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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2022)

This thesis consists of an introduction, four main sections, and conclusion. The introduction gives a quick overview of communication channels and the basics of message passing algorithms. The first section focuses on the challenges of communicating over a fading channel using optical transmitters and receivers. Recognizing the limitations of a purely optical transmission system during environmental fades, the section proposes a hybrid RF-Optical system. The hybrid system consists of a high-throughput optical link closed by a Low Density Parity Check (LDPC) code alongside a separate RF link. The section proposes two different architectures for a hybrid system with varying degrees of mixing between the two links. For each architecture, their performance was evaluated during on a simulated fading channel and Additive White Gaussian Noise (AWGN) channel.The second section of this thesis capitalizes on the recent advancements in deep learning and applies it to the most popular LDPC decoding process known as message passing. The section first deconstructs the steps of message passing into nodes that can be interpreted as a type of Neural Network. Then, utilizing gradient descent methods including Adaptive Movement Estimation (ADAM), multiplicative weights for message passing are found and optimized. The key contribution of the section is the connection between these multiplicative weights and properties intrinsic to the LDPC code structure. By exploiting this relationship, a weight-sharing paradigm based on node degree is proposed, resulting in a Neural-Normalized MinSum (N-NMS) decoder which dramatically reduces the complexity of both training and implementation compared to typical neural network based decoders. The third section discusses a unique case study involving the Consultative Committee for Space Data Systems (CCSDS) 141.11-O-1 Line Product Code (LPC). Being such a short block-length code, two Maximum Likelihood (ML) decoders were evaluated against message passing decoders including MinSum (MS), Belief Propagation (BP), and Neural-Normalized MinSum (N-NMS). Analysis was carried out considering both the decoding performance and resulting hardware complexity of the decoders. Continuing on this, the fourth and final section aims to give additional insight as to why the N-NMS decoder performed so well on the LPC. This section proposes that the unique graph structure of the LPC allowed for key optimizations such as breaking length-4 cycles that the N-NMS training process capitalized on during its training.

    Cover page: Applications of LDPC Codes to RF-Optical Hybrid Systems and the Line Product Code
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2022)
    BACKGROUND: Patient selection for resuscitative endovascular balloon occlusion of the aorta (REBOA) has evolved during the last decade. A recent multicenter collaboration to implement the newest generation REBOA balloon catheter identified variability in patient selection criteria. The aims of this systematic review were to compare recent REBOA patient selection guidelines and to identify current areas of consensus and variability. METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a systematic review of clinical practice guidelines for REBOA patient selection in trauma. Published algorithms from 2015 to 2022 and institutional guidelines from a seven-center REBOA collaboration were compiled and synthesized. RESULTS: Ten published algorithms and seven institutional guidelines on REBOA patient selection were included. Broad consensus exists on REBOA deployment for blunt and penetrating trauma patients with non-compressible torso hemorrhage refractory to blood product resuscitation. Algorithms diverge on precise systolic blood pressure triggers for early common femoral artery access and REBOA deployment, as well as the use of REBOA for traumatic arrest and chest or extremity hemorrhage control. CONCLUSION: Although our convenience sample of institutional guidelines likely underestimates patient selection variability, broad consensus exists in the published literature regarding REBOA deployment for blunt and penetrating trauma patients with hypotension not responsive to resuscitation. Several areas of patient selection variability reflect individual practice environments. LEVEL OF EVIDENCE: Level 5, systematic review.
      Cover page: Systematic review to evaluate algorithms for REBOA use in trauma and identify a consensus for patient selection.
      • Article
      • Peer Reviewed
      Research Grants Program Office (RGPO) Funded Publications (2017)

      Rationale

      Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged patients with HF with genetic predispositions and comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impair overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with proregenerative molecules ex vivo is crucial for improving the therapeutic outcome in patients with HF.

      Objective

      To improve hCPC proliferation and migration responses that are critical for regeneration by targeting proregenerative P2Y2 nucleotide receptor (P2Y2R) activated by extracellular ATP and UTP molecules released following injury/stress.

      Methods and results

      c-Kit+ hCPCs were isolated from cardiac tissue of patients with HF undergoing left ventricular assist device implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2Y2R, in slow-growing hCPCs compared with fast growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y2R. Mechanistically, P2Y2R-induced proliferation and migration were dependent on activation of YAP (yes-associated protein)-the downstream effector of Hippo signaling pathway.

      Conclusions

      Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y2R-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling-a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2Y2R and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in patients with HF.
        Cover page: P2Y2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo SignalingCreative Commons 'BY' version 4.0 license
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2018)
        Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880.
          Cover page: Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell FateCreative Commons 'BY' version 4.0 license
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2018)
          Oversight of human subject research has evolved considerably since its inception. However, previous studies identified a lack of consistency of institutional review board (IRB) determination for the type of review required and whether informed consent is necessary, especially for prospective observational studies, which pose minimal risk of harm. We hypothesized that there is significant inter-institution variation in IRB requirements for the type of review and necessity of informed consent, especially for prospective observational trials without blood/tissue utilization. We also sought to describe investigators' and IRB members' attitudes toward the type of review and need for consent. Eastern Association for the Surgery of Trauma (EAST) and IRB members were sent an electronic survey on IRB review and informed consent requirement. We performed descriptive analyses as well as Fisher's exact test to determine differences between EAST and IRB members' responses. The response rate for EAST members from 113 institutions was 13.5%, whereas a convenience sample of IRB members from 14 institutions had a response rate of 64.4%. Requirement for full IRB review for retrospective studies using patient identifiers was reported by zero IRB member compared with 13.1% of EAST members (p=0.05). Regarding prospective observational trials without blood/tissue collection, 48.1% of EAST members reported their institutions required a full IRB review compared with 9.5% of IRB members (p=0.01). For prospective observational trials with blood/tissue collection, 80% of EAST members indicated requirement to submit a full IRB review compared with only 13.6% of IRB members (p<0.001). Most EAST members (78.6%) stated that informed consent is not ethically necessary in prospective observational trials without blood/tissue collection, whereas most IRB members thought that informed consent was ethically necessary (63.6%, p<0.001). There is significant variation in perception and practice regarding the level of review for prospective observational studies and whether informed consent is necessary. We recommend future interdisciplinary efforts between researchers and IRBs should occur to better standardize local IRB efforts.

          Level of evidence

          IV.
            Cover page: Variations in institutional review board processes and consent requirements for trauma research: an EAST multicenter surveyCreative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UC San Francisco Previously Published Works (2021)
            Cryo-electron microscopy (EM) requires molecular modeling to refine structural details from data. Ensemble models arrive at low free-energy molecular structures, but are computationally expensive and limited to resolving only small proteins that cannot be resolved by cryo-EM. Here, we introduce CryoFold - a pipeline of molecular dynamics simulations that determines ensembles of protein structures directly from sequence by integrating density data of varying sparsity at 3-5 Å resolution with coarse-grained topological knowledge of the protein folds. We present six examples showing its broad applicability for folding proteins between 72 to 2000 residues, including large membrane and multi-domain systems, and results from two EMDB competitions. Driven by data from a single state, CryoFold discovers ensembles of common low-energy models together with rare low-probability structures that capture the equilibrium distribution of proteins constrained by the density maps. Many of these conformations, unseen by traditional methods, are experimentally validated and functionally relevant. We arrive at a set of best practices for data-guided protein folding that are controlled using a Python GUI.
              Cover page: CryoFold: Determining protein structures and data-guided ensembles from cryo-EM density maps
              • Article
              • Peer Reviewed
              Research Grants Program Office (RGPO) Funded Publications (2021)

              Aims

              Telomere attrition in cardiomyocytes is associated with decreased contractility, cellular senescence, and up-regulation of proapoptotic transcription factors. Pim1 is a cardioprotective kinase that antagonizes the aging phenotype of cardiomyocytes and delays cellular senescence by maintaining telomere length, but the mechanism remains unknown. Another pathway responsible for regulating telomere length is the transforming growth factor beta (TGFβ) signalling pathway where inhibiting TGFβ signalling maintains telomere length. The relationship between Pim1 and TGFβ has not been explored. This study delineates the mechanism of telomere length regulation by the interplay between Pim1 and components of TGFβ signalling pathways in proliferating A549 cells and post-mitotic cardiomyocytes.

              Methods and results

              Telomere length was maintained by lentiviral-mediated overexpression of PIM1 and inhibition of TGFβ signalling in A549 cells. Telomere length maintenance was further demonstrated in isolated cardiomyocytes from mice with cardiac-specific overexpression of PIM1 and by pharmacological inhibition of TGFβ signalling. Mechanistically, Pim1 inhibited phosphorylation of Smad2, preventing its translocation into the nucleus and repressing expression of TGFβ pathway genes.

              Conclusion

              Pim1 maintains telomere lengths in cardiomyocytes by inhibiting phosphorylation of the TGFβ pathway downstream effectors Smad2 and Smad3, which prevents repression of telomerase reverse transcriptase. Findings from this study demonstrate a novel mechanism of telomere length maintenance and provide a potential target for preserving cardiac function.
                Cover page: Pim1 maintains telomere length in mouse cardiomyocytes by inhibiting TGFβ signallingCreative Commons 'BY' version 4.0 license
                • Article
                • Peer Reviewed
                UC Davis Previously Published Works (2022)
                Serial femtosecond crystallography (SFX) is a powerful technique that exploits X-ray free-electron lasers to determine the structure of macro-molecules at room temperature. Despite the impressive exposition of structural details with this novel crystallographic approach, the methods currently available to introduce crystals into the path of the X-ray beam sometimes exhibit serious drawbacks. Samples requiring liquid injection of crystal slurries consume large quantities of crystals (at times up to a gram of protein per data set), may not be compatible with vacuum configurations on beamlines or provide a high background due to additional sheathing liquids present during the injection. Proposed and characterized here is the use of an immiscible inert oil phase to supplement the flow of sample in a hybrid microfluidic 3D-printed co-flow device. Co-flow generation is reported with sample and oil phases flowing in parallel, resulting in stable injection conditions for two different resin materials experimentally. A numerical model is presented that adequately predicts these flow-rate conditions. The co-flow generating devices reduce crystal clogging effects, have the potential to conserve protein crystal samples up to 95% and will allow degradation-free light-induced time-resolved SFX.
                  Cover page: Co-flow injection for serial crystallography at X-ray free-electron lasers.
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