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"Young, Tom"
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Motifs for Molecular Recognition Exploiting Hydrophobic Enclosure in Protein-Ligand Binding
The thermodynamic properties and phase behavior of water in confined regions can vary significantly from that observed in the bulk. This is particularly true for systems in which the confinement is on the molecular-length scale. In this study, we use molecular dynamics simulations and a powerful solvent analysis technique based on inhomogenous solvation theory to investigate the properties of water molecules that solvate the confined regions of protein active sites. Our simulations and analysis indicate that the solvation of protein active sites that are characterized by hydrophobic enclosure and correlated hydrogen bonds induce atypical entropic and enthalpic penalties of hydration. These penalties apparently stabilize the protein-ligand complex with respect to the independently solvated ligand and protein, which leads to enhanced binding affinities. Our analysis elucidates several challenging cases, including the super affinity of the streptavidin-biotin system.
Journal Article
Single-stranded DNA oligonucleotides containing CpG motifs are non-stimulatory in vitro but offer protection in vivo against Burkholderia pseudomallei
Therapies that modulate and appropriately direct the immune response are promising candidates for the treatment of infectious diseases. One such candidate therapeutic is DZ13, a short, synthetic, single-stranded DNA molecule. This molecule has enzymatic activity and can modulate the immune response by binding to and degrading the mRNA encoding a key immuno-regulatory molecule. Originally developed and entering clinical trials as an anti-cancer agent, DZ13 has also been evaluated as a treatment for viral infections, and has been shown to provide protection against infection with influenza virus in a mouse model of infection. In this work, we evaluated whether the immuno-modulatory properties of DZ13 could provide protection against the potential biothreat pathogen Burkholderia pseudomallei which causes the neglected tropical disease melioidosis. Treatment of mice infected with B. pseudomallei demonstrated that DZ13 did indeed provide excellent protection after only two post-exposure treatments. However, our data indicated that the enzymatic activity contained in DZ13 was not required for protection, with control oligonucleotide treatments lacking activity against the target mRNA equally as protective against B. pseudomallei . We have designed new sequences to study the mechanism of protection further. These novel sequences offer enhanced protection against infection, but are not directly anti-microbial and do not appear to be stimulating the immune system via TLR9 or other key innate immune sensors, despite containing CpG motifs. The molecular mechanism of these novel sequences remains to be elucidated, but the data highlights that these oligonucleotide-sensing pathways are attractive and relevant targets to modulate during bacterial and viral infections.
Journal Article
World-making stories : Maidu language and community renewal on a shared California landscape
\"World-Making Stories is a collection of Maidu creation stories that will help readers appreciate California's rich cultural tapestry. At the beginning of the twentieth century, renowned storyteller Hanc'ibyjim (Tom Young) performed Maidu and Atsugewi stories for anthropologist Ronald B. Dixon, who published these stories in 1912. The resulting Maidu Texts presented the stories in numbered block texts that, while serving as a source of linguistic decoding, also reflect the state of anthropological linguistics of the era by not conveying a sense of rhetorical or poetic composition. Sixty years later, noted linguist William Shipley engaged the texts as oral literature and composed a free verse literary translation, which he paired with the artwork of Daniel Stolpe and published in a limited-edition four-volume set that circulated primarily to libraries and private collectors. Here M. Eleanor Nevins and the Weje-ebis (Keep Speaking) Jamani Maidu Language Revitalization Project team illuminate these important tales in a new way by restoring Maidu elements omitted by William Shipley and by bending the translation to more closely correspond in poetic form to the Maidu original. The beautifully told stories by Hanc'ibyjim are accompanied by Stolpe's intricate illustrations and by personal and pedagogical essays from scholars and Maidu leaders working to revitalize the language. The resulting World-Making Stories is a necessity for language revitalization programs and an excellent model of indigenous community-university collaboration\"--from the publisher's website.
Book
Recent advances in deep learning based dialogue systems: a systematic survey
Dialogue systems are a popular natural language processing (NLP) task as it is promising in real-life applications. It is also a complicated task since many NLP tasks deserving study are involved. As a result, a multitude of novel works on this task are carried out, and most of them are deep learning based due to their outstanding performance. In this survey, we mainly focus on the deep learning based dialogue systems. We comprehensively review state-of-the-art research outcomes in dialogue systems and analyze them from two angles: model type and system type. Specifically, from the angle of model type, we discuss the principles, characteristics, and applications of different models that are widely used in dialogue systems. This will help researchers acquaint these models and see how they are applied in state-of-the-art frameworks, which is rather helpful when designing a new dialogue system. From the angle of system type, we discuss task-oriented and open-domain dialogue systems as two streams of research, providing insight into the hot topics related. Furthermore, we comprehensively review the evaluation methods and datasets for dialogue systems to pave the way for future research. Finally, some possible research trends are identified based on the recent research outcomes. To the best of our knowledge, this survey is the most comprehensive and up-to-date one at present for deep learning based dialogue systems, extensively covering the popular techniques. We speculate that this work is a good starting point for academics who are new to the dialogue systems or those who want to quickly grasp up-to-date techniques in this area.
Journal Article
Experimental results of wake steering using fixed angles
In this article, the authors present a test of wake steering at a commercial wind farm. A single fixed yaw offset, rather than an optimized offset schedule, is alternately applied to an upstream wind turbine, and the effect on downstream turbines is analyzed. This experimental design allows for comparison with engineering wake models independent of the controller's ability to track a varying offset and correctly measure wind direction. Additionally, by applying the same offset in beneficial and detrimental conditions, we are able to collect important data for assessing second-order wake model predictions. Results of the article from collected data show good agreement with the FLOw Redirection and Induction in Steady State (FLORIS) engineering model and offer support for the asymmetry of wake steering predicted by newer models, such as the Gauss–curl hybrid model.
Journal Article
Untraceable
Jennifer Marsh is an FBI secret service agent who gets caught up in a very personal and deadly cat-and-mouse game with a serial killer. The killer knows that people are drawn to the curious and the dark side of things. They will log onto an 'untraceable' website where the killer conducts violent and painful murders live on the internet. The more people who log on and enter the website, the quicker and more violently the victim dies.
DVD
The Gilley ‘debate’
I suggest that the recent furore over Gilley's article on colonialism raises at least three distinct issues both within academia and the wider space of public debate. The first concerns the category of ‘offence’, who can be offended and by what. The second concerns the nature of colonialism, its contemporary understanding and why that remains politically controversial. The third concerns possible continuities between certain aspects of colonial rule and current forms of Western intervention in Africa. In each case I make some very tentative suggestions as to why one journal article attracted so much attention and antagonism.
Journal Article