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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Santa Barbara Electronic Theses and Dissertations (2018)

The cohort model of lexical retrieval (Marslen-Wilson & Welsh 1978; Marslen-Wilson & Tyler 1980; Marslen-Wilson 1984, 1987), a theory of speech perception not traditionally applied to questions of historical linguistics, offers evidence that the point at which spoken words become unique within their lexicon is cognitively significant. This uniqueness point divides a

word into two regions which appear to be processed by different neural machinery. Historical linguistic research suggests that material which maintains meaningful contrasts is more resistant to reduction than material which does not (Blevins 2005; Blevins & Wedel 2009; Wedel, Jackson, & Kaplan 2013). Perhaps, then, the sublexical regions outlined by the cohort model, which differ in their ability to contrast words, are similarly affected by sound change unevenly distributed across the word. To examine the extent to which this difference in processing could relate to a difference in language change, this study uses the concept of the cohort model to bifurcate genetically-related words selected from eight Indo-European languages which feature uniqueness points within their respective lexicons. Through the comparison of phonological distance among these forms, operationalized as the Levenshtein distance (Levenshtein 1965) between phonemic representations, this analysis finds evidence for an asymmetrical distribution of sound change among cognates: within a word, sound change is more likely to occur after the point at which the word is distinct from all other words in the lexicon.

    Cover page: Cohort effects and asymmetrical word-level sound change
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2024)
    A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34+ hematopoietic stem and progenitor cells (HSPCs). This LVV contains locus control region cores expressing an anti-sickling βAS3-globin gene and two microRNA-adapted short hairpin RNA simultaneously targeting BCL11A and ZNF410 transcripts to maximally induce fetal hemoglobin (HbF) expression. This LVV induces high levels of anti-sickling hemoglobins (HbAAS3 + HbF), while concurrently decreasing sickle hemoglobin (HbS). The decrease in HbS and increased anti-sickling hemoglobin impedes deoxygenated HbS polymerization and red blood cell sickling at low vector copy per cell in transduced SCD patient CD34+ cells differentiated into erythrocytes. The dual alterations in red cell hemoglobins ameliorated the SCD phenotype in the SCD Berkeley mouse model in vivo. With high titer and enhanced transduction of HSPC at a low multiplicity of infection, this LVV will increase the number of patient doses of vector from production lots to decrease costs and help improve accessibility to gene therapy for SCD.
      Cover page: A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease.
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2021)
      To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
        Cover page: Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome
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