Starlab (United States)

Abstract Huntington’s disease (HD) is a progressive neurodegenerative disease caused by the pathologic expansion of a CAG repeat in the first exon of the huntingtin (HTT) gene, resulting in a huntingtin (HTT) protein with an expanded polyglutamine (polyQ) tract. Phosphorylation at residue S421 (pS421) is one of the post-translational modifications proposed to influence the biology of wild-type and mutant (m)HTT, such as HTT stability and clearance, HTT subcellular localization, mHTT toxicity, and regulation of HTT function in axonal transport. However, the detection and quantification of S421-HTT phosphorylation in relevant biological contexts have remained challenging and the consequences of pS421 in HD pathogenesis remains unclear. Here we report the development of a novel ultrasensitive immunoassay enabling the specific and sensitive detection of pS421-HTT in a variety of biologically relevant contexts. With this assay we conducted a longitudinal assessment of pS421 levels in tissues from a mouse model of HD to investigate the relationship between S421 phosphorylation and phenotypic progression. We also identified PRKACA, the cAMP-regulated catalytic α subunit of PKA, as a kinase capable of phosphorylating S421-HTT, demonstrating its ability to regulate endogenous pS421 in human cells. Finally, we exploited the sensitivity of the assay to detect endogenous pS421-HTT in cerebrospinal fluid (CSF) from nonhuman primates, showing for the first time that phosphorylation at S421-HTT can be detected in this bio-fluid. These reagents and assay will enable investigation of the biological consequence and the relevance of pS421 in the natural history of HD.

Molecular nanotechnology is an emerging technology that allows us to build materials and systems with atomic and molecular precision by manipulating atoms and molecules at very small scales, ultimatel

Feynman (1960) first proposed a molecular-scale technology. Drexler (1981, 1986, 1992) went far beyond that proposal and described some of the limitations of these molecular machines. Specifically, he proposed a machine known as an assembler. An assembler in this context is a machine that has the ability to construct essentially anything we program it to construct. Macroscale versions of these machines are called Santa Claus machines (Calder, 1978) and von Neumann machines (Freitas and Gilbreath, 1982). In this chapter, we will examine the rationale for that conjecture and some exploratory engineering leading toward that long-range goal. Subsequent chapters will review progress to date with a focus on the chemical enabling technologies that will bring this long-range goal to fruition.

We describe a prototype system of work in-progress that combines remote sensors with presence detection to address the orientation needs when confronted with unfamiliar spaces. The goal is to explore how these technologies might together make interactive spaces that can support users in their everyday interactions with the world. An application that presents information about our office space using environmental sensing hardware and infrared badges is introduced. An explanation of how the prototype is used, and a description of the rationale behind designing its software infrastructure and hardware selection is provided.

The forthcoming MPEG-7 standard ties together several different approaches in several different communities. It is perhaps the primary task of the standard to bring these disparate elements together and maximise the benefit to industly, consumers, and researchers. The panel will discuss a variety of current issues in MPEG-7, including the impact of such a standard, what opportunities exist for competition in technologies lying outside of the standard the scope and issues arising from complexity of the standard and what applications lie beyond the motivating paradigm of search and retrieval.