper cell lineage is dependent on the pathogen type, and on costimulatory and cytokine signals provided by antigen-presenting cells. Cytokines also regulate many other aspects of the host immune response. Therefore, toward the goal of increasing our knowledge of early immune development, we defined the temporal development of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling function of CD4+ T cells using cross-sectional blood samples from healthy infants ages 0 (birth) to 14 months. We specifically focused on cytokines important in T cell differentiation (IFN-γ, IL-12, and IL-4) or in T cell survival and expansion (IL-2 and IL-7) in infant CD4+ T cells. Independent of the cytokine tested, JAK/STAT signaling in infant compared to adult CD4+ T cells was impaired at birth, but increased during the first year, with the most pronounced changes occurring in the first 6 months. The relative change in JAK/STAT signaling of infant CD4+ T cells with age was distinct for each cytokine tested. Thus, while about 60% of CB CD4+ T cells could efficiently activate STAT6 in response to IL-4, less than 5% of CB CD4+ T cells were able to activate the JAK/STAT pathway in response to IFN-γ, IL-12 or IL-2. By 4–6 months of age, the activation of the cytokine-specific STAT molecules was comparable to adults in response to IL-4 and IFN-γ, while IL-2- and IL-12-induced STAT activation remained below adult levels even at 1 year. These results

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

Slowly resolving global myocardial inflammation/oedema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted cardiac MRI.

PubMed

Neil, Christopher; Nguyen, Thanh Ha; Kucia, Angela; Crouch, Benjamin; Sverdlov, Aaron; Chirkov, Yuliy; Mahadavan, Gnanadevan; Selvanayagam, Joseph; Dawson, Dana; Beltrame, John; Zeitz, Christopher; Unger, Steven; Redpath, Thomas; Frenneaux, Michael; Horowitz, John

2012-09-01

Tako-Tsubo cardiomyopathy (TTC) is associated with regional left ventricular dysfunction, independent of the presence of fixed coronary artery disease. Previous studies have used T2-weighted cardiac MRI to demonstrate the presence of periapical oedema. The authors sought to determine the distribution, resolution and correlates of oedema in TTC. 32 patients with TTC were evaluated at a median of 2 days after presentation, along with 10 age-matched female controls. Extent of oedema was quantified both regionally and globally; scanning was repeated in patients with TTC after 3 months. Correlations were sought between oedema and the extent of hypokinesis, catecholamine release, release of N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and markers of systemic inflammatory activation (high-sensitivity C-reactive protein and platelet response to nitric oxide). In the acute phase of TTC, T2-weighted signal intensity was greater at the apex than at the base (p<0.0001) but was nevertheless significantly elevated at the base (p<0.0001), relative to control values. Over 3 months, T2-weighted signal decreased substantially, but remained abnormally elevated (p<0.02). The regional extent of oedema correlated inversely with radial myocardial strain (except at the apex). There were also direct correlations between global T2-weighted signal and (1) plasma normetanephrine (r=0.39, p=0.04) and (2) peak NT-proBNP (r=0.39, p=0.03), but not with systemic inflammatory markers. TTC is associated with slowly resolving global myocardial oedema, the acute extent of which correlates with regional contractile disturbance and acute release of both catecholamines and NT-proBNP.

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

β2-Microglobulin-mediated signaling as a target for cancer therapy.

PubMed

Nomura, Takeo; Huang, Wen-Chin; Zhau, Haiyen E; Josson, Sajni; Mimata, Hiromitsu; Chung, Leland W K

2014-03-01

β2-microglobulin (β2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. β2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, β2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that β2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that β2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against β2-m have remarkable tumoricidal activity in cancer, through β2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, β-catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of β2-m and β2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding β2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers.

β2-Microglobulin-mediated Signaling as a Target for Cancer Therapy

PubMed Central

Nomura, Takeo; Huang, Wen-Chin; Zhau, Haiyen E.; Josson, Sajni; Mimata, Hiromitsu; Kaur, Mandeep

2014-01-01

β2-microglobulin (β2-m) has become the focus of intense scrutiny since the discovery of its undesirable roles promoting osteomimicry and cancer progression. β2-m is a well-known housekeeping protein that forms complexes with the heavy chain of major histocompatibility complex class I molecules, which are heterodimeric cell surface proteins that present antigenic peptides to cytotoxic T cells. On recognition of foreign peptide antigens on cell surfaces, T cells actively bind and lyse antigen-presenting cancer cells. In addition to its roles in tumor immunity, β2-m has two different functions in cancer cells, either tumor promoting or tumor suppressing, in cancer cell context-dependent manner. Our studies have demonstrated that β2-m is involved extensively in the functional regulation of growth, survival, apoptosis, and even metastasis of cancer cells. We found that β2-m is a soluble growth factor and a pleiotropic signaling molecule which interacts with its receptor, hemochromatosis protein, to modulate epithelial-to-mesenchymal transition (EMT) through iron-responsive pathways. Specific antibodies against β2-m have remarkable tumoricidal activity in cancer, through β2-m action on iron flux, alterations of intracellular reactive oxygen species, DNA damage and repair enzyme activities, β-catenin activation and cadherin switching, and tumor responsiveness to hypoxia. These novel functions of β2-m and β2-m signaling may be common to several solid tumors including human lung, breast, renal, and prostate cancers. Our experimental results could lead to the development of a novel class of antibody-based pharmaceutical agents for cancer growth control. In this review, we briefly summarize the recent data regarding β2-m as a promising new cancer therapeutic target and discuss antagonizing this therapeutic target with antibody therapy for the treatment of localized and disseminated cancers. PMID:23848204

[miR-503-5p inhibits the proliferation of T24 and EJ bladder cancer cells by interfering with the Rb/E2F signaling pathway].

PubMed

Li, Xiaohui; Han, Xingtao; Yang, Jinhui; Sun, Jiantao; Wei, Pengtao

2017-10-01

Objective To observe the effect of microRNA-503-5p (miR-503-5p) on the growth of T24 and EJ bladder cancer cells, and explore the possible molecular mechanism. Methods The miR-504-5p mimics or miR-NC was transfected into T24 and EJ cells. The target gene of miR-503-5p was predicted by bioinformatics. The expressions of E2F transcription factor 3 (E2F3) mRNA and Rb/E2F signaling pathway mRNA were detected by the real-time quantitative PCR (qPCR). The expressions of Rb/E2F signal pathway proteins E2F3, cyclin E, CDK2, Rb and p-Rb were detected by Western blotting. The cell cycle of bladder cancer cell lines was determined by flow cytometry. MTT assay and plate cloning assay were performed to observe the proliferation ability of bladder cancer cells. Results After miR-503-5p mimics transfection, the expression of miR-503-5p in bladder cancer cells significantly increased. The increased expression of miR-503-5p significantly reduced the expressions of E2F3 mRNA and Rb/E2F signaling pathway mRNA in bladder cancer cells. What's more, the expressions of Rb/E2F signal pathway proteins were down-regulated. The bladder cancer cells were arrested in G0/G1 phase, and their growth was significantly inhibited by miR-503-5p. Conclusion The miR-503-5p over-expression can inhibit the growth of bladder cancer cell lines T24 and EJ by down-regulating the expression of the Rb/E2F signaling pathway.

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.

Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination.

PubMed

Roebuck, Joseph R; Haker, Steven J; Mitsouras, Dimitris; Rybicki, Frank J; Tempany, Clare M; Mulkern, Robert V

2009-05-01

Quantitative, apparent T(2) values of suspected prostate cancer and healthy peripheral zone tissue in men with prostate cancer were measured using a Carr-Purcell-Meiboom-Gill (CPMG) imaging sequence in order to assess the cancer discrimination potential of tissue T(2) values. The CPMG imaging sequence was used to image the prostates of 18 men with biopsy-proven prostate cancer. Whole gland coverage with nominal voxel volumes of 0.54 x 1.1 x 4 mm(3) was obtained in 10.7 min, resulting in data sets suitable for generating high-quality images with variable T(2)-weighting and for evaluating quantitative T(2) values on a pixel-by-pixel basis. Region-of-interest analysis of suspected healthy peripheral zone tissue and suspected cancer, identified on the basis of both T(1)- and T(2)-weighted signal intensities and available histopathology reports, yielded significantly (P<.0001) longer apparent T(2) values in suspected healthy tissue (193+/-49 ms) vs. suspected cancer (100+/-26 ms), suggesting potential utility of this method as a tissue specific discrimination index for prostate cancer. We conclude that CPMG imaging of the prostate can be performed in reasonable scan times and can provide advantages over T(2)-weighted fast spin echo (FSE) imaging alone, including quantitative T(2) values for cancer discrimination as well as proton density maps without the point spread function degradation associated with short effective echo time FSE sequences.

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

T2 shuffling: Sharp, multicontrast, volumetric fast spin-echo imaging.

PubMed

Tamir, Jonathan I; Uecker, Martin; Chen, Weitian; Lai, Peng; Alley, Marcus T; Vasanawala, Shreyas S; Lustig, Michael

2017-01-01

A new acquisition and reconstruction method called T 2 Shuffling is presented for volumetric fast spin-echo (three-dimensional [3D] FSE) imaging. T 2 Shuffling reduces blurring and recovers many images at multiple T 2 contrasts from a single acquisition at clinically feasible scan times (6-7 min). The parallel imaging forward model is modified to account for temporal signal relaxation during the echo train. Scan efficiency is improved by acquiring data during the transient signal decay and by increasing echo train lengths without loss in signal-to-noise ratio (SNR). By (1) randomly shuffling the phase encode view ordering, (2) constraining the temporal signal evolution to a low-dimensional subspace, and (3) promoting spatio-temporal correlations through locally low rank regularization, a time series of virtual echo time images is recovered from a single scan. A convex formulation is presented that is robust to partial voluming and radiofrequency field inhomogeneity. Retrospective undersampling and in vivo scans confirm the increase in sharpness afforded by T 2 Shuffling. Multiple image contrasts are recovered and used to highlight pathology in pediatric patients. A proof-of-principle method is integrated into a clinical musculoskeletal imaging workflow. The proposed T 2 Shuffling method improves the diagnostic utility of 3D FSE by reducing blurring and producing multiple image contrasts from a single scan. Magn Reson Med 77:180-195, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Requirements of transcription factor Smad-dependent and -independent TGF-β signaling to control discrete T-cell functions.

PubMed

Gu, Ai-Di; Wang, Yunqi; Lin, Lin; Zhang, Song S; Wan, Yisong Y

2012-01-17

TGF-β modulates immune response by suppressing non-regulatory T (Treg) function and promoting Treg function. The question of whether TGF-β achieves distinct effects on non-Treg and Treg cells through discrete signaling pathways remains outstanding. In this study, we investigated the requirements of Smad-dependent and -independent TGF-β signaling for T-cell function. Smad2 and Smad3 double deficiency in T cells led to lethal inflammatory disorder in mice. Non-Treg cells were spontaneously activated and produced effector cytokines in vivo on deletion of both Smad2 and Smad3. In addition, TGF-β failed to suppress T helper differentiation efficiently and to promote induced Treg generation of non-Treg cells lacking both Smad2 and Smad3, suggesting that Smad-dependent signaling is obligatory to mediate TGF-β function in non-Treg cells. Unexpectedly, however, the development, homeostasis, and function of Treg cells remained intact in the absence of Smad2 and Smad3, suggesting that the Smad-independent pathway is important for Treg function. Indeed, Treg-specific deletion of TGF-β-activated kinase 1 led to failed Treg homeostasis and lethal immune disorder in mice. Therefore, Smad-dependent and -independent TGF-β signaling discretely controls non-Treg and Treg function to modulate immune tolerance and immune homeostasis.

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.

Mesenchymal Stromal Cells Disrupt mTOR-Signaling and Aerobic Glycolysis During T-Cell Activation.

PubMed

Böttcher, Martin; Hofmann, Andreas D; Bruns, Heiko; Haibach, Martina; Loschinski, Romy; Saul, Domenica; Mackensen, Andreas; Le Blanc, Katarina; Jitschin, Regina; Mougiakakos, Dimitrios

2016-02-01

Mesenchymal stromal cells (MSCs) possess numerous regenerative and immune modulating functions. Transplantation across histocompatibility barriers is feasible due to their hypo-immunogenicity. MSCs have emerged as promising tools for treating graft-versus-host disease following allogeneic stem cell transplantation. It is well established that their clinical efficacy is substantially attributed to fine-tuning of T-cell responses. At the same time, increasing evidence suggests that metabolic processes control T-cell function and fate. Here, we investigated the MSCs' impact on the metabolic framework of activated T-cells. In fact, MSCs led to mitigated mTOR signaling. This phenomenon was accompanied by a weaker glycolytic response (including glucose uptake, glycolytic rate, and upregulation of glycolytic machinery) toward T-cell activating stimuli. Notably, MSCs express indoleamine-2,3-dioxygenase (IDO), which mediates T-cell suppressive tryptophan catabolism. Our observations suggest that IDO-induced tryptophan depletion interferes with a tryptophan-sufficiency signal that promotes cellular mTOR activation. Despite an immediate suppression of T-cell responses, MSCs foster a metabolically quiescent T-cell phenotype characterized by reduced mTOR signaling and glycolysis, increased autophagy, and lower oxidative stress levels. In fact, those features have previously been shown to promote generation of long-lived memory cells and it remains to be elucidated how MSC-induced metabolic effects shape in vivo T-cell immunity. © 2015 AlphaMed Press.

The T-cell-specific adapter protein family: TSAd, ALX, and SH2D4A/SH2D4B.

PubMed

Lapinski, Philip E; Oliver, Jennifer A; Bodie, Jennifer N; Marti, Francesc; King, Philip D

2009-11-01

Adapter proteins play key roles in intracellular signal transduction through complex formation with catalytically active signaling molecules. In T lymphocytes, the role of several different types of adapter proteins in T-cell antigen receptor signal transduction is well established. An exception to this is the family of T-cell-specific adapter (TSAd) proteins comprising of TSAd, adapter protein of unknown function (ALX), SH2D4A, and SH2D4B. Only recently has the function of these adapters in T-cell signal transduction been explored. Here, we discuss advances in our understanding of the role of this family of adapter proteins in T cells. Their function as regulators of signal transduction in other cell types is also discussed.

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.

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.

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.

Liver imaging at 3.0 T: diffusion-induced black-blood echo-planar imaging with large anatomic volumetric coverage as an alternative for specific absorption rate-intensive echo-train spin-echo sequences: feasibility study.

PubMed

van den Bos, Indra C; Hussain, Shahid M; Krestin, Gabriel P; Wielopolski, Piotr A

2008-07-01

Institutional Review Board approval and signed informed consent were obtained by all participants for an ongoing sequence optimization project at 3.0 T. The purpose of this study was to evaluate breath-hold diffusion-induced black-blood echo-planar imaging (BBEPI) as a potential alternative for specific absorption rate (SAR)-intensive spin-echo sequences, in particular, the fast spin-echo (FSE) sequences, at 3.0 T. Fourteen healthy volunteers (seven men, seven women; mean age +/- standard deviation, 32.7 years +/- 6.8) were imaged for this purpose. Liver coverage (20 cm, z-axis) was always performed in one 25-second breath hold. Imaging parameters were varied interactively with regard to echo time, diffusion b value, and voxel size. Images were evaluated and compared with fat-suppressed T2-weighted FSE images for image quality, liver delineation, geometric distortions, fat suppression, suppression of the blood signal, contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR). An optimized short- (25 msec) and long-echo (80 msec) BBEPI provided full anatomic, single breath-hold liver coverage (100 and 50 sections, respectively), with resulting voxel sizes of 3.3 x 2.7 x 2.0 mm and 3.3 x 2.7 x 4.0 mm, respectively. Repetition time was 6300 msec, matrix size was 160 x 192, and an acceleration factor of 2.00 was used. b Values of more than 20 sec/mm(2) showed better suppression of the blood signal but b values of 10 sec/mm(2) provided improved volume coverage and signal consistency. Compared with fat-suppressed T2-weighted FSE, the optimized BBEPI sequence provided (a) comparable image quality and liver delineation, (b) acceptable geometric distortions, (c) improved suppression of fat and blood signals, and (d) high CNR and SNR. BBEPI is feasible for fast, low-SAR, thin-section morphologic imaging of the entire liver in a single breath hold at 3.0 T. (c) RSNA, 2008.

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.

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.

Evaluation of dual-source parallel RF excitation for diffusion-weighted whole-body MR imaging with background body signal suppression at 3.0 T.

PubMed

Mürtz, Petra; Kaschner, Marius; Träber, Frank; Kukuk, Guido M; Büdenbender, Sarah M; Skowasch, Dirk; Gieseke, Jürgen; Schild, Hans H; Willinek, Winfried A

2012-11-01

To evaluate the use of dual-source parallel RF excitation (TX) for diffusion-weighted whole-body MRI with background body signal suppression (DWIBS) at 3.0 T. Forty consecutive patients were examined on a clinical 3.0-T MRI system using a diffusion-weighted (DW) spin-echo echo-planar imaging sequence with a combination of short TI inversion recovery and slice-selective gradient reversal fat suppression. DWIBS of the neck (n=5), thorax (n=8), abdomen (n=6) and pelvis (n=21) was performed both with TX (2:56 min) and with standard single-source RF excitation (4:37 min). The quality of DW images and reconstructed inverted maximum intensity projections was visually judged by two readers (blinded to acquisition technique). Signal homogeneity and fat suppression were scored as "improved", "equal", "worse" or "ambiguous". Moreover, the apparent diffusion coefficient (ADC) values were measured in muscles, urinary bladder, lymph nodes and lesions. By the use of TX, signal homogeneity was "improved" in 25/40 and "equal" in 15/40 cases. Fat suppression was "improved" in 17/40 and "equal" in 23/40 cases. These improvements were statistically significant (p<0.001, Wilcoxon signed-rank test). In five patients, fluid-related dielectric shading was present, which improved remarkably. The ADC values did not significantly differ for the two RF excitation methods (p=0.630 over all data, pairwise Student's t-test). Dual-source parallel RF excitation improved image quality of DWIBS at 3.0 T with respect to signal homogeneity and fat suppression, reduced scan time by approximately one-third, and did not influence the measured ADC values. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

β3GnT2 Maintains Adenylyl Cyclase-3 Signaling and Axon Guidance Molecule Expression in the Olfactory Epithelium

PubMed Central

Faden, Ashley A.; Knott, Thomas K.

2011-01-01

In the olfactory epithelium (OE), odorant receptor stimulation generates cAMP signals that function in both odor detection and the regulation of axon guidance molecule expression. The enzyme that synthesizes cAMP, adenylyl cyclase 3 (AC3), is coexpressed in olfactory sensory neurons (OSNs) with poly-N-acetyllactosamine (PLN) oligosaccharides determined by the glycosyltransferase β3GnT2. The loss of either enzyme results in similar defects in olfactory bulb (OB) innervation and OSN survival, suggesting that glycosylation may be important for AC3 function. We show here that AC3 is extensively modified with N-linked PLN, which is essential for AC3 activity and localization. On Western blots, AC3 from the wild-type OE migrates diffusely as a heavily glycosylated 200 kDa band that interacts with the PLN-binding lectin LEA. AC3 from the β3GnT2−/− OE loses these PLN modifications, migrating instead as a 140 kDa glycoprotein. Furthermore, basal and forskolin-stimulated cAMP production is reduced 80–90% in the β3GnT2−/− OE. Although AC3 traffics normally to null OSN cilia, it is absent from axon projections that aberrantly target the OB. The cAMP-dependent guidance receptor neuropilin-1 is also lost from β3GnT2−/− OSNs and axons, while semaphorin-3A ligand expression is upregulated. In addition, kirrel2, a mosaically expressed adhesion molecule that functions in axon sorting, is absent from β3GnT2−/− OB projections. These results demonstrate that PLN glycans are essential in OSNs for proper AC3 localization and function. We propose that the loss of cAMP-dependent guidance cues is also a critical factor in the severe axon guidance defects observed in β3GnT2−/− mice. PMID:21525298

Evaluation of water content around airway in obstructive sleep apnea patients using peripharyngeal mucosal T2 magnetic resonance imaging.

PubMed

Rahmawati, Anita; Chishaki, Akiko; Ohkusa, Tomoko; Hashimoto, Sonomi; Adachi, Kazuo; Nagao, Michinobu; Konishi Nishizaka, Mari; Ando, Shin-Ichi

2017-11-01

Obstructive sleep apnea (OSA) is common sleep disorder characterized by repetitive episodes of airway closure which usually occurs in the retropalatal region of the oropharynx. It has been known that upper airway mucosa in OSA patients is described as edematous, but not fully clarified. This study aimed to investigate and establish magnetic resonance imaging (MRI) parameter to estimate tissue water content at retropalatal level and its relationship with sleep parameters in OSA patients. Forty-eight subjects with OSA underwent overnight polysomnography and cervical MRI with 1.5-tesla [mean (SD) age 55 (14) years and apnea-hypopnea index (AHI) 45.2 (26.1) events/hour, 79.2% male]. On the axial T2-weighted images from epipharynx to oropharynx, the signal intensities of masseter muscle and peripharyngeal mucosa [T2 mucous-to-masseter intensity ratio (T2MMIR)], was used as water content estimation in the retropalatal region. Partial correlation analysis was performed to examine the correlation between T2MMIR and polysomnography parameters. We found that there were strong and positive correlations between the T2MMIR and AHI (r = 0.545, P < 0.05), supine AHI (r = 0.553, P < 0.05) and REM AHI (r = 0.640, P < 0.01) by partial correlation analysis. Besides, in patients with less efficient sleep who had more stage 1 sleep, significantly higher T2MMIR was noted (r = 0.357, P < 0.05). This study confirmed that peripharyngeal T2MMIR can be a simple parameter representing peripharyngeal tissue water contents related to severe OSA. © 2015 John Wiley & Sons Ltd.

Intensity-based dual model method for generation of synthetic CT images from standard T2-weighted MR images - Generalized technique for four different MR scanners.

PubMed

Koivula, Lauri; Kapanen, Mika; Seppälä, Tiina; Collan, Juhani; Dowling, Jason A; Greer, Peter B; Gustafsson, Christian; Gunnlaugsson, Adalsteinn; Olsson, Lars E; Wee, Leonard; Korhonen, Juha

2017-12-01

Recent studies have shown that it is possible to conduct entire radiotherapy treatment planning (RTP) workflow using only MR images. This study aims to develop a generalized intensity-based method to generate synthetic CT (sCT) images from standard T2-weighted (T2 w ) MR images of the pelvis. This study developed a generalized dual model HU conversion method to convert standard T2 w MR image intensity values to synthetic HU values, separately inside and outside of atlas-segmented bone volume contour. The method was developed and evaluated with 20 and 35 prostate cancer patients, respectively. MR images with scanning sequences in clinical use were acquired with four different MR scanners of three vendors. For the generated synthetic CT (sCT) images of the 35 prostate patients, the mean (and maximal) HU differences in soft and bony tissue volumes were 16 ± 6 HUs (34 HUs) and -46 ± 56 HUs (181 HUs), respectively, against the true CT images. The average of the PTV mean dose difference in sCTs compared to those in true CTs was -0.6 ± 0.4% (-1.3%). The study provides a generalized method for sCT creation from standard T2 w images of the pelvis. The method produced clinically acceptable dose calculation results for all the included scanners and MR sequences. Copyright © 2017 Elsevier B.V. All rights reserved.

Carr-Purcell-Meiboom-Gill (CPMG) Imaging of Prostate Cancer: Quantitative T2 Values for Cancer Discrimination

PubMed Central

Roebuck, Joseph R.; Haker, Steven J.; Mitsouras, Dimitris; Rybicki, Frank J.; Tempany, Clare M.; Mulkern, Robert V.

2009-01-01

Quantitative, apparent T2 values of suspected prostate cancer and healthy peripheral zone tissue in men with prostate cancer were measured using a Carr-Purcell-Meiboom-Gill (CPMG) imaging sequence in order to assess the cancer discrimination potential of tissue T2 values. The CPMG imaging sequence was used to image the prostates of 18 men with biopsy proven prostate cancer. Whole gland coverage with nominal voxel volumes of 0.54 × 1.1 × 4 mm3 was obtained in 10.7 minutes, resulting in data sets suitable for generating high quality images with variable T2-weighting and for evaluating quantitative T2 values on a pixel-by-pixel basis. Region-of-interest analysis of suspected healthy peripheral zone tissue and suspected cancer, identified on the basis of both T1- and T2-weighted signal intensities and available histopathology reports, yielded significantly (p < 0.0001) longer apparent T2 values in suspected healthy tissue (193 ± 49 ms) vs. suspected cancer (100 ± 26 ms), suggesting potential utility of this method as a tissue specific discrimination index for prostate cancer. We conclude that CPMG imaging of the prostate can be performed in reasonable scan times and can provide advantages over T2-weighted fast spin echo imaging alone, including quantitative T2 values for cancer discrimination as well as proton density maps without the point spread function degradation associated with short effective echo time fast spin echo (FSE) sequences. PMID:18823731

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

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

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.

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...

The Adenylate Cyclase Toxins of Bacillus anthracis and Bordetella pertussis Promote Th2 Cell Development by Shaping T Cell Antigen Receptor Signaling

PubMed Central

Rossi Paccani, Silvia; Benagiano, Marisa; Capitani, Nagaja; Zornetta, Irene; Ladant, Daniel; Montecucco, Cesare; D'Elios, Mario M.; Baldari, Cosima T.

2009-01-01

The adjuvanticity of bacterial adenylate cyclase toxins has been ascribed to their capacity, largely mediated by cAMP, to modulate APC activation, resulting in the expression of Th2–driving cytokines. On the other hand, cAMP has been demonstrated to induce a Th2 bias when present during T cell priming, suggesting that bacterial cAMP elevating toxins may directly affect the Th1/Th2 balance. Here we have investigated the effects on human CD4+ T cell differentiation of two adenylate cyclase toxins, Bacillus anthracis edema toxin (ET) and Bordetella pertussis CyaA, which differ in structure, mode of cell entry, and subcellular localization. We show that low concentrations of ET and CyaA, but not of their genetically detoxified adenylate cyclase defective counterparts, potently promote Th2 cell differentiation by inducing expression of the master Th2 transcription factors, c-maf and GATA-3. We also present evidence that the Th2–polarizing concentrations of ET and CyaA selectively inhibit TCR–dependent activation of Akt1, which is required for Th1 cell differentiation, while enhancing the activation of two TCR–signaling mediators, Vav1 and p38, implicated in Th2 cell differentiation. This is at variance from the immunosuppressive toxin concentrations, which interfere with the earliest step in TCR signaling, activation of the tyrosine kinase Lck, resulting in impaired CD3ζ phosphorylation and inhibition of TCR coupling to ZAP-70 and Erk activation. These results demonstrate that, notwithstanding their differences in their intracellular localization, which result in focalized cAMP production, both toxins directly affect the Th1/Th2 balance by interfering with the same steps in TCR signaling, and suggest that their adjuvanticity is likely to result from their combined effects on APC and CD4+ T cells. Furthermore, our results strongly support the key role of cAMP in the adjuvanticity of these toxins. PMID:19266022

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.

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

Tonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells.

PubMed

Myers, Darienne R; Lau, Tannia; Markegard, Evan; Lim, Hyung W; Kasler, Herbert; Zhu, Minghua; Barczak, Andrea; Huizar, John P; Zikherman, Julie; Erle, David J; Zhang, Weiguo; Verdin, Eric; Roose, Jeroen P

2017-05-23

CD4 + T cells differentiate into T helper cell subsets in feedforward manners with synergistic signals from the T cell receptor (TCR), cytokines, and lineage-specific transcription factors. Naive CD4 + T cells avoid spontaneous engagement of feedforward mechanisms but retain a prepared state. T cells lacking the adaptor molecule LAT demonstrate impaired TCR-induced signals yet cause a spontaneous lymphoproliferative T helper 2 (T H 2) cell syndrome in mice. Thus, LAT constitutes an unexplained maintenance cue. Here, we demonstrate that tonic signals through LAT constitutively export the repressor HDAC7 from the nucleus of CD4 + T cells. Without such tonic signals, HDAC7 target genes Nur77 and Irf4 are repressed. We reveal that Nur77 suppresses CD4 + T cell proliferation and uncover a suppressive role for Irf4 in T H 2 polarization; halving Irf4 gene-dosage leads to increases in GATA3 + and IL-4 + cells. Our studies reveal that naive CD4 + T cells are dynamically tuned by tonic LAT-HDAC7 signals. Published by Elsevier Inc.

Quantification of glutathione transverse relaxation time T2 using echo time extension with variable refocusing selectivity and symmetry in the human brain at 7 Tesla

NASA Astrophysics Data System (ADS)

Swanberg, Kelley M.; Prinsen, Hetty; Coman, Daniel; de Graaf, Robin A.; Juchem, Christoph

2018-05-01

Glutathione (GSH) is an endogenous antioxidant implicated in numerous biological processes, including those associated with multiple sclerosis, aging, and cancer. Spectral editing techniques have greatly facilitated the acquisition of glutathione signal in living humans via proton magnetic resonance spectroscopy, but signal quantification at 7 Tesla is still hampered by uncertainty about the glutathione transverse decay rate T2 relative to those of commonly employed quantitative references like N-acetyl aspartate (NAA), total creatine, or water. While the T2 of uncoupled singlets can be derived in a straightforward manner from exponential signal decay as a function of echo time, similar estimation of signal decay in GSH is complicated by a spin system that involves both weak and strong J-couplings as well as resonances that overlap those of several other metabolites and macromolecules. Here, we extend a previously published method for quantifying the T2 of GABA, a weakly coupled system, to quantify T2 of the strongly coupled spin system glutathione in the human brain at 7 Tesla. Using full density matrix simulation of glutathione signal behavior, we selected an array of eight optimized echo times between 72 and 322 ms for glutathione signal acquisition by J-difference editing (JDE). We varied the selectivity and symmetry parameters of the inversion pulses used for echo time extension to further optimize the intensity, simplicity, and distinctiveness of glutathione signals at chosen echo times. Pairs of selective adiabatic inversion pulses replaced nonselective pulses at three extended echo times, and symmetry of the time intervals between the two extension pulses was adjusted at one extended echo time to compensate for J-modulation, thereby resulting in appreciable signal-to-noise ratio and quantifiable signal shapes at all measured points. Glutathione signal across all echo times fit smooth monoexponential curves over ten scans of occipital cortex voxels in nine

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

Computational spatiotemporal analysis identifies WAVE2 and cofilin as joint regulators of costimulation-mediated T cell actin dynamics.

PubMed

Roybal, Kole T; Buck, Taráz E; Ruan, Xiongtao; Cho, Baek Hwan; Clark, Danielle J; Ambler, Rachel; Tunbridge, Helen M; Zhang, Jianwei; Verkade, Paul; Wülfing, Christoph; Murphy, Robert F

2016-04-19

Fluorescence microscopy is one of the most important tools in cell biology research because it provides spatial and temporal information to investigate regulatory systems inside cells. This technique can generate data in the form of signal intensities at thousands of positions resolved inside individual live cells. However, given extensive cell-to-cell variation, these data cannot be readily assembled into three- or four-dimensional maps of protein concentration that can be compared across different cells and conditions. We have developed a method to enable comparison of imaging data from many cells and applied it to investigate actin dynamics in T cell activation. Antigen recognition in T cells by the T cell receptor (TCR) is amplified by engagement of the costimulatory receptor CD28. We imaged actin and eight core actin regulators to generate over a thousand movies of T cells under conditions in which CD28 was either engaged or blocked in the context of a strong TCR signal. Our computational analysis showed that the primary effect of costimulation blockade was to decrease recruitment of the activator of actin nucleation WAVE2 (Wiskott-Aldrich syndrome protein family verprolin-homologous protein 2) and the actin-severing protein cofilin to F-actin. Reconstitution of WAVE2 and cofilin activity restored the defect in actin signaling dynamics caused by costimulation blockade. Thus, we have developed and validated an approach to quantify protein distributions in time and space for the analysis of complex regulatory systems. Copyright © 2016, American Association for the Advancement of Science.

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.

[Evaluation of signal noise ratio on analysis of clear cell renal cell carcinoma using DWI with multi-b values].

PubMed

Ding, Jiule; Xing, Wei; Chen, Jie; Dai, Yongming; Sun, Jun; Li, Dengfa

2014-01-21

To explore the influence of signal noise ratio (SNR) on analysis of clear cell renal cell carcinoma (CCRCC) using DWI with multi-b values. The images of 17 cases with CCRCC were analyzed, including 17 masses and 9 pure cysts. The signal intensity of the cysts and masses was measured separately on DWI for each b value. The minimal SNR, as the threshold, was recorded when the signal curve manifest as the single exponential line. The SNR of the CCRCC was calculated on DWI for each b value, and compared with the threshold by independent Two-sample t Test. The signal decreased on DWI with increased b factors for both pure cysts and CCRCC. The threshold is 1.29 ± 0.17, and the signal intensity of the cysts on DWI with multi-b values shown as a single exponential line when b ≤ 800 s/mm(2). For the CCRCC, the SNR is similar to the threshold when b = 1 000 s/mm(2) (t = 0.40, P = 0.69), and is lower when b = 1 200 s/mm(2) (t = -2.38, P = 0.03). The SNR should be sufficient for quantitative analysis of DWI, and the maximal b value is 1000 s/mm(2) for CCRCC.

Nuclear pore complex-mediated modulation of TCR signaling is required for naïve CD4+ T cell homeostasis.

PubMed

Borlido, Joana; Sakuma, Stephen; Raices, Marcela; Carrette, Florent; Tinoco, Roberto; Bradley, Linda M; D'Angelo, Maximiliano A

2018-06-01

Nuclear pore complexes (NPCs) are channels connecting the nucleus with the cytoplasm. We report that loss of the tissue-specific NPC component Nup210 causes a severe deficit of naïve CD4 + T cells. Nup210-deficient CD4 + T lymphocytes develop normally but fail to survive in the periphery. The decreased survival results from both an impaired ability to transmit tonic T cell receptor (TCR) signals and increased levels of Fas, which sensitize Nup210 -/- naïve CD4 + T cells to Fas-mediated cell death. Mechanistically, Nup210 regulates these processes by modulating the expression of Cav2 (encoding Caveolin-2) and Jun at the nuclear periphery. Whereas the TCR-dependent and CD4 + T cell-specific upregulation of Cav2 is critical for proximal TCR signaling, cJun expression is required for STAT3-dependent repression of Fas. Our results uncover an unexpected role for Nup210 as a cell-intrinsic regulator of TCR signaling and T cell homeostasis and expose NPCs as key players in the adaptive immune system.

Pioglitazone improves the ability of learning and memory via activating ERK1/2 signaling pathway in the hippocampus of T2DM rats.

PubMed

Gao, F; Zang, L; Wu, D Y; Li, Y J; Zhang, Q; Wang, H B; Tian, G L; Mu, Y M

2017-06-09

To explore the correlation between effect of PIO (pioglitazone, PIO) on learning as well as memory and ERK1/2 (extracellular signal regulated kinase 1/2, ERK1/2) pathway in T2DM (type 2 diabetes mellitus, T2DM) rats, further to elucidate the potential mechanism of PIO in improvement of learning and memory. 12-week-old male SD rats (number of 10 per group) were randomly divided into control group (CON), T2DM group (DM) and T2DM +PIO group (DM+PG). Rats in DM and DM+PG groups were given high fat diet for 20 weeks, then treated with Streptozotocin (27mg/kg) by intraperitoneal injection at 21week. After 72h, the FBG (fasting blood glucose, FBG) was greater than 7.0mmol/L can considered T2DM rats. DM+PG group was treated with PIO (10 mg·kg -1 ·d -1 ) by gavage daily. After Hyperinsulinemic-Euglycemic Clamp Study and Morris water maze test at 30-week, all of animals were sacrificed. The expressions of RKIP (Raf-1 kinase inhibitor protein, RKIP) and ERK1/2 in hippocampus were detected using Western Blot and real-time PCR. The FBG level: DM group (7.68±0.54mmol/L) was higher than CON group (5.35±0.63mmol/L) and DM+PG group (6.07±0.84mmol/L), the differences were considered statistically significant (P <0.05). Hyperinsulinemic-Euglycemic Clamp Studies: GIR (glucose infusion rate, GIR) of DM group (21.02±5.10 mg·kg -1 ·d -1 ) was less than CON group (27.64±3.87 mg·kg -1 ·d -1 ) and DM+PG group (26.04 ±5.41 mg·kg -1 ·d -1 ), the differences were considered statistically significant (P <0.05). Morris water maze training: The escape latencies and searching platform performance of DM group (24.54±5.02s) decreased significantly compared with CON group (16.73±4.02s) and DM+PG group (18.05±4.12s) (P <0.05). Changes of RKIP, ERK, p-ERK protein relative content in rat hippocampus: Compared with CON groupand DM+PG group, the relative content of RKIP in DM group remarkably increased (P<0.01); ERK protein levels were not considered statistically significant among the

Adoptive Immunotherapy for Epithelial Ovarian Cancer Using T Cells Simultaneously Targeted to Tumor and Tumor-Associated Macrophages

DTIC Science & Technology

2012-11-01

CD28 expander beads. It was originally planned to deliver four CARs to separate T-cell populations using the SFG retroviral vector and retronectin...IL-4Rα has been coupled to the signaling domain of IL-2/15Rβ. Consequently, IL-4 (which is a weak T-cell mitogen) delivers a potent growth signal...symptoms develop, or in the event of progressive tumor growth (indicated by increasing bioluminescence signal intensity). If tumor rejection occurs

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

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.

Computational spatiotemporal analysis identifies WAVE2 and Cofilin as joint regulators of costimulation-mediated T cell actin dynamics

PubMed Central

Roybal, Kole T.; Buck, Taráz E.; Ruan, Xiongtao; Cho, Baek Hwan; Clark, Danielle J.; Ambler, Rachel; Tunbridge, Helen M.; Zhang, Jianwei; Verkade, Paul; Wülfing, Christoph; Murphy, Robert F.

2016-01-01

Fluorescence microscopy is one of the most important tools in cell biology research and it provides spatial and temporal information to investigate regulatory systems inside cells. This technique can generate data in the form of signal intensities at thousands of positions resolved inside individual live cells; however, given extensive cell-to-cell variation, methods do not currently exist to assemble these data into three- or four-dimensional maps of protein concentration that can be compared across different cells and conditions. Here, we have developed one such method and applied it to investigate actin dynamics in T cell activation. Antigen recognition in T cells by the T cell receptor (TCR) is amplified by engagement of the costimulatory receptor CD28 and we have determined how CD28 modulates actin dynamics. We imaged actin and eight core actin regulators under conditions where CD28 in the context of a strong TCR signal was engaged or blocked to yield over a thousand movies. Our computational analysis identified diminished recruitment of the activator of actin nucleation WAVE2 and the actin severing protein cofilin to F-actin as the dominant difference upon costimulation blockade. Reconstitution of WAVE2 and cofilin activity restored the defect in actin signaling dynamics upon costimulation blockade. Thus we have developed and validated an approach to quantify protein distributions in time and space for analysis of complex regulatory systems. PMID:27095595

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...

ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings.

PubMed

Weiss, Jonathan M; Chen, Wei; Nyuydzefe, Melanie S; Trzeciak, Alissa; Flynn, Ryan; Tonra, James R; Marusic, Suzana; Blazar, Bruce R; Waksal, Samuel D; Zanin-Zhorov, Alexandra

2016-07-19

Rho-associated kinase 2 (ROCK2) determines the balance between human T helper 17 (TH17) cells and regulatory T (Treg) cells. We investigated its role in the generation of T follicular helper (TFH) cells, which help to generate antibody-producing B cells under normal and autoimmune conditions. Inhibiting ROCK2 in normal human T cells or peripheral blood mononuclear cells from patients with active systemic lupus erythematosus (SLE) decreased the number and function of TFH cells induced by activation ex vivo. Moreover, inhibition of ROCK2 activity decreased the abundance of the transcriptional regulator Bcl6 (B cell lymphoma 6) and increased that of Blimp1 by reducing the binding of signal transducer and activator of transcription 3 (STAT3) and increasing that of STAT5 to the promoters of the genes Bcl6 and PRDM1, respectively. In the MRL/lpr murine model of SLE, oral administration of the selective ROCK2 inhibitor KD025 resulted in a twofold reduction in the numbers of TFH cells and antibody-producing plasma cells in the spleen, as well as a decrease in the size of splenic germinal centers, which are the sites of interaction between TFH cells and B cells. KD025-treated mice showed a substantial improvement in both histological and clinical scores compared to those of untreated mice and had reduced amounts of Bcl6 and phosphorylated STAT3, as well as increased STAT5 phosphorylation. Together, these data suggest that ROCK2 signaling plays a critical role in controlling the development of TFH cells induced by autoimmune conditions through reciprocal regulation of STAT3 and STAT5 activation. Copyright © 2016, American Association for the Advancement of Science.

Malignant transformation of CD4+ T lymphocytes mediated by oncogenic kinase NPM/ALK recapitulates IL-2-induced cell signaling and gene expression reprogramming

PubMed Central

Marzec, Michal; Halasa, Krzysztof; Liu, Xiaobin; Wang, Hong Y.; Cheng, Mangeng; Baldwin, Donald; Tobias, John W.; Schuster, Stephen J.; Woetmann, Anders; Zhang, Qian; Turner, Suzanne D.; Odum, Niels; Wasik, Mariusz A.

2013-01-01

Anaplastic lymphoma kinase (ALK) physiologically expressed only by nervous system cells displays remarkable capacity to transform CD4+ T lymphocytes and other types of non-neural cells. Here we report that activity of nucleophosphmin (NPM)/ALK chimeric protein, the dominant form of ALK expressed in T-cell lymphomas (ALK+TCL), closely resembles cell activation induced by interleukin 2 (IL-2), the key cytokine supporting growth and survival of normal CD4+ T lymphocytes. Direct comparison of gene expression by ALK+TCL cells treated with an ALK inhibitor and IL-2-dependent ALK-TCL cells stimulated with the cytokine revealed a very similar, albeit inverse, gene regulation pattern. Depending on the analysis method, up to 67% of the modulated genes could be defined as modulated in common by NPM/ALK and IL-2. Based on the gene expression patterns, Jak/STAT and IL-2 signaling pathways topped the list of pathways identified as affected by both IL-2 and NPM/ALK. The expression dependence on NPM/ALK and IL-2 of the five selected genes: CD25 (IL-2Rα), Egr-1, Fosl-1, SOCS3, and Irf-4 was confirmed at the protein level. In both ALK+TCL and IL-2-stimulated ALK-TCL cells, CD25, SOCS3, and Irf-4 genes were activated predominantly by the STAT5 and STAT3 transcription factors, while transcription of Egr-1 and Fosl-1 was induced by the MEK-ERK pathway. Finally, we found that Egr-1, a protein not associated previously with either IL-2 or ALK, contributes to the cell proliferation. These findings indicate that NPM/ALK transforms the target CD4+ T lymphocytes, at least in part, by utilizing the pre-existing, IL-2-dependent signaling pathways. PMID:24218456

Diffusion weighted imaging with background body signal suppression / T2 image fusion in magnetic resonance mammography for breast cancer diagnosis.

PubMed

Nechifor-Boilă, I A; Bancu, S; Buruian, M; Charlot, M; Decaussin-Petrucci, M; Krauth, J-S; Nechifor-Boilă, A C; Borda, A

2013-01-01

Dynamic Contrast-Enhanced Magnetic Resonance Mammography (DCE-MRM) represents the most sensitive examination for breast cancer (BC) diagnosis. However literature data reports very inhomogeneous specificity. The aim of our study was to evaluate the clinical efficiency of a new MRM technique - diffusion weighted imaging with background body signal suppression T2 image fusion in BC diagnosis, compared to DCE-MRM. We retrospectively analyzed 50 consecutive DCE-MRM examinations with DWIBS sequence from the archives of the Department of Radiology, Lyon Sud Hospital, (02.2010- 02.2011), summing up to 64 breast lesions. Fusions were created using the Osirix software from the DWIBS images (b=1000 s mm2) and their T2 correspondents. Interpretation was performed using an adapted BI-RADS system. The final histopathological examination or a minimum 6-months follow-up served as gold standard. Out of the 64 examined breast lesions, 35(54.7%) were classified as malignant by DCE-MRM and 24(37.5%) cases by DWIBS T2, respectively. Thus the DWIBS T2 fusion had a Sensitivity of 62.5%(95%CI:35.4-84.8) and a Specificity of 70.8%(95%CI:55.9-83.3) while DCE-MRM had a higher Sensitivity: 87.5%(95%CI:61.6-98.4) but a lower Specificity: 56.2%(95%CI:41.1-70.5). DWIBS T2 fusion is an innovative MRM technique, with a specificity superior to DCE-MRM, showing a large potential for improving the clinical efficiency of classical MRM. Celsius.

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.

7T MRI-Histologic Correlation Study of Low Specific Absorption Rate T2-Weighted GRASE Sequences in the Detection of White Matter Involvement in Multiple Sclerosis.

PubMed

Bagnato, Francesca; Hametner, Simon; Pennell, David; Dortch, Richard; Dula, Adrienne N; Pawate, Siddharama; Smith, Seth A; Lassmann, Hans; Gore, John C; Welch, Edward B

2015-01-01

The high value of the specific absorption rate (SAR) of radio-frequency (RF) energy arising from the series of RF refocusing pulses in T2-weighted (T2-w) turbo spin echo (TSE) MRI hampers its clinical application at 7.0 Tesla (7T). T2-w gradient and spin echo (GRASE) uses the speed from gradient refocusing in combination with the chemical-shift/static magnetic field (B0) inhomogeneity insensitivity from spin-echo refocusing to acquire T2-w images with a limited number of refocusing RF pulses, thus reducing SAR. To investigate whether low SAR T2-w GRASE could replace T2-w TSE in detecting white matter (WM) disease in MS patients imaged at 7T. The .7 mm3 isotropic T2-w TSE and T2-w GRASE images with variable echo times (TEs) and echo planar imaging (EPI) factors were obtained on a 7T scanner from postmortem samples of MS brains. These samples were derived from brains of 3 female MS patients. WM lesions (WM-Ls) and normal-appearing WM (NAWM) signal intensity, WM-Ls/NAWM contrast-to-noise ratio (CNR) and MRI/myelin staining sections comparisons were obtained. GRASE sequences with EPI factor/TE = 3/50 and 3/75 ms were comparable to the SE technique for measures of CNR in WM-Ls and NAWM and for detection of WM-Ls. In all sequences, however, identification of areas with remyelination, Wallerian degeneration, and gray matter demyelination, as depicted by myelin staining, was not possible. T2-w GRASE images may replace T2-w TSE for clinical use. However, even at 7T, both sequences fail in detecting and characterizing MS disease beyond visible WM-Ls. Copyright © 2015 by the American Society of Neuroimaging.

Determining dark matter properties with a XENONnT/LZ signal and LHC Run 3 monojet searches

NASA Astrophysics Data System (ADS)

Baum, Sebastian; Catena, Riccardo; Conrad, Jan; Freese, Katherine; Krauss, Martin B.

2018-04-01

We develop a method to forecast the outcome of the LHC Run 3 based on the hypothetical detection of O (100 ) signal events at XENONnT. Our method relies on a systematic classification of renormalizable single-mediator models for dark matter-quark interactions and is valid for dark matter candidates of spin less than or equal to one. Applying our method to simulated data, we find that at the end of the LHC Run 3 only two mutually exclusive scenarios would be compatible with the detection of O (100 ) signal events at XENONnT. In the first scenario, the energy distribution of the signal events is featureless, as for canonical spin-independent interactions. In this case, if a monojet signal is detected at the LHC, dark matter must have spin 1 /2 and interact with nucleons through a unique velocity-dependent operator. If a monojet signal is not detected, dark matter interacts with nucleons through canonical spin-independent interactions. In a second scenario, the spectral distribution of the signal events exhibits a bump at nonzero recoil energies. In this second case, a monojet signal can be detected at the LHC Run 3; dark matter must have spin 1 /2 and interact with nucleons through a unique momentum-dependent operator. We therefore conclude that the observation of O (100 ) signal events at XENONnT combined with the detection, or the lack of detection, of a monojet signal at the LHC Run 3 would significantly narrow the range of possible dark matter-nucleon interactions. As we argued above, it can also provide key information on the dark matter particle spin.

Ca²⁺ signal contributing to the synthesis and emission of monoterpenes regulated by light intensity in Lilium 'siberia'.

PubMed

Hu, Zenghui; Li, Tianjiao; Zheng, Jian; Yang, Kai; He, Xiangfeng; Leng, Pingsheng

2015-06-01

The floral scent is an important part of plant volatile compounds, and is influenced by environmental factors. The emission of monoterpenes of Lilium 'siberia' is regulated by light intensity, but the mechanism is large unknown. In this study, the expression of Li-mTPS, a monoterpene synthase gene in the tepals of Lilium 'siberia', and net Ca(2+) flux were investigated after exposure to different levels of light intensity (0, 100, 300, 600, 1000, and 1500 μmol m(-2) s(-1)). Moreover the effect of LaCl3 and ethylene glycol-bis-(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA) on the Li-mTPS expression, monoterpene emission, and net Ca(2+) flux were examined at 600 μmol m(-2) s(-1). The results showed that along with the enhancement of light intensity, the expression level of Li-mTPS increased gradually, and the net Ca(2+) influx was also enhanced showing a similar pattern. It was found that LaCl3 and EGTA effectively inhibited the increase in expression of Li-mTPS and the net Ca(2+) influx induced by light treatment. Moreover, the release amounts of monoterpenes decreased significantly after treatment with LaCl3 and EGTA. So it can be concluded that Ca(2+) signal contributed to the biosynthesis and emission of monoterpenes regulated by light intensity in Lilium 'siberia' tepals. The increased light intensity firstly triggered the Ca(2+) influx to cytoplasm, and then the gene expression of monoterpene synthases downstream was activated to regulate the biosynthesis and emission of monoterpenes. But in the signaling pathway other mechanisms were thought to be involved in the emission of monoterpenes regulated by light intensity, which need to be investigated in future research. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A comparison of the health benefits of reduced-exertion high-intensity interval training (REHIT) and moderate-intensity walking in type 2 diabetes patients.

PubMed

Ruffino, José S; Songsorn, Preeyaphorn; Haggett, Malindi; Edmonds, Daniel; Robinson, Anthony M; Thompson, Dylan; Vollaard, Niels B J

2017-02-01

Reduced-exertion high-intensity interval training (REHIT) is a genuinely time-efficient intervention that can improve aerobic capacity and insulin sensitivity in sedentary individuals. The present study compared the effects of REHIT and moderate-intensity walking on health markers in patients with type 2 diabetes (T2D) in a counter-balanced crossover study. Sixteen men with T2D (mean ± SD age: 55 ± 5 years, body mass index: 30.6 ± 2.8 kg·m -2 , maximal aerobic capacity: 27 ± 4 mL·kg -1 ·min -1 ) completed 8 weeks of REHIT (three 10-min low-intensity cycling sessions/week with two "all-out" 10-20-s sprints) and 8 weeks of moderate-intensity walking (five 30-min sessions/week at an intensity corresponding to 40%-55% of heart-rate reserve), with a 2-month wash-out period between interventions. Before and after each intervention, participants underwent an incremental fitness test, an oral glucose tolerance test (OGTT), a whole-body dual-energy X-ray absorptiometry scan, and continuous glucose monitoring. REHIT was associated with a significantly larger increase in maximal aerobic capacity compared with walking (7% vs. 1%; time × intervention interaction effect: p < 0.05). Both REHIT and walking decreased resting mean arterial pressure (-4%; main effect of time: p < 0.05) and plasma fructosamine (-5%; main effect of time: p < 0.05). Neither intervention significantly improved OGTT-derived measures of insulin sensitivity, glycaemic control measured using continuous glucose monitors, blood lipid profile, or body composition. We conclude that REHIT is superior to a 5-fold larger volume of moderate-intensity walking in improving aerobic fitness, but similar to walking REHIT is not an effective intervention for improving insulin sensitivity or glycaemic control in T2D patients in the short term.

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.

[Imaging characteristics of PROPELLER T2-weighted imaging].

PubMed

Goto, Masami; Aoki, Shigeki; Hayashi, Naoto; Mori, Harushi; Watanabe, Yasushi; Ino, Kenji; Satake, Yoshirou; Nishida, Katuji; Sato, Haruo; Iida, Kyouhito; Mima, Kazuo; Ohtomo, Kuni

2004-11-01

As the PROPELLER sequence is a combination of the radial scan and fast-spin-echo (FSE) sequence, it can be considered an FSE sequence with a motion correlation. However, there are some differences between PROPELLER and FSE owing to differences in k-space trajectory. We clarified the imaging characteristics of PROPELLER T2-weighted imaging (T2WI) for different parameters in comparison with usual FSE T2WI. When the same parameters were used, PROPELLER T2WI showed a higher signal-to-noise ratio (SNR) and lower spatial resolution than usual FSE. Effective echo time (TE) changed with different echo train lengths (ETL) or different bandwidths on PROPELLER, and imaging contrast changed accordingly to be more effective.

Leptin receptor signaling in T cells is required for Th17 differentiation.

PubMed

Reis, Bernardo S; Lee, Kihyun; Fanok, Melania H; Mascaraque, Cristina; Amoury, Manal; Cohn, Lillian B; Rogoz, Aneta; Dallner, Olof S; Moraes-Vieira, Pedro M; Domingos, Ana I; Mucida, Daniel

2015-06-01

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function. Copyright © 2015 by The American Association of Immunologists, Inc.

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.

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

mTOR Complex Signaling through the SEMA4A-Plexin B2 Axis Is Required for Optimal Activation and Differentiation of CD8+ T Cells.

PubMed

Ito, Daisuke; Nojima, Satoshi; Nishide, Masayuki; Okuno, Tatsusada; Takamatsu, Hyota; Kang, Sujin; Kimura, Tetsuya; Yoshida, Yuji; Morimoto, Keiko; Maeda, Yohei; Hosokawa, Takashi; Toyofuku, Toshihiko; Ohshima, Jun; Kamimura, Daisuke; Yamamoto, Masahiro; Murakami, Masaaki; Morii, Eiichi; Rakugi, Hiromi; Isaka, Yoshitaka; Kumanogoh, Atsushi

2015-08-01

Mammalian target of rapamycin (mTOR) plays crucial roles in activation and differentiation of diverse types of immune cells. Although several lines of evidence have demonstrated the importance of mTOR-mediated signals in CD4(+) T cell responses, the involvement of mTOR in CD8(+) T cell responses is not fully understood. In this study, we show that a class IV semaphorin, SEMA4A, regulates CD8(+) T cell activation and differentiation through activation of mTOR complex (mTORC) 1. SEMA4A(-/-) CD8(+) T cells exhibited impairments in production of IFN-γ and TNF-α and induction of the effector molecules granzyme B, perforin, and FAS-L. Upon infection with OVA-expressing Listeria monocytogenes, pathogen-specific effector CD8(+) T cell responses were significantly impaired in SEMA4A(-/-) mice. Furthermore, SEMA4A(-/-) CD8(+) T cells exhibited reduced mTORC1 activity and elevated mTORC2 activity, suggesting that SEMA4A is required for optimal activation of mTORC1 in CD8(+) T cells. IFN-γ production and mTORC1 activity in SEMA4A(-/-) CD8(+) T cells were restored by administration of recombinant Sema4A protein. In addition, we show that plexin B2 is a functional receptor of SEMA4A in CD8(+) T cells. Collectively, these results not only demonstrate the role of SEMA4A in CD8(+) T cells, but also reveal a novel link between a semaphorin and mTOR signaling. Copyright © 2015 by The American Association of Immunologists, Inc.

T-cell receptor signaling activates an ITK/NF-κB/GATA-3 axis in T-cell lymphomas facilitating resistance to chemotherapy

PubMed Central

Wang, Tianjiao; Lu, Ye; Polk, Avery; Chowdhury, Pinki; Zamalloa, Carlos Murga; Fujiwara, Hiroshi; Suemori, Koichiro; Beyersdorf, Niklas; Hristov, Alexandra C.; Lim, Megan S.; Bailey, Nathanael G.; Wilcox, Ryan A.

2016-01-01

Purpose T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T-cell specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR’s role in mediating resistance to chemotherapy. Experimental Design Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following T-cell receptor (TCR) engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines. Results Here we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3, and promotes chemotherapy resistance. Conclusions These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented activation of this signaling axis and overcame chemotherapy resistance. PMID:27780854

Pilot study of a novel tool for input-free automated identification of transition zone prostate tumors using T2- and diffusion-weighted signal and textural features.

PubMed

Stember, Joseph N; Deng, Fang-Ming; Taneja, Samir S; Rosenkrantz, Andrew B

2014-08-01

To present results of a pilot study to develop software that identifies regions suspicious for prostate transition zone (TZ) tumor, free of user input. Eight patients with TZ tumors were used to develop the model by training a Naïve Bayes classifier to detect tumors based on selection of most accurate predictors among various signal and textural features on T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) maps. Features tested as inputs were: average signal, signal standard deviation, energy, contrast, correlation, homogeneity and entropy (all defined on T2WI); and average ADC. A forward selection scheme was used on the remaining 20% of training set supervoxels to identify important inputs. The trained model was tested on a different set of ten patients, half with TZ tumors. In training cases, the software tiled the TZ with 4 × 4-voxel "supervoxels," 80% of which were used to train the classifier. Each of 100 iterations selected T2WI energy and average ADC, which therefore were deemed the optimal model input. The two-feature model was applied blindly to the separate set of test patients, again without operator input of suspicious foci. The software correctly predicted presence or absence of TZ tumor in all test patients. Furthermore, locations of predicted tumors corresponded spatially with locations of biopsies that had confirmed their presence. Preliminary findings suggest that this tool has potential to accurately predict TZ tumor presence and location, without operator input. © 2013 Wiley Periodicals, Inc.

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

Leucine signaling in the pathogenesis of type 2 diabetes and obesity.

PubMed

Melnik, Bodo C

2012-03-15

Epidemiological evidence points to increased dairy and meat consumption, staples of the Western diet, as major risk factors for the development of type 2 diabetes (T2D). This paper presents a new concept and comprehensive review of leucine-mediated cell signaling explaining the pathogenesis of T2D and obesity by leucine-induced over-stimulation of mammalian target of rapamycin complex 1 (mTORC1). mTORC1, a pivotal nutrient-sensitive kinase, promotes growth and cell proliferation in response to glucose, energy, growth factors and amino acids. Dairy proteins and meat stimulate insulin/insulin-like growth factor 1 signaling and provide high amounts of leucine, a primary and independent stimulator for mTORC1 activation. The downstream target of mTORC1, the kinase S6K1, induces insulin resistance by phosphorylation of insulin receptor substrate-1, thereby increasing the metabolic burden of β-cells. Moreover, leucine-mediated mTORC1-S6K1-signaling plays an important role in adipogenesis, thus increasing the risk of obesity-mediated insulin resistance. High consumption of leucine-rich proteins explains exaggerated mTORC1-dependent insulin secretion, increased β-cell growth and β-cell proliferation promoting an early onset of replicative β-cell senescence with subsequent β-cell apoptosis. Disturbances of β-cell mass regulation with increased β-cell proliferation and apoptosis as well as insulin resistance are hallmarks of T2D, which are all associated with hyperactivation of mTORC1. In contrast, the anti-diabetic drug metformin antagonizes leucine-mediated mTORC1 signaling. Plant-derived polyphenols and flavonoids are identified as natural inhibitors of mTORC1 and exert anti-diabetic and anti-obesity effects. Furthermore, bariatric surgery in obesity reduces increased plasma levels of leucine and other branched-chain amino acids. Attenuation of leucine-mediated mTORC1 signaling by defining appropriate upper limits of the daily intake of leucine-rich animal and dairy

Utilizing T-cell Activation Signals 1, 2, and 3 for Tumor-infiltrating Lymphocytes (TIL) Expansion: The Advantage Over the Sole Use of Interleukin-2 in Cutaneous and Uveal Melanoma.

PubMed

Tavera, René J; Forget, Marie-Andrée; Kim, Young Uk; Sakellariou-Thompson, Donastas; Creasy, Caitlin A; Bhatta, Ankit; Fulbright, Orenthial J; Ramachandran, Renjith; Thorsen, Shawne T; Flores, Esteban; Wahl, Arely; Gonzalez, Audrey M; Toth, Christopher; Wardell, Seth; Mansaray, Rahmatu; Radvanyi, Laszlo G; Gombos, Dan S; Patel, Sapna P; Hwu, Patrick; Amaria, Rodabe N; Bernatchez, Chantale; Haymaker, Cara

2018-05-11

In this study, we address one of the major critiques for tumor-infiltrating lymphocyte (TIL) therapy-the time needed for proper expansion of a suitable product. We postulated that T-cell receptor activation in the first phase of expansion combined with an agonistic stimulation of CD137/4-1BB and interleukin-2 would favor preferential expansion of CD8 TIL. Indeed, this novel 3-signal approach for optimal T-cell activation resulted in faster and more consistent expansion of CD8CD3 TIL. This new method allowed for successful expansion of TIL from cutaneous and uveal melanoma tumors in 100% of the cultures in <3 weeks. Finally, providing the 3 signals attributed to optimal T-cell activation led to expansion of TIL capable of recognizing their tumor counterpart in cutaneous and uveal melanoma. This new methodology for the initial phase of TIL expansion brings a new opportunity for translation of TIL therapy in challenging malignancies such as uveal melanoma.

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway.

PubMed

Wang, Bohan; Ning, Hongxiu; Reed-Maldonado, Amanda B; Zhou, Jun; Ruan, Yajun; Zhou, Tie; Wang, Hsun Shuan; Oh, Byung Seok; Banie, Lia; Lin, Guiting; Lue, Tom F

2017-02-16

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157-an inhibitor of PERK-effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy.

Low-Intensity Extracorporeal Shock Wave Therapy Enhances Brain-Derived Neurotrophic Factor Expression through PERK/ATF4 Signaling Pathway

PubMed Central

Wang, Bohan; Ning, Hongxiu; Reed-Maldonado, Amanda B.; Zhou, Jun; Ruan, Yajun; Zhou, Tie; Wang, Hsun Shuan; Oh, Byung Seok; Banie, Lia; Lin, Guiting; Lue, Tom F.

2017-01-01

Low-intensity extracorporeal shock wave therapy (Li-ESWT) is used in the treatment of erectile dysfunction, but its mechanisms are not well understood. Previously, we found that Li-ESWT increased the expression of brain-derived neurotrophic factor (BDNF). Here we assessed the underlying signaling pathways in Schwann cells in vitro and in penis tissue in vivo after nerve injury. The result indicated that BDNF were significantly increased by the Li-ESWT after nerve injury, as well as the expression of BDNF in Schwann cells (SCs, RT4-D6P2T) in vitro. Li-ESWT activated the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK) pathway by increasing the phosphorylation levels of PERK and eukaryotic initiation factor 2a (eIF2α), and enhanced activating transcription factor 4 (ATF4) in an energy-dependent manner. In addition, GSK2656157—an inhibitor of PERK—effectively inhibited the effect of Li-ESWT on the phosphorylation of PERK, eIF2α, and the expression of ATF4. Furthermore, silencing ATF4 dramatically attenuated the effect of Li-ESWT on the expression of BDNF, but had no effect on hypoxia-inducible factor (HIF)1α or glial cell-derived neurotrophic factor (GDNF) in Schwann cells. In conclusion, our findings shed new light on the underlying mechanisms by which Li-ESWT may stimulate the expression of BDNF through activation of PERK/ATF4 signaling pathway. This information may help to refine the use of Li-ESWT to further improve its clinical efficacy. PMID:28212323

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

PubMed Central

2013-01-01

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

Diagnosis of retrodiscal tissue in painful temporomandibular joint (TMJ) by fluid-attenuated inversion recovery (FLAIR) signal intensity.

PubMed

Kuroda, Migiwa; Otonari-Yamamoto, Mika; Sano, Tsukasa; Fujikura, Mamiko; Wakoh, Mamoru

2014-09-09

Aims: The purpose of the present study is to analyze the fluid-attenuated inversion recovery (FLAIR) signal intensity of the retrodiscal tissue in a painful temporomandibular joint (TMJ), and to develop a diagnostic system based on FLAIR data. Methodology: The study was based on 33 joints of 17 patients referred for MR imaging of the TMJ. Regions of interest were placed over retrodiscal tissue and gray matter (GM) on FLAIR images. Using signal intensities of GM as reference points, signal intensity ratios (SIR) of retrodiscal tissue were calculated. SIRs in painful TMJ were compared with those in painless TMJ. Wilcoxon's Rank Sum Test was used to analyze the difference in SIRs between the painful and painless groups (P<0·05). Results: The SIRs of retrodiscal tissue were significantly higher in painful joints than in painless joints. Conclusion: FLAIR sequences provide a high signal in patients having painful TMJ, and it suggests that retrodiscal tissue in painful TMJ contains elements such as protein.

Diagnosis of retrodiscal tissue in painful temporomandibular joint (TMJ) by fluid-attenuated inversion recovery (FLAIR) signal intensity.

PubMed

Kuroda, Migiwa; Otonari-Yamamoto, Mika; Sano, Tsukasa; Fujikura, Mamiko; Wakoh, Mamoru

2015-10-01

The purpose of the present study is to analyze the fluid-attenuated inversion recovery (FLAIR) signal intensity of the retrodiscal tissue in a painful temporomandibular joint (TMJ), and to develop a diagnostic system based on FLAIR data. The study was based on 33 joints of 17 patients referred for MR imaging of the TMJ. Regions of interest were placed over retrodiscal tissue and gray matter (GM) on FLAIR images. Using signal intensities of GM as reference points, signal intensity ratios (SIR) of retrodiscal tissue were calculated. SIRs in painful TMJ were compared with those in painless TMJ. Wilcoxon's Rank Sum Test was used to analyze the difference in SIRs between the painful and painless groups (P<0·05). The SIRs of retrodiscal tissue were significantly higher in painful joints than in painless joints. FLAIR sequences provide a high signal in patients having painful TMJ, and it suggests that retrodiscal tissue in painful TMJ contains elements such as protein.

Inhibition of Gαs/cAMP Signaling Decreases TCR-Stimulated IL-2 transcription in CD4(+) T Helper Cells.

PubMed

Hynes, Thomas R; Yost, Evan A; Yost, Stacy M; Hartle, Cassandra M; Ott, Braden J; Berlot, Catherine H

2015-07-06

The role of cAMP in regulating T cell activation and function has been controversial. cAMP is generally known as an immunosuppressant, but it is also required for generating optimal immune responses. As the effect of cAMP is likely to depend on its cellular context, the current study investigated whether the mechanism of activation of Gαs and adenylyl cyclase influences their effect on T cell receptor (TCR)-stimulated interleukin-2 (IL-2) mRNA levels. The effect of blocking Gs-coupled receptor (GsPCR)-mediated Gs activation on TCR-stimulated IL-2 mRNA levels in CD4(+) T cells was compared with that of knocking down Gαs expression or inhibiting adenylyl cyclase activity. The effect of knocking down Gαs expression on TCR-stimulated cAMP accumulation was compared with that of blocking GsPCR signaling. ZM-241385, an antagonist to the Gs-coupled A2A adenosine receptor (A2AR), enhanced TCR-stimulated IL-2 mRNA levels in primary human CD4(+) T helper cells and in Jurkat T cells. A dominant negative Gαs construct, GαsDN3, also enhanced TCR-stimulated IL-2 mRNA levels. Similar to GsPCR antagonists, GαsDN3 blocked GsPCR-dependent activation of both Gαs and Gβγ. In contrast, Gαs siRNA and 2',5'-dideoxyadenosine (ddA), an adenylyl cyclase inhibitor, decreased TCR-stimulated IL-2 mRNA levels. Gαs siRNA, but not GαsDN3, decreased TCR-stimulated cAMP synthesis. Potentiation of IL-2 mRNA levels by ZM-241385 required at least two days of TCR stimulation, and addition of ddA after three days of TCR stimulation enhanced IL-2 mRNA levels. GsPCRs play an inhibitory role in the regulation of TCR-stimulated IL-2 mRNA levels whereas Gαs and cAMP can play a stimulatory one. Additionally, TCR-dependent activation of Gαs does not appear to involve GsPCRs. These results suggest that the context of Gαs/cAMP activation and the stage of T cell activation and differentiation determine the effect on TCR-stimulated IL-2 mRNA levels.

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.

An essential role for IL-2 receptor in regulatory T cell function

PubMed Central

Levine, Andrew G; Fan, Xiying; Klein, Ulf; Zheng, Ye; Gasteiger, Georg; Feng, Yongqiang; Fontenot, Jason D.; Rudensky, Alexander Y.

2016-01-01

Regulatory T (Treg) cells, expressing abundant amounts of the IL-2 receptor (IL-2R), are reliant on IL-2 produced by activated T cells. This feature implied a key role for a simple network based on IL-2 consumption by Treg cells in their suppressor function. However, congenital deficiency in IL-2R results in reduced expression of the Treg cell lineage specification factor Foxp3, confounding experimental efforts to understand the role of IL-2R expression and signaling in Treg suppressor function. Using genetic gain and loss of function approaches, we demonstrate that IL-2 capture is dispensable for control of CD4+ T cells, but is important for limiting CD8+ T cell activation, and that IL-2R dependent STAT5 transcription factor activation plays an essential role in Treg cell suppressor function separable from T cell receptor signaling. PMID:27595233

Selective targeting of JAK/STAT signaling is potentiated by Bcl-xL blockade in IL-2–dependent adult T-cell leukemia

PubMed Central

Zhang, Meili; Mathews Griner, Lesley A.; Ju, Wei; Duveau, Damien Y.; Guha, Rajarshi; Petrus, Michael N.; Wen, Bernard; Maeda, Michiyuki; Shinn, Paul; Ferrer, Marc; Conlon, Kevin D.; Bamford, Richard N.; O’Shea, John J.; Thomas, Craig J.; Waldmann, Thomas A.

2015-01-01

Adult T-cell leukemia (ATL) develops in individuals infected with human T-cell lymphotropic virus-1 (HTLV-1). Presently there is no curative therapy for ATL. HTLV-1–encoded protein Tax (transactivator from the X-gene region) up-regulates Bcl-xL (B-cell lymphoma-extra large) expression and activates interleukin-2 (IL-2), IL-9, and IL-15 autocrine/paracrine systems, resulting in amplified JAK/STAT signaling. Inhibition of JAK signaling reduces cytokine-dependent ex vivo proliferation of peripheral blood mononuclear cells (PBMCs) from ATL patients in smoldering/chronic stages. Currently, two JAK inhibitors are approved for human use. In this study, we examined activity of multiple JAK inhibitors in ATL cell lines. The selective JAK inhibitor ruxolitinib was examined in a high-throughput matrix screen combined with >450 potential therapeutic agents, and Bcl-2/Bcl-xL inhibitor navitoclax was identified as a strong candidate for multicomponent therapy. The combination was noted to strongly activate BAX (Bcl-2-associated X protein), effect mitochondrial depolarization, and increase caspase 3/7 activities that lead to cleavage of PARP (poly ADP ribose polymerase) and Mcl-1 (myeloid cell leukemia 1). Ruxolitinib and navitoclax independently demonstrated modest antitumor efficacy, whereas the combination dramatically lowered tumor burden and prolonged survival in an ATL murine model. This combination strongly blocked ex vivo proliferation of five ATL patients’ PBMCs. These studies provide support for a therapeutic trial in patients with smoldering/chronic ATL using a drug combination that inhibits JAK signaling and antiapoptotic protein Bcl-xL. PMID:26396258

Pathophysiological hypoxia affects the redox state and IL-2 signalling of human CD4+ T cells and concomitantly impairs survival and proliferation.

PubMed

Gaber, Timo; Tran, Cam Loan; Schellmann, Saskia; Hahne, Martin; Strehl, Cindy; Hoff, Paula; Radbruch, Andreas; Burmester, Gerd-Rüdiger; Buttgereit, Frank

2013-06-01

Inflamed areas are characterized by infiltration of immune cells, local hypoxia and alterations of cellular redox states. We investigated the impact of hypoxia on survival, proliferation, cytokine secretion, intracellular energy and redox state of human CD4(+) T cells. We found that pathophysiological hypoxia (<2% O2 ) significantly decreased CD4(+) T-cell survival after mitogenic stimulation. This effect was not due to an increased caspase-3/7-mediated apoptosis or adenosine-5'-triphosphate (ATP) consumption/depletion. However, the ability of stimulated T cells to proliferate was reduced under hypoxic conditions, despite increased expression of CD25. Pathophysiological hypoxia was also found to modify intracellular ROS (iROS) levels in stimulated T cells over time as compared with levels found in normoxia. Physiological hypoxia (5% O2 ) did not decrease CD4(+) T-cell survival and proliferation or modify iROS levels as compared with normoxia. We conclude that pathophysiological hypoxia affects T-cell proliferation and viability via disturbed IL-2R signalling downstream of STAT5a phosphorylation, but not as a result of impaired cellular energy homeostasis. We suggest iROS links early events in T-cell stimulation to the inhibition of the lymphoproliferative response under pathophysiological hypoxic conditions. The level of iROS may therefore act as a mediator of immune functions leading to down-regulation of long-term T-cell activity in inflamed tissues. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.