Low Latency Geo-distributed Data Analytics

Low latency analytics on geographically distributed dat-asets (across datacenters, edge clusters) is an upcoming and increasingly important challenge. The dominant approach of aggregating all the data to a single data-center significantly inflates the timeliness of analytics. At the same time, running queries over geo-distributed inputs using the current intra-DC analytics frameworks also leads to high query response times because these frameworks cannot cope with the relatively low and variable capacity of WAN links. We present Iridium, a system for low latency geo-distri-buted analytics. Iridium achieves low query response times by optimizing placement of both data and tasks of the queries. The joint data and task placement op-timization, however, is intractable. Therefore, Iridium uses an online heuristic to redistribute datasets among the sites prior to queries ’ arrivals, and places the tasks to reduce network bottlenecks during the query’s ex-ecution. Finally, it also contains a knob to budget WAN usage. Evaluation across eight worldwide EC2 re-gions using production queries show that Iridium speeds up queries by 3 × − 19 × and lowers WAN usage by 15% − 64 % compared to existing baselines

Low latency via redundancy

Low latency is critical for interactive networked applications. But while we know how to scale systems to increase capacity, reducing latency --- especially the tail of the latency distribution --- can be much more difficult. In this paper, we argue that the use of redundancy is an effective way to convert extra capacity into reduced latency. By initiating redundant operations across diverse resources and using the first result which completes, redundancy improves a system's latency even under exceptional conditions. We study the tradeoff with added system utilization, characterizing the situations in which replicating all tasks reduces mean latency. We then demonstrate empirically that replicating all operations can result in significant mean and tail latency reduction in real-world systems including DNS queries, database servers, and packet forwarding within networks

Tachyon: Reliable, Memory Speed Storage for Cluster Computing Frameworks

Tachyon is a distributed file system enabling reliable data sharing at memory speed across cluster computing frameworks. While caching today improves read workloads, writes are either network or disk bound, as replication is used for fault-tolerance. Tachyon eliminates this bottleneck by pushing lineage, a well-known technique, into the storage layer. The key challenge in making a long-running lineage-based storage system is timely data recovery in case of failures. Tachyon addresses this issue by introducing a checkpointing algorithm that guarantees bounded recovery cost and resource allocation strategies for recomputation under commonly used resource schedulers. Our evaluation shows that Tachyon outperforms in-memory HDFS by 110x for writes. It also improves the end-to-end latency of a realistic workflow by 4x. Tachyon is open source and is deployed at multiple companies.National Science Foundation (U.S.) (CISE Expeditions Award CCF-1139158)Lawrence Berkeley National Laboratory (Award 7076018)United States. Defense Advanced Research Projects Agency (XData Award FA8750-12-2-0331

Novel 2D and 3D Assays to Determine the Activity of Anti-Leishmanial Drugs.

The discovery of novel anti-leishmanial compounds remains essential as current treatments have known limitations and there are insufficient novel compounds in development. We have investigated three complex and physiologically relevant in vitro assays, including: (i) a media perfusion based cell culture model, (ii) two 3D cell culture models, and (iii) iPSC derived macrophages in place of primary macrophages or cell lines, to determine whether they offer improved approaches to anti-leishmanial drug discovery and development. Using a Leishmania major amastigote-macrophage assay the activities of standard drugs were investigated to show the effect of changing parameters in these assays. We determined that drug activity was reduced by media perfusion (EC50 values for amphotericin B shifted from 54 (51-57) nM in the static system to 70 (61-75) nM under media perfusion; EC50 values for miltefosine shifted from 12 (11-15) µM in the static system to 30 (26-34) µM under media perfusion) (mean and 95% confidence intervals), with corresponding reduced drug accumulation by macrophages. In the 3D cell culture model there was a significant difference in the EC50 values of amphotericin B but not miltefosine (EC50 values for amphotericin B were 34.9 (31.4-38.6) nM in the 2D and 52.3 (46.6-58.7) nM in 3D; EC50 values for miltefosine were 5.0 (4.9-5.2) µM in 2D and 5.9 (5.5-6.2) µM in 3D (mean and 95% confidence intervals). Finally, in experiments using iPSC derived macrophages infected with Leishmania, reported here for the first time, we observed a higher level of intracellular infection in iPSC derived macrophages compared to the other macrophage types for four different species of Leishmania studied. For L. major with an initial infection ratio of 0.5 parasites per host cell the percentage infection level of the macrophages after 72 h was 11.3% ± 1.5%, 46.0% ± 1.4%, 66.4% ± 3.5% and 75.1% ± 2.4% (average ± SD) for the four cells types, THP1 a human monocytic cell line, mouse bone marrow macrophages (MBMMs), human bone marrow macrophages (HBMMs) and iPSC derived macrophages respectively. Despite the higher infection levels, drug activity in iPSC derived macrophages was similar to that in other macrophage types, for example, amphotericin B EC50 values were 35.9 (33.4-38.5), 33.5 (31.5-36.5), 33.6 (30.5-not calculated (NC)) and 46.4 (45.8-47.2) nM in iPSC, MBMMs, HBMMs and THP1 cells respectively (mean and 95% confidence intervals). We conclude that increasing the complexity of cellular assays does impact upon anti-leishmanial drug activities but not sufficiently to replace the current model used in HTS/HCS assays in drug discovery programmes. The impact of media perfusion on drug activities and the use of iPSC macrophages do, however, deserve further investigation

Comparison of the conformation and stability of the native dimeric, monomeric, tetrameric and the desensitized forms of the nucleotide pyrophosphatase from Mung bean (Phaseolus aureus) seedlings

A homogenous and crystalline form of nucleotide pyrophosphatase (EC 3.6.1.9) from Phaseolus aureus (mung bean) seedlings was used for the study of the regulation of enzyme activity by adenine nucleotides. The native dimeric form of the enzyme had a helical content of about 65% which was reduced to almost zero values by the addition of AMP. In addition to this change in the helical content, AMP converted the native dimer to a tetramer. Desensitization of AMP regulation, without an alteration of the molecular weight, was achieved either by reversible denaturation with 6 M urea or by passage through a column of Blue Sepharose but additionof phydroxymercuribenzoate desensitized the enzyme by dissociating the native dimer to a monomer. The changes in the quaternary structure and conformation of the enzyme consequent to AMP interaction or desensitization were monitored by measuring the helical content, EDTA inactivation and Zn2+ reactivation, stability towards heat denaturation, profiles of urea denaturation and susceptibility towards proteolytic digestion. Based on these results and our earlier work on this enzyme, we propose a model for the regulation of the mung bean nucleotide pyrophosphatase by association-dissociation and conformational changes. The model emphasizes that multiple mechanisms are operative in the desensitization of regulatory proteins

Dynamics in Fip1 regulate eukaryotic mRNA 3^′ end processing

Cleavage and polyadenylation factor (CPF/CPSF) is a multiprotein complex essential for mRNA 3′ end processing in eukaryotes. It contains an endonuclease that cleaves pre-mRNAs, and a polymerase that adds a poly(A) tail onto the cleaved 3′ end. Several CPF subunits, including Fip1, contain intrinsically disordered regions (IDRs). IDRs within multiprotein complexes can be flexible, or can become ordered upon interaction with binding partners. Here, we show that yeast Fip1 anchors the poly(A) polymerase Pap1 onto CPF via an interaction with zinc finger 4 of another CPF subunit, Yth1. We also reconstitute a fully recombinant 850-kDa CPF. By incorporating selectively labeled Fip1 into recombinant CPF, we could study the dynamics of Fip1 within the megadalton complex using nuclear magnetic resonance (NMR) spectroscopy. This reveals that a Fip1 IDR that connects the Yth1- and Pap1-binding sites remains highly dynamic within CPF. Together, our data suggest that Fip1 dynamics within the 3′ end processing machinery are required to coordinate cleavage and polyadenylation.</p

Online Convex Optimization Using Predictions

Making use of predictions is a crucial, but under-explored, area of online algorithms. This paper studies a class of online optimization problems where we have external noisy predictions available. We propose a stochastic prediction error model that generalizes prior models in the learning and stochastic control communities, incorporates correlation among prediction errors, and captures the fact that predictions improve as time passes. We prove that achieving sublinear regret and constant competitive ratio for online algorithms requires the use of an unbounded prediction window in adversarial settings, but that under more realistic stochastic prediction error models it is possible to use Averaging Fixed Horizon Control (AFHC) to simultaneously achieve sublinear regret and constant competitive ratio in expectation using only a constant-sized prediction window. Furthermore, we show that the performance of AFHC is tightly concentrated around its mean

Dynamics in Fip1 regulate eukaryotic mRNA 3^′ end processing

Cleavage and polyadenylation factor (CPF/CPSF) is a multiprotein complex essential for mRNA 3′ end processing in eukaryotes. It contains an endonuclease that cleaves pre-mRNAs, and a polymerase that adds a poly(A) tail onto the cleaved 3′ end. Several CPF subunits, including Fip1, contain intrinsically disordered regions (IDRs). IDRs within multiprotein complexes can be flexible, or can become ordered upon interaction with binding partners. Here, we show that yeast Fip1 anchors the poly(A) polymerase Pap1 onto CPF via an interaction with zinc finger 4 of another CPF subunit, Yth1. We also reconstitute a fully recombinant 850-kDa CPF. By incorporating selectively labeled Fip1 into recombinant CPF, we could study the dynamics of Fip1 within the megadalton complex using nuclear magnetic resonance (NMR) spectroscopy. This reveals that a Fip1 IDR that connects the Yth1- and Pap1-binding sites remains highly dynamic within CPF. Together, our data suggest that Fip1 dynamics within the 3′ end processing machinery are required to coordinate cleavage and polyadenylation.</p

Numerical study of the effect of wall temperature profiles on the premixed methane–air flame dynamics in a narrow channel

Time-accurate simulations of premixed CH/air flame in a narrow, heated channel are performed using the DRM-19 reaction mechanism. The effect of different wall temperature profiles on the flame dynamics is investigated for three different inflow velocity conditions. At a low inflow velocity of 0.2 m s, the flame shows instabilities in the form of spatial oscillations and even flame extinction. With the increase of the inflow velocity, flames are prone to showing more stability at a medium inflow velocity of 0.4 m s, and eventually show flame stabilisation at a high inflow velocity condition of 0.8 m s for all the wall temperature profiles examined. The total chemical heat release rate and total gas-solid heat exchange rate are found to have a combined effect on the flame propagation speed that determines flame behaviours. Since the flame behaviours in terms of the oscillation frequency and amplitude for spatially oscillating flames, or the stream-wise stabilisation location for steady-state flames, are very sensitive to the chosen wall temperature profile, a "real" conjugate heat transfer model is recommended in order to capture all of the relevant combustion physics accurately

On the influence of modelling choices on combustion in narrow channels

This paper examines the effect of modelling choices on the numerical simulation of premixed methane/air combustion in narrow channels. Knowledge on standard and well-accepted numerical methods in literature are collected in a cohesive document. The less well-established modelling choices have been thoroughly evaluated and discussed. A systematic method of computing the grid convergence index (GCI) has been presented for refining the computational grid. Two types of inflow boundary conditions have been tested and compared in terms of their wave-damping characteristics. The effect of different reaction schemes on simulation results have been examined and an appropriate mechanism (DRM-19) has been selected. Various types of ignition strategies to initiate the flame have been tested and compared. The transient ignition process which has not been discussed extensively in existing literature has been quantitatively described in this paper