Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival

Mice with a T cell–specific deletion of Prdm1, encoding Blimp-1, have aberrant T cell homeostasis and develop fatal colitis. In this study, we show that one critical activity of Blimp-1 in T cells is to repress IL-2, and that it does so by direct repression of Il2 transcription, and also by repression of Fos transcription. Using these mechanisms Blimp-1 participates in an autoregulatory loop by which IL-2 induces Prdm1 expression and thus represses its own expression after T cell activation, ensuring that the immune response is appropriately controlled. This activity of Blimp-1 is important for cytokine deprivation–induced T cell death and for attenuating T cell proliferation in antigen-specific responses both in vitro and in vivo

Index tracking and beta arbitrage effects in comovement

This paper develops a stylised model for S&P 500 index changes with two beta-based styles: index trackers and beta arbitrageurs who trade in both high and low beta event stocks to exploit mean reversion towards one. Arbitrageurs engage in common or contrarian trading patterns relative to index funds depending on whether historical betas are below or above one. Thus, the overall comovement effect has two distinct components. After index additions, pre-event low beta stocks drive the overall beta increases due to common demand – albeit for different reasons - from indexers and arbitrageurs. By contrast, arbitrageur shorting of high beta additions diminishes or sometimes reverses the beta increases for these stocks driven by indexers. Analogous results hold for index deletions

Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow

Long-lived plasma cells, residing primarily in the bone marrow, continuously secrete antibody and provide an important component of humoral memory. However, when such cells secrete autoantibodies or become transformed, they can be pathogenic. We have shown recently that the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp-1) is required for the formation of plasma cells. To determine what role Blimp-1 might play in maintenance of plasma cells, we generated mice in which the gene encoding Blimp-1 could be deleted in an inducible manner. Deletion of Blimp-1 either in vitro or in vivo leads to loss of previously formed B220LOCD138HI plasma cells. Using BrdU incorporation, we confirmed that Blimp-1 is required for the maintenance of nondividing, long-lived plasma cells in the bone marrow. Blimp-1 is also required for long-term maintenance of antigen-specific immunoglobulin in serum. Thus Blimp-1 is required not only for the formation but also for the maintenance of long-lived plasma cells. This finding provides the possibility of new drug design strategies for autoimmunity and multiple myeloma focused on blocking Blimp-1 expression or activity

Routing-aware multiple description video coding over mobile ad-hoc networks

Abstract-Supporting video transmission over error-prone mobile ad-hoc networks is becoming increasingly important as these networks become more widely deployed. We propose a routingaware multiple description video coding approach to support video transmission over mobile ad-hoc networks with multiple path transport. We build a statistical model to estimate the packet loss probability of each packet transmitted over the network based on the standard ad-hoc routing messages and network parameters. We then estimate the frame loss probability and dynamically select reference frames in order to alleviate error propagation caused by the packet losses. We conduct experiments using the QualNet simulator that accounts for node mobility, channel properties, MAC operation, multipath routing, and traffic type. The results demonstrate that our proposed method provides 0.7-2.3 dB gains in PSNR for different video sequences under different network settings and guarantees better video quality for a selectably high number of users of the network. Furthermore, we examine the estimation accuracy of our proposed estimation model and show that our model works effectively under various network settings

Immune-mediated lung diseases: A narrative review

The role of immunity in the pathogenesis of various pulmonary diseases, particularly interstitial lung diseases (ILDs), is being increasingly appreciated as mechanistic discoveries advance our knowledge in the field. Immune-mediated lung diseases demonstrate clinical and immunological heterogeneity and can be etiologically categorized into connective tissue disease (CTD)-associated, exposure-related, idiopathic, and other miscellaneous lung diseases including sarcoidosis, and post-lung transplant ILD. The immunopathogenesis of many of these diseases remains poorly defined and possibly involves either immune dysregulation, abnormal healing, chronic inflammation, or a combination of these, often in a background of genetic susceptibility. The heterogeneity and complex immunopathogenesis of ILDs complicate management, and thus a collaborative treatment team should work toward an individualized approach to address the unique needs of each patient. Current management of immune-mediated lung diseases is challenging; the choice of therapy is etiology-driven and includes corticosteroids, immunomodulatory drugs such as methotrexate, cyclophosphamide and mycophenolate mofetil, rituximab, or other measures such as discontinuation or avoidance of the inciting agent in exposure-related ILDs. Antifibrotic therapy is approved for some of the ILDs (e.g., idiopathic pulmonary fibrosis) and is being investigated for many others and has shown promising preliminary results. A dire need for advances in the management of immune-mediated lung disease persists in the absence of standardized management guidelines

Abacavir, efavirenz, didanosine, with or without hydroxyurea, in HIV-infected adults failing initial nucleoside/protease inhibitor-containing regimens

BACKGROUND: Hydroxyurea (HU) is an immunomodulatory agent that has been documented to enhance the antiretroviral activity of nucleoside reverse transcriptase inhibitors, such as abacavir (ABC) and didanosine (ddI), and would be expected to improve virologic efficacy. METHODS: A 48-week, phase IV, multicenter, open-label, proof-of-concept clinical trial was conducted to evaluate second-line, protease inhibitor (PI)-sparing therapy with ABC/efavirenz (EFV)/ddI plus HU or without HU in HIV-infected subjects failing to achieve HIV-1 RNA ≤ 400 copies/mL after ≥ 16 weeks of treatment with lamivudine/zidovudine or lamivudine/stavudine, plus 1 or 2 PIs. Subjects were assigned to ABC (300 mg twice daily)/ EFV (600 mg once daily)/ ddI (400 mg once daily) plus HU (500 mg twice daily) (n = 30) or this regimen without HU (n = 24). RESULTS: Baseline mean HIV-1 RNA was 3.86 log(10 )copies/mL and CD4+ cell count was 345 cells/mm(3). A similar percentage of subjects in the non-HU arm (58%) and HU arm (53%) completed the study. Intent-to-treat: missing = failure analysis showed no differences in proportions of subjects in the non-HU and HU arms achieving undetectable plasma HIV-1 RNA levels at week 24 (<400 copies/mL: 58% [14/24] vs 57% [17/30], P = 0.899; <50 copies/mL (50% [12/24] vs 47% [14/30], P = 0.780). Median change from baseline in CD4+ cell count in the non-HU and HU arms at week 48 was +114 cells/mm(3 )and -63 cells/mm(3 )(P = 0.007), respectively. Both regimens were generally well tolerated, although more subjects in the HU arm withdrew prematurely from the study due to adverse events (23% vs 4%). Four cases of possible ABC-related hypersensitivity were observed. CONCLUSION: ABC/EFV/ddI was an effective and well-tolerated second-line regimen for nucleoside/PI-experienced HIV-infected subjects. The addition of HU blunted the CD4+ cell response, did not appear to enhance antiviral activity, and resulted in more treatment-limiting adverse events

Altering Chemosensitivity by Modulating Translation Elongation

BACKGROUND: The process of translation occurs at a nexus point downstream of a number of signal pathways and developmental processes. Modeling activation of the PTEN/AKT/mTOR pathway in the Emu-Myc mouse is a valuable tool to study tumor genotype/chemosensitivity relationships in vivo. In this model, blocking translation initiation with silvestrol, an inhibitor of the ribosome recruitment step has been showed to modulate the sensitivity of the tumors to the effect of standard chemotherapy. However, inhibitors of translation elongation have been tested as potential anti-cancer therapeutic agents in vitro, but have not been extensively tested in genetically well-defined mouse tumor models or for potential synergy with standard of care agents. METHODOLOGY/PRINCIPAL FINDINGS: Here, we chose four structurally different chemical inhibitors of translation elongation: homoharringtonine, bruceantin, didemnin B and cycloheximide, and tested their ability to alter the chemoresistance of Emu-myc lymphomas harbouring lesions in Pten, Tsc2, Bcl-2, or eIF4E. We show that in some genetic settings, translation elongation inhibitors are able to synergize with doxorubicin by reinstating an apoptotic program in tumor cells. We attribute this effect to a reduction in levels of pro-oncogenic or pro-survival proteins having short half-lives, like Mcl-1, cyclin D1 or c-Myc. Using lymphomas cells grown ex vivo we reproduced the synergy observed in mice between chemotherapy and elongation inhibition and show that this is reversed by blocking protein degradation with a proteasome inhibitor. CONCLUSION/SIGNIFICANCE: Our results indicate that depleting short-lived pro-survival factors by inhibiting their synthesis could achieve a therapeutic response in tumors harboring PTEN/AKT/mTOR pathway mutations

Corporate Governance for Sustainability

The current model of corporate governance needs reform. There is mounting evidence that the practices of shareholder primacy drive company directors and executives to adopt the same short time horizon as financial markets. Pressure to meet the demands of the financial markets drives stock buybacks, excessive dividends and a failure to invest in productive capabilities. The result is a ‘tragedy of the horizon’, with corporations and their shareholders failing to consider environmental, social or even their own, long-term, economic sustainability. With less than a decade left to address the threat of climate change, and with consensus emerging that businesses need to be held accountable for their contribution, it is time to act and reform corporate governance in the EU. The statement puts forward specific recommendations to clarify the obligations of company boards and directors and make corporate governance practice significantly more sustainable and focused on the long term