The Prion Protein Ligand, Stress-Inducible Phosphoprotein 1, Regulates Amyloid-beta Oligomer Toxicity

In Alzheimer\u27s disease (AD), soluble amyloid-beta oligomers (A beta Os) trigger neurotoxic signaling, at least partially, via the cellular prion protein (PrPC). However, it is unknown whether other ligands of PrPC can regulate this potentially toxic interaction. Stress-inducible phosphoprotein 1 (STI1), an Hsp90 cochaperone secreted by astrocytes, binds to PrPC in the vicinity of the A beta O binding site to protect neurons against toxic stimuli. Here, we investigated a potential role of STI1 in A beta O toxicity. We confirmed the specific binding of A beta Os and STI1 to the PrP and showed that STI1 efficiently inhibited A beta O binding to PrP in vitro (IC50 of similar to 70 nM) and also decreased A beta O binding to cultured mouse primary hippocampal neurons. Treatment with STI1 prevented A beta O-induced synaptic loss and neuronal death in mouse cultured neurons and long-term potentiation inhibition in mouse hippocampal slices. Interestingly, STI1-haploinsufficient neurons were more sensitive to A beta O-induced cell death and could be rescued by treatment with recombinant STI1. Noteworthy, both A beta O binding to PrPC and PrPC-dependent A beta O toxicity were inhibited by TPR2A, the PrPC-interacting domain of STI1. Additionally, PrPC-STI1 engagement activated alpha 7 nicotinic acetylcholine receptors, which participated in neuroprotection against A beta O-induced toxicity. We found an age-dependent upregulation of cortical STI1 in the APPswe/PS1dE9 mouse model of AD and in the brains of AD-affected individuals, suggesting a compensatory response. Our findings reveal a previously unrecognized role of the PrPC ligand STI1 in protecting neurons in AD and suggest a novel pathway that may help to offset A beta O-induced toxicity

Jumbo Store: Providing Efficient Incremental Upload and Versioning for a Utility Rendering Service

We have developed a new storage system called the Jumbo Store (JS) based on encoding directory tree snapshots as graphs called HDAGs whose nodes are small variable-length chunks of data and whose edges are hash pointers. We store or transmit each node only once and encode using landmark-based chunking plus some new tricks. This leads to very efficient incremental upload and storage of successive snapshots: we report compression factors over 16x for real data; a comparison shows that our incremental upload sends only 1/5 as much data as Rsync. To demonstrate the utility of the Jumbo Store, we have integrated it into HP Labs ’ prototype Utility Rendering Service (URS), which accepts rendering data in the form of directory tree snapshots from small teams of animators, renders one or more requested frames using a processor farm, and then makes the rendered frames available for download. Efficient incremental upload is crucial to the URS’s usability and responsiveness because of the teams ’ slow Internet connections. We report on the JS’s performance during a major field test of the URS where the URS was offered to 11 groups of animators for 10 months during an animation showcase to create high-quality short animations.

Business-driven IT for SAP -- The Model Information Flow

Enterprises rely on efficient and flexible IT services. While complexity of services is increasing, personnel to provide and manage services will remain limited. At the same time, IT environments are becoming more dynamic, from the business side as well as from the infrastructure side. The ability to incorporate change faster, more efficiently and reliably has become a measure of quality of enterprise IT organizations. IT responds to these challenges by decoupling functions into services and by improving the linkages between business processes and the supporting IT systems. Service-oriented Architecture has become the accepted pattern for modern enterprise IT. This paper presents the Model Information Flow. It is part of a collaboration between HP Labs and SAP Research. The goal of the collaboration is to explore new approaches of model-driven planning, design and management of enterprise applications in a shared and virtualized IT infrastructure. The goal is to substantially improve the linkage between the business and the IT layer and the ability to manage and accommodate change more efficiently and in a largely automated manner