Helicase activity on DNA as a propagating front

We develop a propagating front analysis, in terms of a local probability of zipping, for the helicase activity of opening up a double stranded DNA (dsDNA). In a fixed-distance ensemble (conjugate to the fixed-force ensemble) the front separates the zipped and unzipped phases of a dsDNA and a drive acts locally around the front. Bounds from variational analysis and numerical estimates for the speed of a helicase are obtained. Different types of helicase behaviours can be distinguished by the nature of the drive.Comment: 5 pages, 5 eps figures; replaced by the published versio

Forecasting the cost of processing multi-join queries via hashing for main-memory databases (Extended version)

Database management systems (DBMSs) carefully optimize complex multi-join queries to avoid expensive disk I/O. As servers today feature tens or hundreds of gigabytes of RAM, a significant fraction of many analytic databases becomes memory-resident. Even after careful tuning for an in-memory environment, a linear disk I/O model such as the one implemented in PostgreSQL may make query response time predictions that are up to 2X slower than the optimal multi-join query plan over memory-resident data. This paper introduces a memory I/O cost model to identify good evaluation strategies for complex query plans with multiple hash-based equi-joins over memory-resident data. The proposed cost model is carefully validated for accuracy using three different systems, including an Amazon EC2 instance, to control for hardware-specific differences. Prior work in parallel query evaluation has advocated right-deep and bushy trees for multi-join queries due to their greater parallelization and pipelining potential. A surprising finding is that the conventional wisdom from shared-nothing disk-based systems does not directly apply to the modern shared-everything memory hierarchy. As corroborated by our model, the performance gap between the optimal left-deep and right-deep query plan can grow to about 10X as the number of joins in the query increases.Comment: 15 pages, 8 figures, extended version of the paper to appear in SoCC'1

Initial Vibration Analysis of the Advanced Stirling Radioisotope Generator's (ASRG's) Affect on Spacecraft Instruments

Assess if nominal Advanced Stirling Radioisotope Generator (ASRG) vibration levels are sufficiently benign for unimpeded spacecraft instrument operation

Relationships among seismic velocity, metamorphism, and seismic and aseismic fault slip in the Salton Sea Geothermal Field region

Author Posting. © American Geophysical Union, 2015. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Solid Earth 120 (2015): 2600–2615, doi:10.1002/2014JB011579.The Salton Sea Geothermal Field is one of the most geothermally and seismically active areas in California and presents an opportunity to study the effect of high-temperature metamorphism on the properties of seismogenic faults. The area includes numerous active tectonic faults that have recently been imaged with active source seismic reflection and refraction. We utilize the active source surveys, along with the abundant microseismicity data from a dense borehole seismic network, to image the 3-D variations in seismic velocity in the upper 5 km of the crust. There are strong velocity variations, up to ~30%, that correlate spatially with the distribution of shallow heat flow patterns. The combination of hydrothermal circulation and high-temperature contact metamorphism has significantly altered the shallow sandstone sedimentary layers within the geothermal field to denser, more feldspathic, rock with higher P wave velocity, as is seen in the numerous exploration wells within the field. This alteration appears to have a first-order effect on the frictional stability of shallow faults. In 2005, a large earthquake swarm and deformation event occurred. Analysis of interferometric synthetic aperture radar data and earthquake relocations indicates that the shallow aseismic fault creep that occurred in 2005 was localized on the Kalin fault system that lies just outside the region of high-temperature metamorphism. In contrast, the earthquake swarm, which includes all of the M > 4 earthquakes to have occurred within the Salton Sea Geothermal Field in the last 15 years, ruptured the Main Central Fault (MCF) system that is localized in the heart of the geothermal anomaly. The background microseismicity induced by the geothermal operations is also concentrated in the high-temperature regions in the vicinity of operational wells. However, while this microseismicity occurs over a few kilometer scale region, much of it is clustered in earthquake swarms that last from hours to a few days and are localized near the MCF system.This work was funded by USGS NEHRP proposal G10AP00101 and NSF proposal 0943906.2015-10-2

Strain prioritization and genome mining for enediyne natural products

The enediyne family of natural products has had a profound impact on modern chemistry, biology, and medicine, and yet only 11 enediynes have been structurally characterized to date. Here we report a genome survey of 3,400 actinomycetes, identifying 81 strains that harbor genes encoding the enediyne polyketide synthase cassettes that could be grouped into 28 distinct clades based on phylogenetic analysis. Genome sequencing of 31 representative strains confirmed that each clade harbors a distinct enediyne biosynthetic gene cluster. A genome neighborhood network allows prediction of new structural features and biosynthetic insights that could be exploited for enediyne discovery. We confirmed one clade as new C-1027 producers, with a significantly higher C-1027 titer than the original producer, and discovered a new family of enediyne natural products, the tiancimycins (TNMs), that exhibit potent cytotoxicity against a broad spectrum of cancer cell lines. Our results demonstrate the feasibility of rapid discovery of new enediynes from a large strain collection. IMPORTANCE Recent advances in microbial genomics clearly revealed that the biosynthetic potential of soil actinomycetes to produce enediynes is underappreciated. A great challenge is to develop innovative methods to discover new enediynes and produce them in sufficient quantities for chemical, biological, and clinical investigations. This work demonstrated the feasibility of rapid discovery of new enediynes from a large strain collection. The new C-1027 producers, with a significantly higher C-1027 titer than the original producer, will impact the practical supply of this important drug lead. The TNMs, with their extremely potent cytotoxicity against various cancer cells and their rapid and complete cancer cell killing characteristics, in comparison with the payloads used in FDA-approved antibody-drug conjugates (ADCs), are poised to be exploited as payload candidates for the next generation of anticancer ADCs. Follow-up studies on the other identified hits promise the discovery of new enediynes, radically expanding the chemical space for the enediyne family

Velocity and processivity of helicase unwinding of double-stranded nucleic acids

Helicases are molecular motors which unwind double-stranded nucleic acids (dsNA) in cells. Many helicases move with directional bias on single-stranded (ss) nucleic acids, and couple their directional translocation to strand separation. A model of the coupling between translocation and unwinding uses an interaction potential to represent passive and active helicase mechanisms. A passive helicase must wait for thermal fluctuations to open dsNA base pairs before it can advance and inhibit NA closing. An active helicase directly destabilizes dsNA base pairs, accelerating the opening rate. Here we extend this model to include helicase unbinding from the nucleic-acid strand. The helicase processivity depends on the form of the interaction potential. A passive helicase has a mean attachment time which does not change between ss translocation and ds unwinding, while an active helicase in general shows a decrease in attachment time during unwinding relative to ss translocation. In addition, we describe how helicase unwinding velocity and processivity vary if the base-pair binding free energy is changed.Comment: To appear in special issue on molecular motors, Journal of Physics - Condensed Matte

Upgrade of the Glasgow photon tagging spectrometer for Mainz MAMI-C

The Glasgow photon tagging spectrometer at Mainz has been upgraded so that it can be used with the 1500 MeV electron beam now available from the Mainz microtron MAMI-C. The changes made and the resulting properties of the spectrometer are discussed.Comment: 20 pages, 12 figure

Antagonism of the proinflammatory and pronociceptive actions of canonical and biased agonists of protease-activated receptor-2

Diverse proteases cleave protease-activated receptor-2 (PAR2) on primary sensory neurons and epithelial cells to evoke pain and inflammation. Trypsin and tryptase activate PAR2 by a canonical mechanism that entails cleavage within the extracellular N-terminus revealing a tethered ligand that activates the cleaved receptor. Cathepsin-S and elastase are biased agonists that cleave PAR2 at different sites to activate distinct signalling pathways. Although PAR2 is a therapeutic target for inflammatory and painful diseases, the divergent mechanisms of proteolytic activation complicate the development of therapeutically useful antagonists

Objectively measured physical activity and fat mass in a large cohort of children

Background Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity. Methods and Findings We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend < 0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls. Conclusions We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity

Airborne assault on corregidor: a study in weather, terrain, and cultural landscapes

In many ways, military forces using advanced technologies have been able to overcome a number of the inherent and traditional challenges posed by physical geography. However, geography continues to play a significant role in military planning and operations in two areas that have received little attention in the literature, namely airborne operations and the cultural landscape. This case study sought to contribute to these discussions by analysing the American operation to seize Corregidor Island in February 1945. As a primarily airborne assault, the operation was heavily contingent on weather, but also on terrain for sufficient drop zones, and the cultural landscape and terrain intelligence of the American forces proved vital in this regard. Through analysing archival military planning documents, maps, images and other primary and secondary sources, this study found that the physical terrain and enemy defences dictated the overall plan, but two features of the cultural landscape, the parade ground and golf course, were essential to the airborne operation, serving as the smallest drop zones used in World War II by US forces. While these two spaces enabled the assault, their small size, the buildings surrounding them, and the prevailing winds made this mission the most dangerous and highest jump casualty airborne operation of the war. Despite the casualties incurred by these features, the bombed-out buildings and debris on the drop zones arguably prevented even greater casualties because of the cover these provided once paratroopers were assembled on the ground. The intent of this discussion is to demonstrate how airborne operations are inherently contingent on geography and the challenges and opportunities the cultural landscape could pose during a military operation.Keywords: military geography, airborne operations, Corregidor, cultural landscape,terrain intelligenc