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Lost In Translation __TOP__

Two lost souls visiting Tokyo -- the young, neglected wife of a photographer and a washed-up movie star shooting a TV commercial -- find an odd solace and pensive freedom to be real in each other's company, away from their lives in America.

Lost in Translation


Some view disclaimers as the solution to justify an imperfect translation. Ask yourself and your managers: What are we trying to achieve? If an agency provides imperfect information but includes a disclaimer, the agency is essentially saying that it cannot guarantee the accuracy of the information they have provided. If so, how is this:

As worthwhile as Shields' contributions are, it would be a mistake to let them eclipse the rest of this fine soundtrack. Interestingly, many of the other pieces on Lost in Translation sound more like Shields' previous work than his own tracks. Chief among them is Death in Vegas' lovely "Girls," a slow-building epic that combines breathy vocals, deceptively simple guitars, and distant but powerful drumming in a way that evokes My Bloody Valentine but doesn't borrow from them too shamelessly. Likewise, the Jesus & Mary Chain's "Just Like Honey" is nearly as swooningly romantic as "Sometimes." Sebastien Tellier's "Fantino" and Squarepusher's "Tommib" fit in well with Shields' work and also recall the work of Air, whose "Alone in Kyoto" is a smoothly flowing, Asian-inspired piece that reflects both their own sound and the film's setting. Ironically enough, Happy End's "Kaze Wo Atsumete" is the only song by an authentically Japanese group, but it sounds a lot like Gilbert O'Sullivan's "Alone Again, Naturally," which was used to devastating effect in The Virgin Suicides. Phoenix's "Too Young," a stylish re-creation of '80s soft rock, is another highlight from Lost in Translation, which works equally well as background music or as a way to replay the movie in your head (the hidden track of Bill Murray's drunken karaoke rendition of "More Than This" heightens this effect). Perfectly defined in its hazy beauty, this soundtrack loses nothing in its translation from a quietly wonderful movie into a quietly wonderful album.

FIGURE 1. mRNA and protein quality control pathways in mammalian cells. Normal interactions of the nascent chains lead to proper protein transport/folding (1). Loss of these interactions due to defect in the interacting factor or mutation in the polypeptide nascent chain (2) leads to protein degradation (3), misfolding, aggregation, and amyloid formation (4), or mRNA elimination in the RAPP pathway (5). mRNA surveillance quality control systems (6), nonsense-mediated decay (NMD), non-stop decay (NSD), and no-go decay (NGD) detect and eliminate defective mRNAs with PTCs, mRNAs without natural stop codon, and mRNAs at the stalled in translation ribosomes, respectively. Nascent chains at the stalled ribosomes or during stress are ubiquitinated in the ribosome quality control complex (RQC) pathway and removed by proteasome. During ER stress pre-emptive quality control (pQC) cotranslationally reroutes secretory and membrane proteins to cytoplasm for degradation. Many proteins are misfolded during stress and they are removed by multiple cellular systems, like UPR, ERAD, and ubiquitin/proteasome system (7).

FIGURE 2. Simplified scheme of interactions at the polypeptide exit site at the ribosome under normal conditions. Nascent chains and ribosomes interact with different proteins during translation to achieve proper folding and correct targeting. While nascent chains of cytosolic proteins (A) are synthesized in environment of RAC, NAC, Ssb (HSP70) and further folded with assistance of chaperones and chaperonins, the secretory proteins (B) briefly interact with NAC before full exposure of the signal sequence, and when signal sequence is emerged from the ribosome tunnel, SRP binds it leading to temporary elongation arrest and targeting to the ER membrane for further transport through translocon into ER lumen, then to Golgi, and finally outside of the cell. Only major interacting partners are shown, their sizes are not to scale, and their positions on the ribosome and contacts are presented for a general understanding of the process and do not reflect very complex nature of their interactions with the nascent chains and the ribosomes. Mammalian proteins are shown, their yeast counterparts are in square brackets.

FIGURE 4. Model for regulation of aberrant protein production (RAPP) in mammalian cells. Normal cotranslational interactions are important for protein biogenesis. Nascent chains of secretory proteins interact with signal recognition particle (SRP). This interaction leads to proper protein targeting to ER, folding and transport (A). Loss of this normal interaction with SRP due to a critical mutation in the secretory protein (B) or loss of the interacting factor (C) leads to engagement of AGO2 (a protein involved in translational silencing). This interaction directs aberrant protein mRNA for degradation initiating the RAPP process.

Translational medicine covers a broad range of scientific, regulatory and clinical disciplines and there is no single organization currently in existence to embrace the field in its globality. Therefore, while scientific and clinical aspects related to individual fields can be addressed within the realm of specialized societies, other practical aspects often related to education, regulation, business and economic issues remain orphaned, with no focused outlet through which to address emerging issues. An organization embracing the complexities of translational medicine should be considered with the goal of contributing information to all arenas of the need for translational efforts.

A translational medicine organization is particularly important in today's era of federal budget constraints. For example, most "standard" therapies for cancer do not affect survival [17], and billions of dollars are spent on drugs and therapeutic interventions that do not impact the natural history of most common diseases. Should advocacy efforts seek to shift funds from other research areas to translational research? Would it be savvier to join with other advocates of medical research to increase public and congressional awareness of the integrated need to understand basic as well as human biology? And who should be responsible for such advocacy? The National Institutes of Health has recently staked a claim on this issue by defining a roadmap to accelerate medical discoveries to improve human health Should more institutions join the effort? And how should industry integrate with this effort? To be effective, barriers will only be removed by the collaborative efforts of multiple system stakeholders [7].

Reality-driven research in humans faces obstacles of its own. First, communication between basic and clinical scientists is rare and sporadic [2]. Few meetings are devoted primarily to bringing the two entities together to promote mutually beneficial exchange. The paradigm between basic and clinical science has oftentimes put these two disciplines at odds with each other. It is not in the interest of basic scientists to accept changes unless publishing and study section standards are realigned to reward clinical relevance. Clinical scientists for their part are often overwhelmed with information coming from the basic science community. How can such a wealth of information be processed into a useful compendium that might contribute the understanding of human disease? Furthermore, clinical scientists may be too distracted by the intensity of clinical care to be able to seriously help bridge this gap. Are clinical research grants providing sufficient support to academic clinicians to truly promote translational research [19]? For instance, traditionally, R01 grants have been used to measure a scientist's "independence". However, such approach may distance newer basic or clinical investigators from the integrated approach often required for translational efforts. Should advocacy efforts voice the importance of more interdisciplinary grants?

Regulatory requirements provide formidable challenges for investigators. Major efforts have been made by regulatory agencies by releasing guidance documents. However, several obstacles remain. For example, preclinical evidence is usually required despite its unclear relevance to human disease. Similarly, it remains unclear whether toxicity testing in animal models is relevant to humans, particularly when biological agents with strong species-specificity are considered. Perhaps directly testing in humans, particularly for life threatening diseases when standard therapies have failed, should be considered in a limited number of patients. Clinical trial designs for the early development of novel therapies could be simplified according to the anticipated biologic activity of the agent tested [24]. While biopharmaceutical companies employ contractors or staff to address and meet regulatory requirements as required by regulations and the law, many academic institutions do not provide appropriate regulatory support. Most translational research is supported by grants; however, few provide funding for regulatory staff or consultation. Academic institutions do not provide support to non hypothesis driven research such as product development. In addition, a grant application focused on translational research characterizing identity, purity, stability and potency is rarely funded. Yet these characteristics are needed for advance testing of novel agents.

Paradoxically, many currently accepted therapies are known to provide no statistically significant survival benefit yet they have both approval for distribution and coverage by insurance companies. The National Cancer Institute leadership has recently put emphasis on "discovery, development and delivery" (NCI Director's report 2003) and, with the purpose of eliminating or reducing obstacles in translational research, the NCI Director's office has appointed new deputies charged with streamlining the discovery to delivery process. This strategy will hopefully yield results, at least in the context of cancer research, in a new modus operandi in clinical research where new agents could be quickly moved through the process and either approved or discarded. 041b061a72


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