A large body of evidence from viral systems has established that transcription factors play an important and direct role in activating viral DNA replication. Among the transcriptional activation domains that can stimulate viral DNA replication are acidic domains such as those derived from herpes simplex virus VP16 and the tumor suppressor p53. Here we show that acidic activation domains can also activate a cellular origin of replication in a chromosomal context. When tethered to the yeast ARS1 (autonomously replicating sequence 1) origin of replication, both VP16 and p53 activation domains can enhance origin function. In addition, the C-terminal acidic region of the yeast transcription factor ABF1, which normally activates the ARS1 origin, is sufficient for activating ARS1 function when tethered to the origin. Mutations at residues Trp-53 and Phe-54 of a 20-residue (41 to 60) activation region of p53 abolish the activation of both replication and transcription, suggesting that the same structural determinants may be employed to activate both processes in yeast. Furthermore, using a two-dimensional gel electrophoresis method, we demonstrate that the GAL4-p53 chimeric activator can activate initiation of chromosomal replication from an origin inserted at the native ARS1 locus. These findings strongly suggest functional conservation of the mechanisms used by the acidic activation domains to activate viral DNA replication in mammalian cells and chromosomal replication in yeast.The eukaryotic origins of DNA replication characterized to date contain two functional elements: a core sequence that determines the site of initiation and a nearby auxiliary element that stimulates initiation efficiency (11,16,36,55). Analogous to the TATA box of a transcription promoter, the core sequence of an origin of replication serves as the binding site for an initiator protein which in turn nucleates the assembly of a large initiation protein complex. The auxiliary elements of an origin usually contain binding sites for proteins that in other DNA contexts function as transcription factors. It has been well established that transcription factors play an important and direct role in viral DNA replication (15,30,64).Most of our current understanding of transcription factors' role in replication comes from studies of DNA tumor viruses (17,33,52,63,68). For example, the flanking auxiliary sequences of the simian virus 40 and polyomavirus origins are located adjacent to the core region that forms the binding site for the large T antigen, the viral initiator protein. The auxiliary sequences contain binding sites for several cellular transcription factors such as Sp1, AP1 and p53 for simian virus 40 and AP1 and PEA3 for polyomavirus. These cis elements act synergistically to increase the initiation frequency up to 1,000-fold (17,25,26). Heterologous transcription factors can also activate viral replication when tethered to the origins of replication. For example, factors such as NF-B, VP16, E1A, bovine polyomavirus E2, and GAL4 can stimulate ...

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Spatial resolution is a critical imaging parameter in magnetic resonance imaging (MRI). The image super-resolution (SR) is an effective and cost efficient alternative technique to improve the spatial resolution of MR images. Over the past several years, the convolutional neural networks (CNN)-based SR methods have achieved state-of-the-art performance. However, CNNs with very deep network structures usually suffer from the problems of degradation and diminishing feature reuse, which add difficulty to network training and degenerate the transmission capability of details for SR. To address these problems, in this work, a progressive wide residual network with a fixed skip connection (named FSCWRN) based SR algorithm is proposed to reconstruct MR images, which combines the global residual learning and the shallow network based local residual learning. The strategy of progressive wide networks is adopted to replace deeper networks, which can partially relax the abovementioned problems, while a fixed skip connection helps provide rich local details at high frequencies from a fixed shallow layer network to subsequent networks. The experimental results on one simulated MR image database and three real MR image databases show the effectiveness of the proposed FSCWRN SR algorithm, which achieves improved reconstruction performance compared with other algorithms.

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Anti-CD19 CAR-modified T cells have shown therapeutic efficacy in patients with B-lineage malignancies and were well tolerated in most patients. Conditioning chemotherapy is a prerequisite to improve the clinical outcome.

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With the emergence of free and open source software (F/OSS) projects (e.g. Linux) as serious contenders to well-established proprietary software, advocates of F/OSS are quick to generalize the superiority of this approach to software development. On the other hand, some wellestablished software development firms view F/OSS as a threat and vociferously refute the claims of F/OSS advocates. This article represents a tutorial on F/OSS that tries objectively to identify and present open source software's concepts, benefits, and challenges. From our point of view, F/OSS is more than just software. We conceptualize it as an IPO system that consists of the license as the boundary of the system, the community that provides the input, the development process, and the software as the output. After describing the evolution and definition of F/OSS, we identify three approaches to benefiting from F/OSS that center on (1) the software, (2) the community, and (3) the license respectively. Each approach is fit for a specific situation and provides a unique set of benefits and challenges. We further illustrate our points by refuting common misconceptions associated with F/OSS based upon our conceptual framework.