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Open Access Publications from the University of California

Scholarly Works (9 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2021)

As pH measurement technologies evolve and are increasingly used to study the ocean’s CO2 system, there is a need to assess the uncertainty of seawater pH measurements, particularly those based on the spectrophotometric method using an indicator dye, which is used to calibrate alternative pH measurement methods, including autonomous pH sensors. In this dissertation, I investigated methodological and instrumental contributions to uncertainty in spectrophotometric pH measurements, developed tools for their quality control, and evaluated their likely quality based on their consistency with other seawater CO2 parameters. The accuracy of seawater pH measurements has been questioned due to observations from open ocean cruises of a significant pH-dependent discrepancy between measured pH and pH calculated from dissolved inorganic carbon (CT) and total alkalinity (AT), using a thermodynamic model of seawater acid-base systems. Based on an analysis of high quality CO2 measurements on four open ocean cruises, I showed that a combination of plausible biases in the constants and assumptions used to calculate pH can explain the observed inconsistencies and that there is likely an unaccounted, possibly organic, contribution to the AT measured in the open ocean. Next, I developed methods for analyzing spectra to identify and possibly correct instrumental contributions to spectrophotometric pH measurement error, such as those that may arise from degradation of the spectrophotometer lamp. In another chapter, laboratory and chemical modeling experiments were conducted to evaluate how adjustments for effect of the indicator addition on the sample pH contribute to uncertainty in the final pH result. Assumptions about the indicator’s behavior can result in error in the pH correction, but is minor, except when using high dye concentrations in short pathlength cells. Finally, I evaluated the performance of pH measurements using impure m-cresol purple, which contains absorbing impurities that can bias pH measurements. Calibrated impure dye measurements can still be inconsistent with purified dye measurements depending on the assumptions about the impurity absorption behavior or the purity of the reference dye. This dissertation contributes to understanding of the uncertainty of spectrophotometric pH measurements and our ability to use ocean pH data to characterize the CO2 system.

    Cover page: Uncertainty of spectrophotometric pH measurements in seawater and implications for ocean carbon chemistry
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2019)
      • Article
      • Peer Reviewed
      UC Berkeley Previously Published Works (2016)
      Biologically mediated particulate organic and inorganic carbon (POC and PIC) export from surface waters is the principal determinant of the vertical oceanic distribution of pH and dissolved inorganic carbon and thus sets the conditions for air-sea exchange of CO2; exported organic matter also provides the energy fueling communities in the mesopelagic zone. However, observations are temporally and spatially sparse. Here we report the first hourly-resolved optically quantified POC and PIC sedimentation rate time series from an autonomous Lagrangian Carbon Flux Explorer (CFE), which monitored particle flux using an imaging optical sedimentation recorder (OSR) at depths below 140m in the Santa Cruz Basin, CA, in May 2012, and in January and March 2013. Highest POC vertical flux (∼ 100-240mmolCm-2d-1) occurred in January, when most settling material was millimeter- to centimeter-sized aggregates but when surface biomass was low; fluxes were ∼ 18 and ∼ 6mmolCm-2d-1, respectively, in March and May, under high surface biomass conditions. An unexpected discovery was that January 2013 fluxes measured by CFE were 20 times higher than that measured by simultaneously deployed surface-tethered OSR; multiple lines of evidence indicate strong undersampling of aggregates larger than 1mm in the latter case. Furthermore, the January 2013 CFE fluxes were about 10 times higher than observed during multiyear sediment trap observations in the nearby Santa Barbara and San Pedro basins. The strength of carbon export in biologically dynamic California coastal waters is likely underestimated by at least a factor of 3 and at times by a factor of 20.
        • Article
        • Peer Reviewed
        UC San Diego Previously Published Works (2014)
          Cover page: Augmenting the Biological Pump: The Shortcomings of Geoengineered Upwelling
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2019)
          This work presents the first direct evidence of multivalent binding between bone morphogenetic protein-2 (BMP-2) and cartilage oligomeric matrix protein (COMP) using high-resolution atomic force microscopy (AFM) imaging. AFM topographic images reveal the molecular morphology of COMP, a pentameric protein whose five identical monomer units bundle together at N-termini, extending out with flexible chains to C-termini. Upon addition of BMP-2, COMP molecules undergo conformational changes at the C-termini to enable binding with BMP-2 molecules. AFM enables local structural changes of COMP to be revealed upon binding various numbers, 1-5, of BMP-2 molecules. These BMP-2/COMP complexes exhibit very different morphologies from those of COMP: much more compact and thus less flexible. These molecular-level insights deepen current understanding of the mechanism of how the BMP-2/COMP complex enhances osteogenesis among osteoprogenitor cells, i.e., multivalent presentation of BMP-2 via the stable and relatively rigid BMP-2/COMP complex could form a lattice of interaction between multiple BMP-2 and BMP-2 receptors. These ligand-receptor clusters lead to fast initiation and sustained activation of the Smad signaling pathway, resulting in enhanced osteogenesis. This work is also of translational importance as the outcome may enable use of lower BMP-2 dosage for bone repair and regeneration.
            Cover page: Label-Free and Direct Visualization of Multivalent Binding of Bone Morphogenetic Protein‑2 with Cartilage Oligomeric Matrix Protein
            • Article
            • Peer Reviewed
            UC Davis Previously Published Works (2016)

            Study design

            The aim of this study is to test the effect of cartilage oligomeric matrix protein (COMP) on enhancing rhBMP-2 induced spinal fusion in a prospective 8-week interventional trial of spinal fusion in rats.

            Objective

            To determine whether the amount of bone morphogenetic protein-2 (BMP-2) required to achieve spinal fusion in a pre-clinical model can be reduced by the addition of COMP.

            Summary of background data

            BMPs are applied clinically at supraphysiological doses to promote spinal fusion by inducing osseous growth, but dose-related limitations include ectopic bone formation and local inflammatory reactions. COMP is a matricellular BMP-binding protein expressed during endochondral ossification and fracture healing. In vitro studies demonstrate enhanced activity of BMP bound to COMP. We hypothesized that BMP bound to COMP could achieve equivalent spinal fusion rates at lower doses and with fewer complications.

            Methods

            Posterolateral intertransverse process spinal fusion at L4 to L5 was performed in 36 Lewis rats. COMP (10 μg) was tested with or without "low-dose" rhBMP-2 (2 μg), and the results were compared with the "low-dose" (2 μg rhBMP-2) and "high-dose" (10 μg rhBMP-2) groups. All groups utilized insoluble collagen bone matrix carrier (ICBM). Fusion was evaluated by radiology, histology, and manual palpation. BMP release kinetics were evaluated in vitro.

            Results

            Fusion grading of microCT images demonstrated that the fusion rate with the COMP+LoBMP was statistically equivalent to HiBMP, and significantly better than LoBMP without COMP. These results were confirmed with radiographs and manual palpation. BMP release kinetics suggest that COMP increased local concentrations of BMP due to decreased growth factor retention on the scaffold.

            Conclusion

            COMP enhances BMP-induced bone formation, enabling lower doses of BMP to achieve the same level of spinal fusion. COMP may function by affecting the availability and biological presentation of BMP-2. A decrease of BMP-2 required for fusion may reduce dose-related adverse effects, surgical costs, and improve clinical outcomes.

            Level of evidence

            N/A.
              Cover page: Binding to COMP Reduces the BMP2 Dose for Spinal Fusion in a Rat Model
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2022)
              BACKGROUND: Continuous outpatient inotrope infusion therapy (COIIT) can be used as palliative or interim treatment in patients with advanced heart failure (AHF). Despite widespread use, there is a relative lack of data informing best practices. This study aimed to examine whether patterns of COIIT use differed by region and to explore whether observed differences influenced clinical outcomes. METHODS: Retrospective study of AHF patients receiving COIIT from May 2009 through June 2016. The primary outcome was regional difference, the secondary outcome was persistence (duration) on therapy. Cox proportional hazards model was used to calculate hazard ratios for treatment regimens. RESULTS: There were 3,286 patients, mean (SD) age 61.9 (14.4) years and 74.0% (2,433) male. Inotrope selection and beta blocker use varied by region by chi square (χ2 (21) = 166.9, p < 0.001). Persistence was greater on milrinone compared to dobutamine (HR (for discontinuation) 0.54, CI 0.41-0.70, p < 0.001). Concurrent beta-blocker was associated with greater persistence for patients receiving milrinone (HR 0.13, CI 0.08-0.20, p < 0.001) and dobutamine (HR 0.36, CI 0.18-0.71, p < 0.001). CONCLUSIONS: Patterns of COIIT use varied by region, and variations in use were associated with differences in clinical outcomes.
                Cover page: Geographic variation in the use of continuous outpatient inotrope infusion therapy and beta blockers.
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2023)

                Purpose

                To extend the MR MultiTasking-based Multidimensional Assessment of Cardiovascular System (MT-MACS) technique with larger spatial coverage and water-fat separation for comprehensive aortocardiac assessment.

                Methods

                MT-MACS adopts a low-rank tensor image model for 7D imaging, with three spatial dimensions for volumetric imaging, one cardiac motion dimension for cine imaging, one respiratory motion dimension for free-breathing imaging, one T2-prepared inversion recovery time dimension for multi-contrast assessment, and one T2*-decay time dimension for water-fat separation. Nine healthy subjects were recruited for the 3T study. Overall image quality was scored on bright-blood (BB), dark-blood (DB), and gray-blood (GB) contrasts using a 4-point scale (0-poor to 3-excellent) by two independent readers, and their interreader agreement was evaluated. Myocardial wall thickness and left ventricular ejection fraction (LVEF) were quantified on DB and BB contrasts, respectively. The agreement in these metrics between MT-MACS and conventional breath-held, electrocardiography-triggered 2D sequences were evaluated.

                Results

                MT-MACS provides both water-only and fat-only images with excellent image quality (average score = 3.725/3.780/3.835/3.890 for BB/DB/GB/fat-only images) and moderate to high interreader agreement (weighted Cohen's kappa value = 0.727/0.668/1.000/1.000 for BB/DB/GB/fat-only images). There were good to excellent agreements in myocardial wall thickness measurements (intraclass correlation coefficients [ICC] = 0.781/0.929/0.680/0.878 for left atria/left ventricle/right atria/right ventricle) and LVEF quantification (ICC = 0.716) between MT-MACS and 2D references. All measurements were within the literature range of healthy subjects.

                Conclusion

                The refined MT-MACS technique provides multi-contrast, phase-resolved, and water-fat imaging of the aortocardiac systems and allows evaluation of anatomy and function. Clinical validation is warranted.
                  Cover page: MR Multitasking‐based multi‐dimensional assessment of cardiovascular system (MT‐MACS) with extended spatial coverage and water‐fat separation
                  • Article
                  • Peer Reviewed
                  UC Davis Previously Published Works (2020)
                  This work reports the first direct observations of binding and complex formation between transforming growth factor beta 1 (TGF-β1) and cartilage oligomeric matrix protein (COMP) using high-resolution atomic force microscopy (AFM). Each COMP molecule consists of pentamers whose five identical monomeric units bundle at N-termini. From this central point, the five monomers' flexible arms extend outward with C-terminal domains at the distal ends, forming a bouquet-like structure. In commonly used buffer solutions, TGF-β1 molecules typically form homodimers (majority), double dimers (minority), and aggregates (trace amount). Mixing TGF-β1 and COMP leads to rapid binding and complex formation. The TGF-β1/COMP complexes contain one to three COMP and multiple TGF-β1 molecules. For complexes with one COMP, the structure is more compact and less flexible than that of COMP alone. For complexes with two or more COMP molecules, the conformation varies to a large degree from one complex to another. This is attributed to the presence of double dimers or aggregates of TGF-β1 molecules, whose size and multiple binding sites enable binding to more than one COMP. The number and location of individual TGF-β1 dimers are also clearly visible in all complexes. This molecular-level information provides a new insight into the mechanism of chondrogenesis enhancement by TGF-β1/COMP complexes, i.e., simultaneous and multivalent presentation of growth factors. These presentations help explain the high efficacy in sustained activation of the signaling pathway to augment chondrogenesis.
                    Cover page: Direct Visualization of the Binding of Transforming Growth Factor Beta 1 with Cartilage Oligomeric Matrix Protein via High-Resolution Atomic Force Microscopy
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