mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses

Heritage branding orientation: The case of Ach. Brito and the dynamics between corporate and product heritage brands

The notion of heritage branding orientation is introduced and explicated. Heritage branding orientation is designated as embracing both product and corporate brands and differs from corporate heritage brand orientation which has an explicit corporate focus. Empirical insights are drawn from an in-depth and longitudinal case study of Ach. Brito, a celebrated Portuguese manufacturer of soaps and toiletries. This study shows how, by the pursuance of a strategy derived from a heritage branding orientation Ach. Brito – after a prolonged period of decline – achieved a dramatic strategic turnaround. The findings reveal how institutional heritage can be a strategic resource via its adoption and activation at both the product and corporate levels. Moreover, the study showed how the bi-lateral interplay between product and corporate brand levels can be mutually reinforcing. In instrumental terms, the study shows how heritage can be activated and articulated in different ways. For instance, it can re-position both product and/or corporate brands; it can be meaningfully informed by product brand heritage and shape corporate heritage; and can be of strategic importance to both medium-sized and small enterprises

Lifetime Studies at Metrology Light Source and ANKA

Abstract The Metrology Light Source (MLS), situated in Berlin (Germany) is an electron storage ring operating from 105 MeV to 630 MeV and is serving as the national primary radiation source standard from the near infrared to the extrem ultraviolet spectral region INTRODUCTION To provide users of synchrotron radiation with temporally stable experimental conditions, the lifetime τ of the stored beam with current I is a parameter of concern. This is valid for machines with a decaying beam such as ANKA and MLS, but as well for machines operated in top up mode such as BESSY II in Berlin. In 2012, the standard user operation at MLS yielded a lifetime of 3.5 hours at 150 mA beam current. Although reasonable due to the energy, this is a low value compared to 16 hours at ANKA and it would benefit the users of synchrotron radiation if it could be improved. THEORY There are two major loss mechanisms determining the lifetime of the electrons in an accelerator: The scattering of the electrons with residual gas atoms and the scattering of the electrons with other electrons within the bunch. The latter is known as the "Touschek effect", named after Bruno Touschek who first observed the effect at the small AdA electron-positron collider. The two contributions are called gas lifetime and Touschek lifetime respectively. The gas lifetime depends on the pressure P and a scattering cross section σ gas for particle losses, for which the interested reader is referred to The cross section itself is a function of the acceptance of the accelerator δ acc = Δp max /p 0 , while the pressure P depends in some respect on the beam current. The electrons in a bunch perform transverse betatron oscillations. Being an incoherent motion, this leads to * [email protected] Coulomb scattering. During the scattering process, transverse momentum gets transferred to longitudinal momentum. If the particles momentum deviation exceeds the momentum acceptance it will be lost. The resulting Touschek lifetime depends on the rate of scattering processes and therefore on the density within the bunch, i.e. on the bunch volume and the bunch current. Furthermore, it depends on the momentum acceptance with the power of three with σ x,y,s being the rms-bunch sizes and length and D(ξ) being a slowly varying function with respect to the acceptance δ acc . D also depends on the optical functions around the ring through ξ. The loss rates from Touschek effect and gas scattering add to the total loss rate 1/τ which can be measured. Multiplying the number of particles N (or the stored current I) to the Touschek lifetime τ T results in a constant: N · τ T = const. Therefore, when plotting I · τ for a Touschek dominated lifetime a constant can be expected with respect to current. Acceptance Touschek lifetime and gas lifetime depend on the acceptance of the accelerator. Two acceptances are important here, and whichever is the smallest is the limiting one: • RF-acceptance • Geometrical acceptance. The RF-acceptance δ acc,RF approximately depends on the applied cavity voltage V as [4] The geometrical acceptance depends on the minimal aperture of the vacuum chamber a(s) and the dimensions of the beam. For MLS a first order approximation considering only the horizontal plane is: with D x being the horizontal dispersion function. In the upper plot of Predictions In the lower part of EXPERIMENT In LIFETIME IMPROVEMENT The lifetime at MLS can be improved if the acceptance is only RF-limited even to larger voltages than 300 kV. To do so, the geometrical acceptance has to be improved. In order to find optics with an increased Touschek lifetime, brute force optics scans using a Fortran code were performed In Eq. 4, the horizontal dispersion function D x is in the denominator. By decreasing the dispersion function at the place with minimum aperture, the geometrical acceptance δ acc,geom can be improved. At MLS each quadrupole is powered independently. By tuning some quadrupoles of one family against the remaining ones of that family, the dispersion function was tuned to be zero at the septum. In The peak lifetime with respect to cavity voltage is now located at 500 kV, being the maximum applicable cavity voltage at the moment. In The total lifetime increase is as high as 80 %. By solely increasing the acceptance, and the change in optical functions, the lifetime would have been expected to increase by about 30 %. An explanation for the additional increase could be a strong halo around the beam due to intra-beam scattering. With this, the effect of leading the beam through the centre of the vacuum chamber at the septum could be explained as well. CONCLUSION AND OUTLOOK The theory of the Touschek effect describes the dependencies on energy and acceptance well. By understanding the different loss mechanisms and the methods to manipulate the different acceptances, it was possible to generate a new user optics with an by 80 % improved lifetime. To completely explain the total lifetime increase, further measurements are needed. To further increase the lifetime, alternate optics determined by optics scans will be tested ACKNOWLEDGMENT The authors like to thank Andreas Jankowiak (HZB) and Gerhard Ulm (PTB) for supporting this work. REFERENCES [1] R. Klein et al., Phys. Rev. ST-AB 11, 110701, 2008. [2] A.-S. Müller et al., "Energy Calibration Of The ANKA Storage Ring", Proceedings of EPAC 2004. [3] T. Goetsch, "Lifetime Studies at Metrology Light Source and Angströmquelle Karlsruhe" -Diploma Thesis, Karlsruhe Institut für Technologie, May 2013. [4] M. Sands, "The Physics Of Electron Storage Rings -An Introduction", National Technical Information Service, Springfield, Virginia, 1970. [5] J. le Duff, "Current And Current Density Limitations In Existing Electron Storage Rings", In: Nucl. Instr. and Meth. in Physics Research, 1985

Monitoring increases in fracture connectivity during hydraulic stimulations from temporal variations in shear wave splitting polarization

Hydraulic overpressure can induce fractures and increase permeability in a range of geological settings, including volcanological, glacial and petroleum reservoirs. Here we consider an example of induced hydraulic fracture stimulation in a tight-gas sandstone. Successful exploitation of tight-gas reservoirs requires fracture networks, either naturally occurring, or generated through hydraulic stimulation. The study of seismic anisotropy provides a means to infer properties of fracture networks, such as the dominant orientation of fracture sets and fracture compliances. Shear wave splitting from microseismic data acquired during hydraulic fracture stimulation allows us to not only estimate anisotropy and fracture properties, but also to monitor their evolution through time. Here, we analyse shear wave splitting using microseismic events recorded during a multistage hydraulic fracture stimulation in a tight-gas sandstone reservoir. A substantial rotation in the dominant fast polarization direction (ψ) is observed between the events of stage 1 and those from later stages. Although large changes in ψ have often been linked to stress-induced changes in crack orientation, here we argue that it can better be explained by a smaller fracture rotation coupled with an increase in the ratio of normal to tangential compliance (ZN/ZT) from 0.3 to 0.6. ZN/ZT is sensitive to elements of the internal architecture of the fracture, as well as fracture connectivity and permeability. Thus, monitoring ZN/ZT with shear wave splitting can potentially allow us to remotely detect changes in permeability caused by hydraulic stimulation in a range of geological settings

Different physiology of interferon-α/-γ in models of liver regeneration in the rat

Liver regeneration may take place after liver injury through replication of hepatocytes or hepatic progenitor cells called oval cells. Interferons (IFN) are natural cytokines with pleiotrophic effects including antiviral and antiproliferative actions. No data are yet available on the physiology and cellular source of natural IFNs during liver regeneration. To address this issue, we have analyzed the levels and biologic activities of IFN-α/IFN-γ in two models of partial hepatectomy. After 2/3rd partial hepatectomy (PH), hepatic levels of IFN-α and IFN-γ declined transiently in contrast to a transient increase of the IFN-γ serum level. After administration of 2-acetylaminofluorene and partial hepatectomy (AAF/PH model), however, both IFN-α and IFN-γ expression were up-regulated in regenerating livers. Again, the IFN-γ serum level was transiently increased. Whereas hepatic IFN-γ was up-regulated early (day 1–5), but not significantly, in the AAF/PH model, IFN-α was significantly up-regulated at later time points in parallel to the peak of oval cell proliferation (days 7–9). Biological activity of IFN-α was shown by activation of IFN-α-specific signal transduction and induction of IFN-α specific-gene expression. We found a significant infiltration of the liver with inflammatory monocyte-like mononuclear phagocytes (MNP) concomitant to the frequency of oval cells. We localized IFN-α production only in MNPs, but not in oval cells. These events were not observed in normal liver regeneration after standard PH. We conclude that IFN-γ functions as an acute-phase cytokine in both models of liver regeneration and may constitute a systemic component of liver regeneration. IFN-α was increased only in the AAF/PH model, and was associated with proliferation of oval cells. However, oval cells seem not to be the source of IFN-α. Instead, inflammatory MNP infiltrating AAF/PH-treated livers produce IFN-α. These inflammatory MNPs may be involved in the regulation of the oval cell compartment through local expression of cytokines, including IFN-α

Interleukin-6 Induces Gr-1+CD11b+ Myeloid Cells to Suppress CD8+ T Cell-Mediated Liver Injury in Mice

Agonist antibodies against CD137 (4-1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice.We expressed IL-6 in the liver by hydrodynamic gene delivery in mice treated with 2A or control mAb and studied how IL-6 treatment affected host immunity and T cell-mediated liver injury. We found that ectopic IL-6 expression in the liver elevated intrahepatic leukocyte infiltration but prevented CD8+ T cell-mediated liver injury. In IL-6 treated mice, CD8+ T cells proliferation and IFN-γ expression were inhibited in the liver. We discovered that IL-6 increased accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the liver and spleen. These MDSCs had the ability to inhibit T cells proliferation and activation. Finally, we showed that the MDSCs were sufficient and essential for IL-6-mediated protection of anti-CD137 mAb-induced liver injury.We concluded that IL-6 induced Gr-1+CD11b+ MDSCs in the liver to inhibit T cell-mediated liver injury. The findings have defined a novel mechanism of IL-6 in protecting liver from CD8+ T cell-mediated injury

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 μm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 μm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex

Human cytomegalovirus immediate-early 1 protein rewires upstream STAT3 to downstream STAT1 signaling switching an IL6-type to an IFNγ-like response

MN and CP were supported by the Wellcome Trust (www.wellcome.ac.uk) Institutional Strategic Support Fund and CP was supported by the Deutsche Forschungsgemeinschaft (PA 815/2-1; www.dfg.de).The human cytomegalovirus (hCMV) major immediate-early 1 protein (IE1) is best known for activating transcription to facilitate viral replication. Here we present transcriptome data indicating that IE1 is as significant a repressor as it is an activator of host gene expression. Human cells induced to express IE1 exhibit global repression of IL6- and oncostatin M-responsive STAT3 target genes. This repression is followed by STAT1 phosphorylation and activation of STAT1 target genes normally induced by IFNγ. The observed repression and subsequent activation are both mediated through the same region (amino acids 410 to 445) in the C-terminal domain of IE1, and this region serves as a binding site for STAT3. Depletion of STAT3 phenocopies the STAT1-dependent IFNγ-like response to IE1. In contrast, depletion of the IL6 receptor (IL6ST) or the STAT kinase JAK1 prevents this response. Accordingly, treatment with IL6 leads to prolonged STAT1 instead of STAT3 activation in wild-type IE1 expressing cells, but not in cells expressing a mutant protein (IE1dl410-420) deficient for STAT3 binding. A very similar STAT1-directed response to IL6 is also present in cells infected with a wild-type or revertant hCMV, but not an IE1dl410-420 mutant virus, and this response results in restricted viral replication. We conclude that IE1 is sufficient and necessary to rewire upstream IL6-type to downstream IFNγ-like signaling, two pathways linked to opposing actions, resulting in repressed STAT3- and activated STAT1-responsive genes. These findings relate transcriptional repressor and activator functions of IE1 and suggest unexpected outcomes relevant to viral pathogenesis in response to cytokines or growth factors that signal through the IL6ST-JAK1-STAT3 axis in hCMV-infected cells. Our results also reveal that IE1, a protein considered to be a key activator of the hCMV productive cycle, has an unanticipated role in tempering viral replication.Publisher PDFPeer reviewe