The Role of MAPKs in B Cell Receptor-Induced Down-Regulation of Egr-1 in Immature B Lymphoma Cells

Cross-linking of the B cell receptor (BCR) on the immature B lymphoma cell line BKS-2 induces growth inhibition and apoptosis accompanied by rapid down-regulation of the immediate-early gene egr-1. In these lymphoma cells, egr-1 is expressed constitutively and has a prosurvival role, as Egr-1-specific antisense oligonucleotides or expression of a dominant-negative inhibitor of Egr-1 also prevented the growth of BKS-2 cells. Moreover, enhancement of Egr-1 protein with phorbol 12-myristate 13-acetate or an egr-1 expression vector rescued BKS-2 cells from BCR signal-induced growth inhibition. Nuclear run-on and mRNA stability assays indicated that BCR-derived signals act at the transcriptional level to reduce egr-1 expression. Inhibitors of ERK and JNK (but not of p38 MAPK) reduced egr-1 expression at the protein level. Transcriptional regulation appears to have a role because egr-1 promoter-driven luciferase expression was reduced by ERK and JNK inhibitors. Promoter truncation experiments suggested that several serum response elements are required for MAPK-mediated egr-1 expression. Our study suggests that BCR signals reduce egr-1 expression by inhibiting activation of ERK and JNK. Unlike ERK and JNK, p38 MAPK reduces constitutive expression of egr-1. Unlike the immature B lymphoma cells, normal immature B cells did not exhibit constitutive MAPK activation. BCR-induced MAPK activation was modest and transient with a small increase in egr-1 expression in normal immature B cells consistent with their inability to proliferate in response to BCR cross-linking

Observations of neutral carbon in 29 high-z lensed dusty star forming galaxies and the comparison of gas mass tracers

The nature and evolution of high-redshift dusty star-forming galaxies (high-z DSFGs) remain an open question. Their massive gas reservoirs play an important role in driving the intense star-formation rates hosted in these galaxies. We aim to estimate the molecular gas content of high-z DSFGs by using various gas mass tracers such as the [CI], CO, [CII] emission lines and the dust content. These tracers need to be well calibrated as they are all limited by uncertainties on factors such as aCO, XCI, aCII and GDR, thereby affecting the determination of the gas mass accurately. The main goal of our work is to check the consistency between the gas mass tracers and cross-calibrate the uncertain factors. We observe the two [CI] line transitions for 29 SPT-SMGs with the ALMA-ACA. Additionally, we also present new APEX observations of [CII] line for 9 of these galaxies. We find a nearly linear relation between the infrared luminosity and [CI] luminosity if we fit the starbursts and main-sequence galaxies separately. We measure a median [CI]-derived excitation temperature of 34.5+/-2.1 K. We probe the properties of the interstellar medium (ISM) such as density and radiation field intensity using [CI] to mid- or high-J CO lines and [CI] to infrared luminosity ratio, and find similar values to the SMG populations in literature. Finally, the gas masses estimated from [CI], CO, dust, and [CII] do not exhibit any significant trend with the infrared luminosity or the dust temperature. We provide the various cross-calibrations between these tracers. Our study confirms that [CI] is a suitable tracer of the molecular gas content, and shows an overall agreement between all the classical gas tracers used at high redshift. However, their absolute calibration and thus the gas depletion timescale measurements remain uncertain.Comment: Accepted for publication in A&A, 25 pages, 11 figures, 6 table

Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma

Copyright @ 2013 Macmillan Publishers Limited. This is the author's accepted manuscript. The final published article is available from the link below.Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.Kay Kendall Leukemia Fund, NIH, Cancer Research UK, Italian Association for Cancer Research and the Foundation for Liver Research

The ALMA-ALPINE [CII] survey: Kennicutt-Schmidt relation in four massive main-sequence galaxies at <i>z</i> ∼ 4.5

Aims. The Kennicutt-Schmidt (KS) relation between the gas and the star formation rate (SFR) surface density (Σ$_{gas}$ − Σ$_{SFR}$) is essential to understand star formation processes in galaxies. To date, it has been measured up to z ∼ 2.5 in main-sequence galaxies. In this Letter our aim is to put constraints at z ∼ 4.5 using a sample of four massive main-sequence galaxies observed by ALMA at high resolution. Methods. We obtained ∼0.3″-resolution [CII] and continuum maps of our objects, which we then converted into gas and obscured SFR surface density maps. In addition, we produced unobscured SFR surface density maps by convolving Hubble ancillary data in the rest-frame UV. We then derived the average Σ$_{SFR}$ in various Σ$_{gas}$ bins, and estimated the uncertainties using a Monte Carlo sampling. Results. Our galaxy sample follows the KS relation measured in main-sequence galaxies at lower redshift, and is slightly lower than the predictions from simulations. Our data points probe the high end both in terms of Σ$_{gas}$ and Σ$_{SFR}$, and gas depletion timescales (285–843 Myr) remain similar to z ∼ 2 objects. However, three of our objects are clearly morphologically disturbed, and we could have expected shorter gas depletion timescales (≲100 Myr) similar to merger-driven starbursts at lower redshifts. This suggests that the mechanisms triggering starbursts at high redshift may be different than in the low- and intermediate-z Universe

Interleukin-10 Mediated Autoregulation of Murine B-1 B-Cells and Its Role in Borrelia hermsii Infection

B cells are typically characterized as positive regulators of the immune response, primarily by producing antibodies. However, recent studies indicate that various subsets of B cells can perform regulatory functions mainly through IL-10 secretion. Here we discovered that peritoneal B-1 (B-1P) cells produce high levels of IL-10 upon stimulation with several Toll-like receptor (TLR) ligands. High levels of IL-10 suppressed B-1P cell proliferation and differentiation response to all TLR ligands studied in an autocrine manner in vitro and in vivo. IL-10 that accumulated in cultures inhibited B-1P cells at second and subsequent cell divisions mainly at the G1/S interphase. IL-10 inhibits TLR induced B-1P cell activation by blocking the classical NF-κB pathway. Co-stimulation with CD40 or BAFF abrogated the IL-10 inhibitory effect on B-1P cells during TLR stimulation. Finally, B-1P cells adoptively transferred from the peritoneal cavity of IL-10−/− mice showed better clearance of Borrelia hermsii than wild-type B-1P cells. This study described a novel autoregulatory property of B-1P cells mediated by B-1P cell derived IL-10, which may affect the function of B-1P cells in infection and autoimmunity

The ALMA-ALPINE [CII] survey: Kennicutt-Schmidt relation in four massive main-sequence galaxies at z~4.5

The Kennicutt-Schmidt (KS) relation between the gas and the star formation rate (SFR) surface density ($\Sigma_{\rm gas}$-$\Sigma_{\rm SFR}$) is essential to understand star formation processes in galaxies. So far, it has been measured up to z~2.5 in main-sequence galaxies. In this letter, we aim to put constraints at z~4.5 using a sample of four massive main-sequence galaxies observed by ALMA at high resolution. We obtained ~0.3"-resolution [CII] and continuum maps of our objects, which we then converted into gas and obscured SFR surface density maps. In addition, we produced unobscured SFR surface density maps by convolving Hubble ancillary data in the rest-frame UV. We then derived the average $\Sigma_{\rm SFR}$ in various $\Sigma_{\rm gas}$ bins, and estimated the uncertainties using a Monte Carlo sampling. Our galaxy sample follows the KS relation measured in main-sequence galaxies at lower redshift and is slightly lower than predictions from simulations. Our data points probe the high end both in terms of $\Sigma_{\rm gas}$ and $\Sigma_{\rm gas}$, and gas depletion timescales (285-843 Myr) remain similar to z~2 objects. However, three of our objects are clearly morphologically disturbed, and we could have expected shorter gas depletion timescales (~100 Myr) similar to merger-driven starbursts at lower redshifts. This suggests that the mechanisms triggering starbursts at high redshift may be different than in the low- and intermediate-z Universe.Comment: 9 pages, 7 figures, 2 tables, accepted by A&A (letter

Resilience to chronic stress is associated with specific neurobiological, neuroendocrine and immune responses

Research into the molecular basis of stress resilience is a novel strategy to identify potential therapeutic strategies to treat stress-induced psychopathologies such as anxiety and depression. Stress resilience is a phenomenon which is not solely driven by effects within the central nervous system (CNS) but involves multiple systems, central and peripheral, which interact with and influence each other. Accordingly, we used the chronic social defeat stress paradigm and investigated specific CNS, endocrine and immune responses to identify signatures of stress-resilience and stress susceptibility in mice. Our results showed that mice behaviourally susceptible to stress (indexed by a reduction in social interaction behaviour) had higher plasma corticosterone levels and adrenal hypertrophy. An increase in inflammatory circulating monocytes was another hallmark of stress susceptibility. Furthermore, prefrontal cortex mRNA expression of corticotrophin-releasing factor (Crf) was increased in susceptible mice relative to resilient mice. We also report differences in hippocampal synaptic plasticity between resilient and susceptible mice. Ongoing studies will interpret the functional relevance of these signatures which could potentially inform the development of novel psychotherapeutic strategies

Requirement of cellular DDX3 for hepatitis C virus replication is unrelated to its interaction with the viral core protein

The cellular DEAD-box protein DDX3 was recently shown to be essential for hepatitis C virus (HCV) replication. Prior to that, we had reported that HCV core binds to DDX3 in yeast-two hybrid and transient transfection assays. Here, we confirm by co-immunoprecipitation that this interaction occurs in cells replicating the JFH1 virus. Consistent with this result, immunofluorescence staining of infected cells revealed a dramatic redistribution of cytoplasmic DDX3 by core protein to the virus assembly sites around lipid droplets. Given this close association of DDX3 with core and lipid droplets, and its involvement in virus replication, we investigated the importance of this host factor in the virus life cycle. Mutagenesis studies located a single amino acid in the N-terminal domain of JFH1 core that when changed to alanine significantly abrogated this interaction. Surprisingly, this mutation did not alter infectious virus production and RNA replication, indicating that the core–DDX3 interaction is dispensable in the HCV life cycle. Consistent with previous studies, siRNA-led knockdown of DDX3 lowered virus production and RNA replication levels of both WT JFH1 and the mutant virus unable to bind DDX3. Thus, our study shows for the first time that the requirement of DDX3 for HCV replication is unrelated to its interaction with the viral core protein

Volatility as a concept to understand the impact of stress on the microbiome

The microbiome-gut-brain-axis is a complex phenomenon spanning several dynamic systems in the body which can be parsed at a molecular, cellular, physiological and ecological level. A growing body of evidence indicates that this axis is particularly sensitive to the effects of stress and that it may be relevant to stress resilience and susceptibility. Although stress-induced changes in the composition of the microbiome have been reported, the degree of compositional change over time, which we define as volatility, has not been the subject of in-depth scrutiny. Using a chronic psychosocial stress paradigm in male mice, we report that the volatility of the microbiome significantly correlated with several readouts of the stress response, including behaviour and corticosterone response. We then validated these findings in a second independent group of stressed mice. Additionally, we assessed the relationship between volatility and stress parameters in a cohort of health volunteers who were undergoing academic exams and report similar observations. Finally, we found inter-species similarities in the microbiome stress response on a functional level. Our research highlights the effects of stress on the dynamic microbiome and underscores the informative value of volatility as a parameter that should be considered in all future analyses of the microbiome