Analyzing Machupo virus-receptor binding by molecular dynamics simulations

In many biological applications, we would like to be able to computationally predict mutational effects on affinity in protein-protein interactions. However, many commonly used methods to predict these effects perform poorly in important test cases. In particular, the effects of multiple mutations, non-alanine substitutions, and flexible loops are difficult to predict with available tools and protocols. We present here an existing method applied in a novel way to a new test case; we interrogate affinity differences resulting from mutations in a host-virus protein-protein interface. We use steered molecular dynamics (SMD) to computationally pull the machupo virus (MACV) spike glycoprotein (GP1) away from the human transferrin receptor (hTfR1). We then approximate affinity using the maximum applied force of separation and the area under the force-versus-distance curve. We find, even without the rigor and planning required for free energy calculations, that these quantities can provide novel biophysical insight into the GP1/hTfR1 interaction. First, with no prior knowledge of the system we can differentiate among wild type and mutant complexes. Moreover, we show that this simple SMD scheme correlates well with relative free energy differences computed via free energy perturbation. Second, although the static co-crystal structure shows two large hydrogen-bonding networks in the GP1/hTfR1 interface, our simulations indicate that one of them may not be important for tight binding. Third, one viral site known to be critical for infection may mark an important evolutionary suppressor site for infection-resistant hTfR1 mutants. Finally, our approach provides a framework to compare the effects of multiple mutations, individually and jointly, on protein-protein interactions.Comment: 33 pages, 8 figures, 5 table

Cache Serializability: Reducing Inconsistency in Edge Transactions

Read-only caches are widely used in cloud infrastructures to reduce access latency and load on backend databases. Operators view coherent caches as impractical at genuinely large scale and many client-facing caches are updated in an asynchronous manner with best-effort pipelines. Existing solutions that support cache consistency are inapplicable to this scenario since they require a round trip to the database on every cache transaction. Existing incoherent cache technologies are oblivious to transactional data access, even if the backend database supports transactions. We propose T-Cache, a novel caching policy for read-only transactions in which inconsistency is tolerable (won't cause safety violations) but undesirable (has a cost). T-Cache improves cache consistency despite asynchronous and unreliable communication between the cache and the database. We define cache-serializability, a variant of serializability that is suitable for incoherent caches, and prove that with unbounded resources T-Cache implements this new specification. With limited resources, T-Cache allows the system manager to choose a trade-off between performance and consistency. Our evaluation shows that T-Cache detects many inconsistencies with only nominal overhead. We use synthetic workloads to demonstrate the efficacy of T-Cache when data accesses are clustered and its adaptive reaction to workload changes. With workloads based on the real-world topologies, T-Cache detects 43-70% of the inconsistencies and increases the rate of consistent transactions by 33-58%.Comment: Ittay Eyal, Ken Birman, Robbert van Renesse, "Cache Serializability: Reducing Inconsistency in Edge Transactions," Distributed Computing Systems (ICDCS), IEEE 35th International Conference on, June~29 2015--July~2 201

Fast multi-image matching via density-based clustering

We consider the problem of finding consistent matches across multiple images. Previous state-of-the-art solutions use constraints on cycles of matches together with convex optimization, leading to computationally intensive iterative algorithms. In this paper, we propose a clustering-based formulation. We first rigorously show its equivalence with the previous one, and then propose QuickMatch, a novel algorithm that identifies multi-image matches from a density function in feature space. We use the density to order the points in a tree, and then extract the matches by breaking this tree using feature distances and measures of distinctiveness. Our algorithm outperforms previous state-of-the-art methods (such as MatchALS) in accuracy, and it is significantly faster (up to 62 times faster on some bechmarks), and can scale to large datasets (with more than twenty thousands features).Accepted manuscriptSupporting documentatio

Hare: a file system for non-cache-coherent multicores

Hare is a new file system that provides a POSIX-like interface on multicore processors without cache coherence. Hare allows applications on different cores to share files, directories, and file descriptors. The challenge in designing Hare is to support the shared abstractions faithfully enough to run applications that run on traditional shared-memory operating systems, with few modifications, and to do so while scaling with an increasing number of cores. To achieve this goal, Hare must support features (such as shared file descriptors) that traditional network file systems don't support, as well as implement them in a way that scales (e.g., shard a directory across servers to allow concurrent operations in that directory). Hare achieves this goal through a combination of new protocols (including a 3-phase commit protocol to implement directory operations correctly and scalably) and leveraging properties of non-cache-coherent multiprocessors (e.g., atomic low-latency message delivery and shared DRAM). An evaluation on a 40-core machine demonstrates that Hare can run many challenging Linux applications (including a mail server and a Linux kernel build) with minimal or no modifications. The results also show these applications achieve good scalability on Hare, and that Hare's techniques are important to achieving scalability.Quanta Computer (Firm

Adaptive sampling-based profiling techniques for optimizing the distributed JVM runtime

Extending the standard Java virtual machine (JVM) for cluster-awareness is a transparent approach to scaling out multithreaded Java applications. While this clustering solution is gaining momentum in recent years, efficient runtime support for fine-grained object sharing over the distributed JVM remains a challenge. The system efficiency is strongly connected to the global object sharing profile that determines the overall communication cost. Once the sharing or correlation between threads is known, access locality can be optimized by collocating highly correlated threads via dynamic thread migrations. Although correlation tracking techniques have been studied in some page-based sof Tware DSM systems, they would entail prohibitively high overheads and low accuracy when ported to fine-grained object-based systems. In this paper, we propose a lightweight sampling-based profiling technique for tracking inter-thread sharing. To preserve locality across migrations, we also propose a stack sampling mechanism for profiling the set of objects which are tightly coupled with a migrant thread. Sampling rates in both techniques can vary adaptively to strike a balance between preciseness and overhead. Such adaptive techniques are particularly useful for applications whose sharing patterns could change dynamically. The profiling results can be exploited for effective thread-to-core placement and dynamic load balancing in a distributed object sharing environment. We present the design and preliminary performance result of our distributed JVM with the profiling implemented. Experimental results show that the profiling is able to obtain over 95% accurate global sharing profiles at a cost of only a few percents of execution time increase for fine- to medium- grained applications. © 2010 IEEE.published_or_final_versionThe 24th IEEE International Symposium on Parallel & Distributed Processing (IPDPS 2010), Atlanta, GA., 19-23 April 2010. In Proceedings of the 24th IPDPS, 2010, p. 1-1

SNAP: Stateful Network-Wide Abstractions for Packet Processing

Early programming languages for software-defined networking (SDN) were built on top of the simple match-action paradigm offered by OpenFlow 1.0. However, emerging hardware and software switches offer much more sophisticated support for persistent state in the data plane, without involving a central controller. Nevertheless, managing stateful, distributed systems efficiently and correctly is known to be one of the most challenging programming problems. To simplify this new SDN problem, we introduce SNAP. SNAP offers a simpler "centralized" stateful programming model, by allowing programmers to develop programs on top of one big switch rather than many. These programs may contain reads and writes to global, persistent arrays, and as a result, programmers can implement a broad range of applications, from stateful firewalls to fine-grained traffic monitoring. The SNAP compiler relieves programmers of having to worry about how to distribute, place, and optimize access to these stateful arrays by doing it all for them. More specifically, the compiler discovers read/write dependencies between arrays and translates one-big-switch programs into an efficient internal representation based on a novel variant of binary decision diagrams. This internal representation is used to construct a mixed-integer linear program, which jointly optimizes the placement of state and the routing of traffic across the underlying physical topology. We have implemented a prototype compiler and applied it to about 20 SNAP programs over various topologies to demonstrate our techniques' scalability