ADDING PERSISTENCE TO MAIN MEMORY PROGRAMMING

Unlocking the true potential of the new persistent memories (PMEMs) requires eliminating traditional persistent I/O abstractions altogether, by introducing persistent semantics directly into main memory programming. Such a programming model elevates failure atomicity to a first-class application property in addition to in-memory data layout, concurrency-control, and fault tolerance, and therefore requires redesign of programming abstractions for both program correctness and maximum performance gains. To address these challenges, this thesis proposes a set of system software designs that integrate persistence with main memory programming, and makes the following contributions. First, this thesis proposes a PMEM-aware I/O runtime, NVStream, that supports fast durable streaming I/O. NVStream uses a memory-based I/O interface that integrates with existing I/O data movement operations of an application to accelerate persistent data writes. NVStream carefully designs its persistent data storage layout and crash-consistent semantics to match both application and PMEM characteristics. Specifically, we leverage the streaming nature of I/O in HPC workflows, to benefit from using a log-structured PMEM storage engine design, that uses relaxed write orderings and append-only failure-atomic semantics to form strongly consistent application checkpoints. Furthermore, we identify that optimizing the I/O software stack exposes the PMEM bandwidth limitations as a bottleneck during parallel HPC I/O writes, and propose a novel data movement design – PHX. PHX uses alternative network data movement paths available in datacenters to ease up the bandwidth pressure on the PMEM memory interconnects, all while maintaining the correctness of the persistent data. Next, the thesis explores the challenges and opportunities of using PMEM for true main memory persistent programming – a single data domain for both runtime and persistent applicationstate. Such a programming model includes maintaining ACID properties during each and every update to applications persistent structures. ACID-qualified persistent programming for multi-threaded applications is hard, as the programmer has to reason about both crash-consistency and synchronization – crash-sync – semantics for programming correctness. The thesis contributes new understanding of the correctness requirements for mixing different crash-consistent and synchronization protocols, characterizes the performance of different crash-sync realizations for different applications and hardware architectures, and draws actionable insights for future designs of PMEM systems. Finally, the application state stored on node-local persistent memory is still vulnerable to catastrophic node failures. The thesis proposes a replicated persistent memory runtime, Blizzard, that supports truly fault tolerant, concurrent and persistent data-structure programming. Blizzard carefully integrates userspace networking with byte addressable PMEM for a fast, persistent memory replication runtime. The design also incorporates a replication-aware crash-sync protocol that supports consistent and concurrent updates on persistent data-structures. Blizzard offers applications the flexibility to use the data structures that best match their functional requirements, while offering better performance, and providing crucial reliability guarantees lacking from existing persistent memory runtimes.Ph.D

Direct and scalable deposition of atomically thin low-noise MoS2 membranes on apertures

Published in final edited form as: ACS Nano. 2015 July 28; 9(7): 7352–7359. doi:10.1021/acsnano.5b02369.Molybdenum disulfide (MoS2) flakes can grow beyond the edge of an underlying substrate into a planar freestanding crystal. When the substrate edge is in the form of an aperture, reagent-limited nucleation followed by edge growth facilitate direct and selective growth of freestanding MoS2 membranes. We have found conditions under which MoS2 grows preferentially across micrometer-scale prefabricated solid-state apertures in silicon nitride membranes, resulting in sealed membranes that are one to a few atomic layers thick. We have investigated the structure and purity of our membranes by a combination of atomic-resolution transmission electron microscopy, elemental analysis, Raman spectroscopy, photoluminescence spectroscopy, and low-noise ion-current recordings through nanopores fabricated in such membranes. Finally, we demonstrate the utility of fabricated ultrathin nanopores in such membranes for single-stranded DNA translocation detection.R21 HG006873 - NHGRI NIH HHS; R21-HG006873 - NHGRI NIH HHSPublished versio

Lipin-1 Deficiency-Associated Recurrent Rhabdomyolysis and Exercise-Induced Myalgia Persisting into Adulthood: A Case Report and Review of Literature

Phosphatidate phosphatase-1 (lipin-1) is encoded by LPIN1 gene. Lipin-1 deficiency has been reported as the second most common cause of early-onset rhabdomyolysis after primary fatty acid oxidation disorders. We report a case of a 32-year-old Sri Lankan female with a history of more than 10 episodes of rhabdomyolysis and exercise intolerance since childhood. These episodes were triggered by infections and exercise. A temporal relationship between the acute episodes and use of drugs such as theophylline, mefenamic acid, co-trimoxazole, and combined oral contraceptive pills was also noted. There was marked elevation of serum creatine kinase and transaminases during acute episodes. Family history revealed parental consanguinity and an affected sibling who died of an acute episode associated with muscle weakness, dark coloured urine, and cyanosis, at the age of 2 years. The histochemical findings of the patient under discussion were consistent with a metabolic myopathy affecting membrane integrity. A homozygous, likely pathogenic variant c.1684G>T encoding p.(Glu562∗) was identified by clinical exome sequencing. Even though the studies to date give no convincing evidence of a possible causal or contributory relationship between the drugs under discussion and lipin-1 related rhabdomyolysis, this case highlights the importance of pharmacovigilance and reporting adverse drug reactions in patients with lipin-1 deficiency

Direct and Scalable Chemical Vapor Deposition of Ultrathin Low-Noise MoS2 Membranes on Apertures

We show that atomically thin molybdenum disulfide (MoS2) crystals can grow without any underlying substrates into free-standing atomically-thin layers, maintaining their planar 2D form. Using this property, we present a new mechanism for 2D crystal synthesis, i.e. reagent-limited nucleation near an aperture edge followed by reactions that allow crystal growth into the free-space of the aperture. Such an approach enables us, for the first time, the direct and selective growth of freestanding membranes of atomically thin MoS2 layers across micrometer-scale pre-fabricated solid-state apertures in SiNx membranes. Under optimal conditions, MoS2 grows preferentially across apertures, resulting in sealed membranes that are one to a few atomic layers thick. Since our method involves free-space growth and is devoid of either substrates or transfer, it is conceivably the most contamination-free method for obtaining 2D crystals reported so far. The membrane quality was investigated using atomic-resolution transmission electron microscopy, Raman spectroscopy, photoluminescence spectroscopy, and low-noise ion-current recordings through nanopores fabricated in such membranes.Comment: This paper is withdrawn by the author due to critical errors in the data and incomplete data in the pape

Nanopore-Based Measurements of Protein Size, Fluctuations, and Conformational Changes

Proteins are structurally dynamic macromolecules, and it is challenging to quantify the conformational properties of their native state in solution. Nanopores can be efficient tools to study proteins in a solution environment. In this method, an electric field induces electrophoretic and/or electro-osmotic transport of protein molecules through a nanopore slightly larger than the protein molecule. High-bandwidth ion current measurement is used to detect the transit of each protein molecule. First, our measurements reveal a correlation between the mean current blockade amplitude and the radius of gyration for each protein. Next, we find a correlation between the shape of the current signal amplitude distributions and the protein fluctuation as obtained from molecular dynamics simulations. Further, the magnitude of the structural fluctuations, as probed by experiments and simulations, correlates with the ratio of α-helix to β-sheet content. We highlight the resolution of our measurements by resolving two states of calmodulin, a canonical protein that undergoes a conformational change in response to calcium binding

Differential Enzyme Flexibility Probed Using Solid-State Nanopores

Enzymes and motor proteins are dynamic macromolecules that coexist in a number of conformations of similar energies. Protein function is usually accompanied by a change in structure and flexibility, often induced upon binding to ligands. However, while measuring protein flexibility changes between active and resting states is of therapeutic significance, it remains a challenge. Recently, our group has demonstrated that breadth of signal amplitudes in measured electrical signatures as an ensemble of individual protein molecules is driven through solid-state nanopores and correlates with protein conformational dynamics. Here, we extend our study to resolve subtle flexibility variation in dihydrofolate reductase mutants from unlabeled single molecules in solution. We first demonstrate using a canonical protein system, adenylate kinase, that both size and flexibility changes can be observed upon binding to a substrate that locks the protein in a closed conformation. Next, we investigate the influence of voltage bias and pore geometry on the measured electrical pulse statistics during protein transport. Finally, using the optimal experimental conditions, we systematically study a series of wild-type and mutant dihydrofolate reductase proteins, finding a good correlation between nanopore-measured protein conformational dynamics and equilibrium bulk fluorescence probe measurements. Our results unequivocally demonstrate that nanopore-based measurements reliably probe conformational diversity in native protein ensembles