Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2015)

Ciliopathies, diseases that arise from defective ciliary function, afflict many tissues to various degrees. However the genetic basis underlying the range of phenotypes is unclear. Two protein complexes at the ciliary transition zone are linked to the ciliopathies Meckel syndrome (MKS) and nephronophthisis (NPHP); the BBSome is a third complex linked to Bardet-Biedl syndrome. To model the complex inheritance of ciliopathies, we made double mutants between MKS, NPHP, and BBS genes, focusing on tctn-1, the C. elegans ortholog of the Tectonic family of ciliopathy genes. Loss of TCTN-1 or TCTN-1 and an MKS complex component does not disrupt ciliary structure. In contrast, loss of TCTN-1 and an NPHP complex component disrupts ciliary structure, as does loss of an NPHP and a BBS complex component. Thus, the MKS, NPHP and BBS complexes have overlapping ciliogenic functions in C. elegans. Similar genetic interactions that modify ciliopathy phenotypes are conserved in mammals, as mice mutant for both an MKS family gene and an NPHP family gene display exacerbated phenotypes compared to single mutants. Tctn1 and Bbs1 also show a synthetic genetic interaction in mammals. Together, our data support the hypothesis that multiple mutations within an individual organism may explain the expressivity observed in ciliopathy patients.

In addition, we investigated the role of Odr4 in mammals, a gene that is required for the localization of GPCRs to cilia in C. elegans. Preliminary studies demonstrate that Odr4 is required for embryonic development and binds to the Ufm1-specific protease, UfSP2.

    Cover page: Conservation and Divergence of Genetic Interactions and Functions Regulating Cilia and Embryogenesis
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2015)
    Reporting recently in Nature Cell Biology, Lu et al. (2015) identify two Eps15-homology-domain-containing proteins as critical effectors of ciliary vesicle formation, an early event in ciliogenesis. Functional dissection reveals that one of them works to convert small vesicles associated with mother centriole distal appendages into a larger ciliary vesicle.
      Cover page: Ciliary Vesicle Formation: A Prelude to Ciliogenesis
      • Article
      • Peer Reviewed
      UC Davis Previously Published Works (2016)

      Objectives

      To determine whether lifestyle factors, measured late in life, could compress the disabled period toward the end of life.

      Design

      Community-based cohort study of older adults followed from 1989 to 2015.

      Setting

      Four U.S. communities.

      Participants

      Community-living men and women aged 65 and older (N = 5,248, mean age 72.7 ± 5.5, 57% female, 15.2% minority) who were not wheelchair dependent and were able to give informed consent at baseline.

      Measurements

      Multiple lifestyle factors, including smoking, alcohol consumption, physical activity, diet, body mass index (BMI), social networks, and social support, were measured at baseline. Activities of daily living (ADLs) were assessed at baseline and throughout follow-up. Years of life (YoL) was defined as years until death. Years of able life (YAL) was defined as years without any ADL difficulty. YAL/YoL%, the proportion of life lived able, was used to indicate the relative compression or expansion of the disabled period.

      Results

      The average duration of disabled years was 4.5 (out of 15.4 mean YoL) for women and 2.9 (out of 12.4 mean YoL) for men. In a multivariable model, obesity was associated with 7.3 percentage points (95% confidence interval (CI) = 5.4-9.2) lower YAL/YoL% than normal weight. Scores in the lowest quintile of the Alternate Healthy Eating Index were associated with a 3.7% (95% CI = 1.6-5.9) lower YAL/YoL% than scores in the highest quintile. Every 25 blocks walked in a week was associated with 0.5 percentage points (95% CI = 0.3-0.8) higher YAL/YoL%.

      Conclusion

      The effects of healthy lifestyle factors on the proportion of future life lived free of disability indicate that the disabled period can be compressed, given the right combination of these factors.
        Cover page: Can a Healthy Lifestyle Compress the Disabled Period in Older Adults?
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2014)

        Objectives

        To determine the contribution of gradations of subclinical vascular disease (SVD) to the likelihood of longer survival and to determine what allows some individuals with SVD to live longer.

        Design

        Cohort study.

        Setting

        Cardiovascular Health Study.

        Participants

        Individuals born between June 30, 1918, and June 30, 1921 (N = 2,082; aged 70-75 at baseline (1992-93)).

        Measurements

        A SVD index was scored as 0 for no abnormalities, 1 for mild abnormalities, and 2 for severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as 80 and younger, 81 to 84, 85 to 89, and 90 and older.

        Results

        A 1-point lower SVD score was associated with 1.22 greater odds (95% confidence interval = 1.14-1.31) of longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction between kidney function, smoking, and C-reactive protein and SVD; the association between SVD and longer survival appeared to be modestly greater in persons with poor kidney function, inflammation, or a history of smoking.

        Conclusion

        A lower burden of SVD is associated with longer survival, independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and promote longer survival.
          Cover page: Subclinical Vascular Disease Burden and Longer Survival
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2014)

          Background

          Advanced glycation endproducts are biologically active compounds that accumulate in disordered metabolism and normal aging. Carboxymethyl-lysine (CML), a ubiquitous human advanced glycation endproduct, has been associated with age-related conditions and mortality. Our objective was to ascertain the relationship between CML and geriatric outcomes (disability and frailty) in a large cohort of older men and women.

          Methods

          In 1996-1997, serum CML was measured in 3,373 Cardiovascular Health Study participants (mean age 78.1 ± 4.8 years). Disability, defined as difficulty in any of six activities of daily living, was assessed every 6-12 months for 14 years. Frailty was defined according to five standard criteria at the 1996-1997 visit. Cox proportional hazard models estimated the relationship between CML and incident disability (N = 2,643). Logistic regression models estimated the relationship between CML and prevalent frailty.

          Results

          Adjusting for multiple potential confounders, higher CML was associated with incident disability (hazard ratio per standard deviation [225 ng/mL] increase: 1.05, 95% CI 1.01-1.11). In men, odds of frailty increased with higher CML values (odds ratio = 1.30 per standard deviation, 95% CI 1.14-1.48), but the relationship was attenuated by adjustment for cognitive status, kidney function, and arthritis. CML was not associated with frailty in women.

          Conclusions

          Higher serum CML levels in late life are associated with incident disability and prevalent frailty. Further work is needed to understand CML's value as a risk stratifier, biomarker, or target for interventions that promote healthy aging.
            Cover page: Serum Carboxymethyl-Lysine, Disability, and Frailty in Older Persons: The Cardiovascular Health Study
            Top