63 research outputs found
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Network Positions and the Probability of Being Acquired: An Empirical Analysis in the Biopharmaceutical Industry
This paper examines the relationship between the firm's direct ties, its inter-firm network prominence and its likelihood of being acquired. The authors argue that firm's direct ties and prominence enhance the firm's visibility and signal its quality – and thus foster the firm's likelihood of being acquired. However, higher levels of direct ties and prominence, by providing access to resources and the firm's status, respectively, increase the firm's ability to remain independent and thus reduce its likelihood of being acquired. Thus, the authors posit the overall relation as an inverted U-shaped. Furthermore, they show that, for firms that undergo an initial public offering, the aforementioned relation becomes much weaker. The hypotheses are empirically tested in the biopharmaceutical industry and important theoretical and managerial implications are discussed
DNA Nicks Promote Efficient and Safe Targeted Gene Correction
Targeted gene correction employs a site-specific DNA lesion to promote homologous recombination that eliminates mutation in a disease gene of interest. The double-strand break typically used to initiate correction can also result in genomic instability if deleterious repair occurs rather than gene correction, possibly compromising the safety of targeted gene correction. Here we show that single-strand breaks (nicks) and double-strand breaks both promote efficient gene correction. However, breaks promote high levels of inadvertent but heritable genomic alterations both locally and elsewhere in the genome, while nicks are accompanied by essentially no collateral local mutagenesis, and thus provide a safer approach to gene correction. Defining efficacy as the ratio of gene correction to local deletion, nicks initiate gene correction with 70-fold greater efficacy than do double-strand breaks (29.0±6.0% and 0.42±0.03%, respectively). Thus nicks initiate efficient gene correction, with limited local mutagenesis. These results have clear therapeutic implications, and should inform future design of meganucleases for targeted gene correction
Pegylated IFN-α sensitizes melanoma cells to chemotherapy and causes premature senescence in endothelial cells by IRF-1-mediated signaling
Pegylated interferon-α2b (pIFN-α) is an integral part of the drug regimen currently employed against melanoma. Interferon regulatory factor-1 (IRF-1) has an important role in the transcriptional regulation of the IFN response, cell cycle and apoptosis. We have studied pIFN-α-induced responses when combined with the chemotherapy agent, vinblastine (VBL), in tumor and endothelial cell lines and the connection to IRF-1 signaling. Levels of IRF-1/IRF-2 protein expression were found to be decreased in tumor versus normal tissues. pIFN-α induced IRF-1 signaling in human melanoma (M14) and endothelial (EA.hy926) cells and enhanced cell death when combined with VBL. Upon combined IFN-α and VBL treatment, p21 expression, poly (ADP-ribose) polymerase cleavage and activated Bak levels were increased in M14 cells. An increase in p21 and cyclin D1 expression occurred in EA.hy926 cells after 6 h of treatment with pIFN-α, which dissipated by 24 h. This biphasic response, characteristic of cellular senescence, was more pronounced upon combined treatment. Exposure of the EA.hy926 cells to pIFN-α was associated with an enlarged, multinucleated, β-galactosidase-positive senescent phenotype. The overall therapeutic mechanism of IFN-α combined with chemotherapy may be due to both direct tumor cell death via IRF-1 signaling and by premature senescence of endothelial cells and subsequent effects on angiogenesis in the tumor microenvironment
The eEF1γ Subunit Contacts RNA Polymerase II and Binds Vimentin Promoter Region
Here, we show that the eukaryotic translation elongation factor 1 gamma (eEF1γ) physically interacts with the RNA polymerase II (pol II) core subunit 3 (RPB3), both in isolation and in the context of the holo-enzyme. Importantly, eEF1γ has been recently shown to bind Vimentin mRNA. By chromatin immunoprecipitation experiments, we demonstrate, for the first time, that eEF1γ is also physically present on the genomic locus corresponding to the promoter region of human Vimentin gene. The eEF1γ depletion causes the Vimentin protein to be incorrectly compartmentalised and to severely compromise cellular shape and mitochondria localisation. We demonstrate that eEF1γ partially colocalises with the mitochondrial marker Tom20 and that eEF1γ depletion increases mitochondrial superoxide generation as well as the total levels of carbonylated proteins. Finally, we hypothesise that eEF1γ, in addition to its role in translation elongation complex, is involved in regulating Vimentin gene by contacting both pol II and the Vimentin promoter region and then shuttling/nursing the Vimentin mRNA from its gene locus to its appropriate cellular compartment for translation
Complexity Theory for a New Managerial Paradigm: A Research Framework
In this work, we supply a theoretical framework of how organizations
can embed complexity management and sustainable development into their policies
and actions. The proposed framework may lead to a new management paradigm,
attempting to link the main concepts of complexity theory, change management,
knowledge management, sustainable development, and cybernetics. We highlight
how the processes of organizational change have occurred as a result of the move to
adapt to the changes in the various global and international business environments
and how this transformation has led to the shift toward the present innovation
economy. We also point how organizational change needs to deal with sustainability,
so that the change may be consistent with present needs, without compromising
the future
RNA interference approaches for treatment of HIV-1 infection
HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery
Application of mito-priming to generate BCL-2 addicted cells
The majority of apoptotic stimuli trigger cell death through the mitochondrial pathway of apoptosis. Invariably, mitochondrial apoptosis requires engagement of mitochondrial outer membrane permeabilization or MOMP to initiate cell death. We have developed a new method, called mito-priming, that allows for rapid and synchronous induction of mitochondrial apoptosis in an on-target manner. Mito-priming uses coexpression of pro- and antiapoptotic Bcl-2 proteins to render cells sensitive to the addition of Bcl-2 targeting BH3-mimetic drugs. This chapter describes how to design mito-priming constructs and apply them to generate mito-primed lines. Second, we describe how to validate cell death sensitivity of mito-primed lines using different methods. Finally, we describe how to generate MOMP-resistant cell lines, using CRISPR-Cas9 mediated deletion of BAX and BAK. Facilitating the investigation of mitochondrial apoptosis, mito-priming provides a clean, robust way to induce mitochondrial apoptosis both in vitro and in vivo
Are Top Executives Rewarded for Environmental Performance? The Role of the Board of Directors in the Context of China
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