Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells

BACKGROUND: Glucocorticoids are frequently used as a primary chemotherapeutic agent in many types of human lymphoid malignancies because they induce apoptosis through activation of the glucocorticoid receptor, with subsequent alteration of a complex network of cellular mechanisms. Despite clinical usage for over fifty years, the complete mechanism responsible for glucocorticoid-related apoptosis or resistance remains elusive. The mitogen-activated protein kinase pathway is a signal transduction network that influences a variety of cellular responses through phosphorylation of specific target substrates, including the glucocorticoid receptor. In this study we have evaluated the pharmaceutical scenarios which converge on the mitogen-activated protein kinase pathway to alter glucocorticoid sensitivity in clones of human acute lymphoblastic CEM cells sensitive and refractory to apoptosis in response to the synthetic glucocorticoid dexamethasone. RESULTS: The glucocorticoid-resistant clone CEM-C1-15 displays a combination of high constitutive JNK activity and dexamethasone-induced ERK activity with a weak induction of p38 upon glucocorticoid treatment. The cells become sensitive to glucocorticoid-evoked apoptosis after: (1) inhibition of JNK and ERK activity, (2) stimulation of the cAMP/PKA pathway with forskolin, or (3) inhibition of mTOR with rapamycin. Treatments 1–3 in combination with dexamethasone alter the intracellular balance of phospho-MAPKs by lowering JNK phosphorylation and increasing the level of glucocorticoid receptor phosphorylated at serine 211, a modification known to enhance receptor activity. CONCLUSION: Our data support the hypothesis that mitogen-activated protein kinases influence the ability of certain malignant lymphoid cells to undergo apoptosis when treated with glucocorticoid. Activated/phosphorylated JNK and ERK appear to counteract corticoid-dependent apoptosis. Inhibiting these MAPKs restores corticoid sensitivity to a resistant clone of CEM cells. Forskolin, which activates the cAMP pathway, and rapamycin, which inhibits mTOR, also inhibit JNK. Further, the sensitizing treatments result in a largely dexamethasone-dependent increase in the total pool of glucocorticoid receptor phosphorylated at serine 211. The phospho-serine 211 receptor is known to be more potent in activating gene transcription and apoptosis. The interactive effects demonstrated here in reverting resistant cells to corticoid sensitivity could provide therapeutic clinical potential in the treatment of lymphoid malignancies

Gene expression profiling of leukemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to glucocorticoids

<p>Abstract</p> <p>Background</p> <p>Glucocorticoids (GC's) play an integral role in treatment strategies designed to combat various forms of hematological malignancies. GCs also are powerful inhibitors of the immune system, through regulation of appropriate cytokines and by causing apoptosis of immature thymocytes. By activating the glucocorticoid receptor (GR), GCs evoke apoptosis through transcriptional regulation of a complex, interactive gene network over a period of time preceding activation of the apoptotic enzymes. In this study we used microarray technology to determine whether several disparate types of hematologic cells, all sensitive to GC-evoked apoptosis, would identify a common set of regulated genes. We compared gene expression signatures after treatment with two potent synthetic GCs, dexamethasone (Dex) and cortivazol (CVZ) using a panel of hematologic cells. Pediatric CD4+/CD8+ T-cell leukemia was represented by 3 CEM clones: two sensitive, CEM-C7–14 and CEM-C1–6, and one resistant, CEM-C1–15, to Dex. CEM-C1–15 was also tested when rendered GC-sensitive by several treatments. GC-sensitive pediatric B-cell leukemia was represented by the SUP-B15 line and adult B-cell leukemia by RS4;11 cells. Kasumi-1 cells gave an example of the rare Dex-sensitive acute myeloblastic leukemia (AML). To test the generality of the correlations in malignant cell gene sets, we compared with GC effects on mouse non-transformed thymocytes.</p> <p>Results</p> <p>We identified a set of genes regulated by GCs in all GC-sensitive malignant cells. A portion of these were also regulated in the thymocytes. Because we knew that the highly Dex-resistant CEM-C1–15 cells could be killed by CVZ, we tested these cells with the latter steroid and again found that many of the same genes were now regulated as in the inherently GC-sensitive cells. The same result was obtained when we converted the Dex-resistant clone to Dex-sensitive by treatment with forskolin (FSK), to activate the adenyl cyclase/protein kinase A pathway (PKA).</p> <p>Conclusion</p> <p>Our results have identified small sets of genes that correlate with GC-sensitivity in cells from several hematologic malignancies. Some of these are also regulated in normal mouse thymocytes.</p

On the frequency and remnants of Hypernovae

Under the hypothesis that some fraction of massive stellar core collapses give rise to unusually energetic events, termed hypernovae, I examine the required rates assuming some fraction of such events yield gamma ray bursts. I then discuss evidence from studies of pulsars and r-process nucleosynthesis that independently suggests the existence of a class of unusually energetic events. Finally I describe a scenario which links these different lines of evidence as supporting the hypernova hypothesis.Comment: TeX, To appear in ApJ Letter

Aqueous Processes and Microbial Habitability of Gale Crater Sediments from the Blunts Point to the Glenn Torridon Clay Unit

A driving factor for sending the Mars Science Laboratory, Curiosity rover to Gale Crater was the orbital detection of clay minerals in the Glen Torridon (GT) clay unit. Clay mineral detections in GT suggested a past aqueous environment that was habitable, and could contain organic evidence of past microbiology. The mission of the Sample Analysis at Mars (SAM) instrument onboard Curiosity was to detect organic evidence of past microbiology and to detect volatile bearing mineralogy that can inform on whether past geochemical conditions would have supported microbiological activity. The objective of this work was to 1) evaluate the depositional/alteration conditions of Blunts Point (BP) to GT sediments 2) search for evidence of organics, and 3) evaluate microbial habitability in the BP, Vera Rubin Ridge (VRR), and GT sedimentary rock

Atmospheric Acetaldehyde: Importance of Air-Sea Exchange and a Missing Source in the Remote Troposphere.

We report airborne measurements of acetaldehyde (CH3CHO) during the first and second deployments of the National Aeronautics and Space Administration (NASA) Atmospheric Tomography Mission (ATom). The budget of CH3CHO is examined using the Community Atmospheric Model with chemistry (CAM-chem), with a newly-developed online air-sea exchange module. The upper limit of the global ocean net emission of CH3CHO is estimated to be 34 Tg a-1 (42 Tg a-1 if considering bubble-mediated transfer), and the ocean impacts on tropospheric CH3CHO are mostly confined to the marine boundary layer. Our analysis suggests that there is an unaccounted CH3CHO source in the remote troposphere and that organic aerosols can only provide a fraction of this missing source. We propose that peroxyacetic acid (PAA) is an ideal indicator of the rapid CH3CHO production in the remote troposphere. The higher-than-expected CH3CHO measurements represent a missing sink of hydroxyl radicals (and halogen radical) in current chemistry-climate models

THE COMMUNITY LEVERAGED UNIFIED ENSEMBLE (CLUE) IN THE 2016 NOAA/HAZARDOUS WEATHER TESTBED SPRING FORECASTING EXPERIMENT

One primary goal of annual Spring Forecasting Experiments (SFEs), which are coorganized by NOAA’s National Severe Storms Laboratory and Storm Prediction Center and conducted in the National Oceanic and Atmospheric Administration’s (NOAA) Hazardous Weather Testbed, is documenting performance characteristics of experimental, convection-allowing modeling systems (CAMs). Since 2007, the number of CAMs (including CAM ensembles) examined in the SFEs has increased dramatically, peaking at six different CAM ensembles in 2015. Meanwhile, major advances have been made in creating, importing, processing, verifying, and developing tools for analyzing and visualizing these large and complex datasets. However, progress toward identifying optimal CAM ensemble configurations has been inhibited because the different CAM systems have been independently designed, making it difficult to attribute differences in performance characteristics. Thus, for the 2016 SFE, a much more coordinated effort among many collaborators was made by agreeing on a set of model specifications (e.g., model version, grid spacing, domain size, and physics) so that the simulations contributed by each collaborator could be combined to form one large, carefully designed ensemble known as the Community Leveraged Unified Ensemble (CLUE). The 2016 CLUE was composed of 65 members contributed by five research institutions and represents an unprecedented effort to enable an evidence-driven decision process to help guide NOAA’s operational modeling efforts. Eight unique experiments were designed within the CLUE framework to examine issues directly relevant to the design of NOAA’s future operational CAM-based ensembles. This article will highlight the CLUE design and present results from one of the experiments examining the impact of single versus multicore CAM ensemble configurations

THE COMMUNITY LEVERAGED UNIFIED ENSEMBLE (CLUE) IN THE 2016 NOAA/HAZARDOUS WEATHER TESTBED SPRING FORECASTING EXPERIMENT

One primary goal of annual Spring Forecasting Experiments (SFEs), which are coorganized by NOAA’s National Severe Storms Laboratory and Storm Prediction Center and conducted in the National Oceanic and Atmospheric Administration’s (NOAA) Hazardous Weather Testbed, is documenting performance characteristics of experimental, convection-allowing modeling systems (CAMs). Since 2007, the number of CAMs (including CAM ensembles) examined in the SFEs has increased dramatically, peaking at six different CAM ensembles in 2015. Meanwhile, major advances have been made in creating, importing, processing, verifying, and developing tools for analyzing and visualizing these large and complex datasets. However, progress toward identifying optimal CAM ensemble configurations has been inhibited because the different CAM systems have been independently designed, making it difficult to attribute differences in performance characteristics. Thus, for the 2016 SFE, a much more coordinated effort among many collaborators was made by agreeing on a set of model specifications (e.g., model version, grid spacing, domain size, and physics) so that the simulations contributed by each collaborator could be combined to form one large, carefully designed ensemble known as the Community Leveraged Unified Ensemble (CLUE). The 2016 CLUE was composed of 65 members contributed by five research institutions and represents an unprecedented effort to enable an evidence-driven decision process to help guide NOAA’s operational modeling efforts. Eight unique experiments were designed within the CLUE framework to examine issues directly relevant to the design of NOAA’s future operational CAM-based ensembles. This article will highlight the CLUE design and present results from one of the experiments examining the impact of single versus multicore CAM ensemble configurations

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses

Views and experiences of people with intellectual disabilities regarding intimate relationships: a qualitative metasynthesis

The aims of this review were to systematically identify, critically appraise and synthesize the results of existing qualitative literature exploring the views and experiences of intimate relationships amongst people with intellectual disabilities. Fourteen peer-reviewed articles were identified through a systematic search of eight databases, reference lists, citations, and relevant journals. The identified articles were appraised for quality, then synthesized using a metaethnography approach. No study met all quality criteria and references to ethical approval were often lacking. Interpretation of the findings suggested three key themes: the meaning of intimate relationships, external constraints and facilitators, and managing external constraints. Though many people with intellectual disabilities desire and benefit from intimate relationships, they experience restrictions that others do not, which can lead to isolation and loneliness. Intimate relationships are not always necessarily linked with sexual behavior; therefore, intimate relationships warrant their own focus in future research, as well as in education and training for people with intellectual disabilities and their caregivers. Within this, a commitment to transparency over research processes is needed, in particular with reference to how ethical approval was obtained, since this has been a shortcoming of research with this focus to date