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Open Access Publications from the University of California

Scholarly Works (67 results)

  • Article
Conference Proceedings (2003)
    Cover page: Technology as an Economic Engine for Southern California
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2013)
    Small RNA molecules regulate eukaryotic gene expression during development and in response to stresses including viral infection. Specialized ribonucleases and RNA-binding proteins govern the production and action of small regulatory RNAs. After initial processing in the nucleus by Drosha, precursor microRNAs (pre-miRNAs) are transported to the cytoplasm, where Dicer cleavage generates mature microRNAs (miRNAs) and short interfering RNAs (siRNAs). These double-stranded products assemble with Argonaute proteins such that one strand is preferentially selected and used to guide sequence-specific silencing of complementary target mRNAs by endonucleolytic cleavage or translational repression. Molecular structures of Dicer and Argonaute proteins, and of RNA-bound complexes, have offered exciting insights into the mechanisms operating at the heart of RNA-silencing pathways.
      Cover page: Molecular Mechanisms of RNA InterferenceCreative Commons 'BY' version 4.0 license
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2018)
      CRISPR-based genome editing technologies are poised to enable countless new therapies to prevent, treat, or cure diseases with a genetic basis. However, the safe and effective delivery of genome editing enzymes represents a substantial challenge that must be tackled to enable the next generation of genetic therapies. In this Review, we summarize recent progress in developing enzymatic tools to combat genetic disease and examine current efforts to deliver these enzymes to the cells in need of correction. Viral vectors already in use for traditional gene therapy are being applied to enable in vivo CRISPR-based therapeutics, as are emerging technologies such as nanoparticle-based delivery of CRISPR components and direct delivery of preassembled RNA-protein complexes. Success in these areas will allow CRISPR-based genome editing therapeutics to reach their full potential.
        Cover page: The Promise and Challenge of In Vivo Delivery for Genome Therapeutics
        • Thesis
        • Peer Reviewed
        UC Santa Cruz Electronic Theses and Dissertations (2020)

        Southern hemisphere humpbacks whales are seasonally fasting mammals who concentrate foraging in summer when Southern Ocean waters are most productive, coincident when their primary prey, the Antarctic krill, are most accessible. To accumulate blubber energy stores necessary to fuel energetically costly migrations and breeding events during the winter fasting period, humpbacks optimize foraging behaviors to exploit the ephemeral distribution and behavior of their prey. While humpback foraging in fall, prior to a northward migration, is well described, foraging upon arrival to the foraging grounds in summer is poorly understood. Between 2010-2019 we deployed suction cup attached biologgers onto 83 adult humpbacks along the Western Antarctic Peninsula throughout the austral summer and early fall. Tags remained attached for 18 hours on average, recording high resolution motion, depth and audio of the animal. Using idiosyncratic motion signals, we manually detected feeding lunges for each deployment, yielding 33,246 total detected lunge events between depths of 0 – 461 meters. Our results did not support previous hypotheses of increased humpback foraging from summer to fall along the WAP, conversely, we found a 51% reduction in daily feeding rates over the same period. There was nearly continuous daylight during the early summer period where whales fed during all hours of the day, this changed such that foraging occurred mostly during nighttime hours in the fall. Changes in lunge depths observed over the season indicate that humpbacks track the diel vertical migrations of krill that appear to change over the foraging season. Our results provide novel information on seasonal changes in foraging behavior of humpback whales and demonstrate that these animals, contrary to nearly all other animals that seasonally fast, likely maximize their food intake immediately upon exiting the fasting period. More direct information on krill densities concurrent to whale foraging would allow quantification of food intake to better test this hypothesis.

          Cover page: Intra-seasonal variation in feeding rates and diel foraging behavior in a seasonally fasting mammal, the humpback whale (Megaptera novaeangliae)
          • Thesis
          • Peer Reviewed
          UC San Diego Electronic Theses and Dissertations (2018)

          The field of molecular dynamics is rapidly advancing as new theoretical techniques, software optimizations and computer architectures are unveiled seemingly daily. In this dissertation, I first review the best practices and recent developments in molecular dynamics based alchemical free energy calculations in the AMBER molecular dynamics suite. I then present a graphics processor enabled implementation of alchemical free energy calculations with performance 360 times that of the existing CPU implementation, while maintaining equivalent accuracy through the judicious use of a combination of floating point and fixed precision. Next, I discuss the application of constant pH molecular dynamics to investigate the role of water in beta secretase-1 catalysis. This protein has a known pH dependence and is a key target in the fight against Alzheimer’s Disease. I present a hypothesis for the role of the flap region in regulating beta secretase-1 catalysis. Finally, I have investigated benzene egress from the binding pocket of the L99A mutant of T4 lysozyme using accelerated molecular dynamics. It is found that benzene exits the binding pocket by a multistep process from the buried cavity to ultimate release through an opening between the F/G, H and I helices.

            Cover page: Improvements and Applications of Alchemical Free Energy, Constant pH and Accelerated Molecular Dynamics Calculations in the AMBER Molecular Dynamics Suite.
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2019)
            Beta-secretase 1 (BACE-1) is an aspartyl protease implicated in the overproduction of β-amyloid fibrils responsible for Alzheimer disease. The process of β-amyloid genesis is known to be pH dependent, with an activity peak between solution pH of 3.5 and 5.5. We have studied the pH-dependent dynamics of BACE-1 to better understand the pH dependent mechanism. We have implemented support for graphics processor unit (GPU) accelerated constant pH molecular dynamics within the AMBER molecular dynamics software package and employed this to determine the relative population of different aspartyl dyad protonation states in the pH range of greatest β-amyloid production, followed by conventional molecular dynamics to explore the differences among the various aspartyl dyad protonation states. We observed a difference in dynamics between double-protonated, mono-protonated, and double-deprotonated states over the known pH range of higher activity. These differences include Tyr 71-aspartyl dyad proximity and active water lifetime. This work indicates that Tyr 71 stabilizes catalytic water in the aspartyl dyad active site, enabling BACE-1 activity.
              • Thesis
              • Peer Reviewed
              UC San Diego Electronic Theses and Dissertations (2018)

              As technology moves forward with newer hardware, new computational techniques, and new algorithms, it is important for science to keep up with these advances. Without people maintaining code to the latest standards and modifying the underlying algorithms to closely match the shifting hardware landscape, scientific software easily becomes outdated and deprecated on the latest architectures. Similarly as technology advances and acapability increases so the underlying methods should be adapted, extended or replaced in order to fully realize the scientific potential of the underlying improvements in the hardware. This research focuses on developing faster and higher accuracy free energy prediction methods as well as the development of simulation techniques necessary to improve the sampling efficiency of all atom, condensed phase, molecular dynamics simulations on exa-scale computational hardware. Specifically, it will cover efforts to develop GPU accelerated thermodynamic integration algorithms, low level code optimization on next generation CPU architectures, techniques for more efficient 3D domain decomposition and work to explore more efficient sampling techniques. These methods have been implemented as part of this work within the Amber software package. Additionally, to show the accuracy and performance of the code, comparisons against previous Amber versions as well as existing free energy prediction packages such as Schrodinger's FEP+ will be analyzed and discussed.

                Cover page: Effective Utilization of Next Generation Hardware for Complex Molecular Dynamics Simulations
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2018)
                Timely implementation of principles of evidence-based public health (EBPH) is critical for bridging the gap between discovery of new knowledge and its application. Public health organizations need sufficient capacity (the availability of resources, structures, and workforce to plan, deliver, and evaluate the preventive dose of an evidence-based intervention) to move science to practice. We review principles of EBPH, the importance of capacity building to advance evidence-based approaches, promising approaches for capacity building, and future areas for research and practice. Although there is general agreement among practitioners and scientists on the importance of EBPH, there is less clarity on the definition of evidence, how to find it, and how, when, and where to use it. Capacity for EBPH is needed among both individuals and organizations. Capacity can be strengthened via training, use of tools, technical assistance, assessment and feedback, peer networking, and incentives. Modest investments in EBPH capacity building will foster more effective public health practice.
                  Cover page: Building Capacity for Evidence-Based Public Health: Reconciling the Pulls of Practice and the Push of Research
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2019)
                    Cover page: Evidence-Based Medicine and the American Thoracic Society Guidelines—Reply
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2021)

                    Objectives

                    There is wide variation in long-term acute care hospital (LTACH) use nationwide, the most intensive and expensive post-acute care setting, although appropriateness of use is uncertain. Therefore, we examined the appropriateness and reasons for transfer in a high-use region, and how Medicare criteria for LTACH payment identifies appropriate transfers.

                    Design

                    Multicenter retrospective observational cohort.

                    Setting and participants

                    Consecutive hospitalized Medicare beneficiaries transferred to an LTACH from 2017 to 2018 from an accountable care organization in Texas.

                    Methods

                    The primary outcome was clinical appropriateness of transfer ascertained by 2 physician reviewers. We abstracted patients' characteristics and primary reasons for transfer. We examined the positive predictive value (PPV) of meeting Medicare criteria for full LTACH payment [preceding intensive care unit (ICU) stay ≥3 days or prolonged mechanical ventilation] for identifying appropriate transfers, and how this differed if Medicare adopted an 8-day minimum ICU stay criterion recommended by the Medicare Payment Advisory Commission (MedPAC).

                    Results

                    Of 105 LTACH transfers, 33 (31.4%) were clinically appropriate. The most common reason among appropriate transfers was respiratory care (58%), but 42% had other indications. Inappropriate transfers most commonly were for wound care (28%), intravenous medication infusions (28%), or patient (17%) and physician preference (26%). The PPV for meeting Medicare LTACH payment criteria was 55%. The PPV improved to 77% if Medicare adopted the 8-day minimum ICU stay criterion, with only a modest absolute increase in appropriate transfers not meeting the more stringent criteria (12% to 17%).

                    Conclusions and implications

                    Two-thirds of LTACH transfers in a high-LTACH-use region are clinically inappropriate, and are most commonly transferred for wound care, intravenous infusions, or patient and physician preference. Medicare payment criteria modestly distinguished between appropriate and inappropriate transfers. Adoption of MedPAC's recommended 8-day minimum ICU stay criterion could safely reduce inappropriate transfers, although generalizability to low LTACH-use regions is uncertain.
                      Cover page: Appropriateness of Long-Term Acute Care Hospital Transfer: A Multicenter Study of Medicare ACO Beneficiaries
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