The transcriptional repressor Bcl6 promotes pre-TCR induced differentiation to CD4+CD8+ thymocyte and attenuates Notch1 activation

Pre-TCR signal transduction is required for developing thymocytes to differentiate from CD4-CD8- double negative (DN) to CD4+CD8+ double positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor Bcl6 and that Bcl6 is required for differentiation to DP. Conditional deletion of Bcl6 from thymocytes reduced pre-TCR-induced differentiation to DP cell, disrupted expansion and enrichment of icTCRβ+ cells within the DN population and increased DN4 cell death. It also increased Notch1 activation and Notch-mediated transcription in the DP population. Thus, Bcl6 is required in thymocyte development for efficient differentiation from DN3 to DP cell and to attenuate Notch1 activation in DP cells. Given the importance of inappropriate NOTCH1 signalling in T-ALL, and the involvement of Bcl6 in other types of leukaemia, this study is important to our understanding of T-ALL

Neural correlates of anosognosia in Alzheimer\u2019s disease and mild cognitive impairment: A multi-method assessment

Patients with Alzheimer\u2019s Disease (AD) and Mild Cognitive Impairment (MCI) may present anosognosia for their cognitive deficits. Three different methods have been usually used to measure anosognosia in patients with AD and MCI, but no studies have established if they share similar neuroanatomical correlates. The purpose of this study was to investigate if anosognosia scores obtained with the three most commonly used methods to assess anosognosia relate to focal atrophy in AD and MCI patients, in order to improve understanding of the neural basis of anosognosia in dementia. Anosognosia was evaluated in 27 patients (15 MCI and 12 AD) through clinical rating (Clinical Insight Rating Scale, CIRS), patient-informant discrepancy (Anosognosia Questionnaire Dementia, AQ-D), and performance discrepancy on different cognitive domains (self-appraisal discrepancies, SADs). Voxel-based morphometry correlational analyses were performed on magnetic resonance imaging (MRI) data with each anosognosia score. Increasing anosognosia on any anosognosia measurement (CIRS, AQ-D, SADs) was associated with increasing gray matter atrophy in the medial temporal lobe including the right hippocampus. Our results support a unitary mechanism of anosognosia in AD and MCI, in which medial temporal lobes play a key role, irrespectively of the assessment method used. This is in accordance with models suggesting that anosognosia in AD is primarily caused by a decline in mnemonic processes

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

PARP14 promotes the warburg effect in hepatocellular carcinoma by inhibiting JNK1-dependent PKM2 phosphorylation and activation

Most tumour cells use aerobic glycolysis (the Warburg effect) to support anabolic growth and evade apoptosis. Intriguingly, the molecular mechanisms that link the Warburg effect with the suppression of apoptosis are not well understood. In this study, using loss-of-function studies in vitro and in vivo, we show that the anti-apoptotic protein poly(ADP-ribose) polymerase (PARP)14 promotes aerobic glycolysis in human hepatocellular carcinoma (HCC) by maintaining low activity of the pyruvate kinase M2 isoform (PKM2), a key regulator of the Warburg effect. Notably, PARP14 is highly expressed in HCC primary tumours and associated with poor patient prognosis. Mechanistically, PARP14 inhibits the pro-apoptotic kinase JNK1, which results in the activation of PKM2 through phosphorylation of Thr365. Moreover, targeting PARP14 enhances the sensitization of HCC cells to anti-HCC agents. Our findings indicate that the PARP14-JNK1-PKM2 regulatory axis is an important determinant for the Warburg effect in tumour cells and provide a mechanistic link between apoptosis and metabolism

Gamma irradiation resistance of early age Ba(OH)₂-Na₂SO₄-slag cementitious grouts

The gamma irradiation resistance of early age Ba(OH)₂-Na₂SO₄-slag cementitious grouts, formulated for the immobilisation of sulfate bearing nuclear waste, was assessed. The observable crystalline phases were not modified upon heating (50 °C) or upon gamma irradiation up to a total dose of 2.9 MGy over 256 h, but the compressive strengths of the irradiated samples increased significantly. ²⁷Al and ²⁹Si MAS NMR spectroscopy showed that the main binding phase, a calcium aluminosilicate hydrate (C-A-S-H) type gel, had a more ordered and polymerised structure upon heating and irradiation compared to that identified in reference samples. This is associated with a higher degree of reaction of the slag. Samples formulated with the waste simulant Na₂SO₄, but without Ba(OH)₂, became porous and cracked upon heating and irradiation, but still retained their compressive strength. The Ba(OH)₂-Na₂SO₄-slag grouts evaluated in this work withstand gamma irradiation without showing identifiable damage, and are thus a technically feasible solution for immobilisation of sulfate-bearing nuclear wastes

The ERK and JNK pathways in the regulation of metabolic reprogramming.

Most tumor cells reprogram their glucose metabolism as a result of mutations in oncogenes and tumor suppressors, leading to the constitutive activation of signaling pathways involved in cell growth. This metabolic reprogramming, known as aerobic glycolysis or the Warburg effect, allows tumor cells to sustain their fast proliferation and evade apoptosis. Interfering with oncogenic signaling pathways that regulate the Warburg effect in cancer cells has therefore become an attractive anticancer strategy. However, evidence for the occurrence of the Warburg effect in physiological processes has also been documented. As such, close consideration of which signaling pathways are beneficial targets and the effect of their inhibition on physiological processes are essential. The MAPK/ERK and MAPK/JNK pathways, crucial for normal cellular responses to extracellular stimuli, have recently emerged as key regulators of the Warburg effect during tumorigenesis and normal cellular functions. In this review, we summarize our current understanding of the roles of the ERK and JNK pathways in controlling the Warburg effect in cancer and discuss their implication in controlling this metabolic reprogramming in physiological processes and opportunities for targeting their downstream effectors for therapeutic purposes.Brunel Research Initiative & Enterprise Fund, Brunel University of London (to CB), Kay Kendall Leukemia Fund (KKL443) (to CB), 250 Great Minds Fellowship, University of Leeds (to SP), AMMF Cholangiocarcinoma Charity (to SP and PMC), and Bloodwise (17014) (to SP and CB)

Method for determining statistical mean and variance of electromagnetic energy transmission between coupled cavities

In this paper a statistical approach is employed to solve high frequency electromagnetism problems of coupled cavities at a reduced computational cost. The case of interest is a system of two reverberant cavities that have random or uncertain properties coupled by an aperture. If a conventional numerical approach is employed for this problem then very significant computational effort is required since Maxwell's equations need to be solved for both the cavity and the system. The key aspect of the proposed approach is to avoid solving Maxwell's equations inside the cavity by employing a relation known as the diffuse field reciprocity principle, which leads directly to the ensemble mean response of the system and its variance; all that is required is the impedance matrix of the coupling element associated with radiation into infinite space. Theoretical developments leading to the mean and variance are presented. This technique is then applied to a numerical example

A coupled acoustic/elastic discontinuous Galerkin finite element method: Application to ultrasonic imaging of 3D-printed synthetic materials

International audienceWe present the derivation of upwind numerical fluxes for the space discontinuous Galerkin (dG) finite element method applied to the numerical modeling of wave propagation in multidimensional coupled acoustic/elastic media. The space dG method is formulated using the first-order velocity-pressure and velocity-stress systems for acoustic and elastic media, respectively. After eigenanalysis of the first-order hyperbolic systems highlighting the eigenmodes of wave propagation, the upwind numerical fluxes on the acoustic/acoustic and acoustic/elastic interface are obtained in terms of exact solutions of relevant Riemann problems. Thanks to the proposed approach, explicit closed-form expressions of the upwind numerical fluxes are obtained on the acoustic/elastic interface for the general case of multidimensional anisotropic heterogeneous solid media coupled with acoustic fluids. The developed numerical fluxes are validated by analytical/numerical comparison considering the example of an acoustic domain with a circular elastic inclusion. Finally, the coupled solver is used to perform a multiparametric study on the microstructure’s echogenicity in a 3D-printed synthetic material under ultrasonic imaging

A hybrid approach to calculate mean response and variance in a reverberant environment

In this paper a statistical approach is employed to solve high frequency EMC problems at a reduced computational cost. The case of interest is a system lying within a reverberant cavity that has random or uncertain properties. If a conventional numerical approach is employed for this problem then very significant computational effort is required since Maxwell's equations need to be solved for both the cavity and the system. The key aspect of the proposed approach is to avoid solving Maxwell's equations inside the cavity by employing a relation known as the diffuse field reciprocity principle, which leads directly to the ensemble mean response of the system and its variance; all that is required is the impedance matrix of the system associated with radiation into infinite space. Theoretical developments leading to the mean and variance are presented. Thistechnique is then applied to a numerical example