Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Population Health
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12264
Corrigendum: 1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function
This corrects the article DOI: 10.1038/srep45040.
PMID: 28548086
ISSN: 2045-2322
CID: 5584602
Proceedings of the National Academy of Sciences of the United States of America (PNAS). 2017:114(21):5455-5460.DOI: 10.1073/pnas.1611506114
Entropic forces drive self-organization and membrane fusion by SNARE proteins
SNARE proteins are the core of the cell's fusion machinery and mediate virtually all known intracellular membrane fusion reactions on which exocytosis and trafficking depend. Fusion is catalyzed when vesicle-associated v-SNAREs form trans-SNARE complexes ("SNAREpins") with target membrane-associated t-SNAREs, a zippering-like process releasing ∼65 kT per SNAREpin. Fusion requires several SNAREpins, but how they cooperate is unknown and reports of the number required vary widely. To capture the collective behavior on the long timescales of fusion, we developed a highly coarse-grained model that retains key biophysical SNARE properties such as the zippering energy landscape and the surface charge distribution. In simulations the ∼65-kT zippering energy was almost entirely dissipated, with fully assembled SNARE motifs but uncomplexed linker domains. The SNAREpins self-organized into a circular cluster at the fusion site, driven by entropic forces that originate in steric-electrostatic interactions among SNAREpins and membranes. Cooperative entropic forces expanded the cluster and pulled the membranes together at the center point with high force. We find that there is no critical number of SNAREs required for fusion, but instead the fusion rate increases rapidly with the number of SNAREpins due to increasing entropic forces. We hypothesize that this principle finds physiological use to boost fusion rates to meet the demanding timescales of neurotransmission, exploiting the large number of v-SNAREs available in synaptic vesicles. Once in an unfettered cluster, we estimate ≥15 SNAREpins are required for fusion within the ∼1-ms timescale of neurotransmitter release.
PMCID:5448213
PMID: 28490503
ISSN: 1091-6490
CID: 5494892
Midlife and Late-Life Vascular Risk Factors and White Matter Microstructural Integrity: The Atherosclerosis Risk in Communities Neurocognitive Study
BACKGROUND:Diffusion tensor imaging measures of white matter (WM) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established. Our study quantifies the association between vascular risk factors in midlife and late life with measures of late-life WM microstructural integrity. METHODS AND RESULTS/RESULTS:We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3-T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC-NCS). We quantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit (1987-1989, ages 44-65, midlife) and visit 5 of ARIC (2011-2013, ages 67-90, late life, concurrent with ARIC-NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit 5 for ARIC participants. We also considered whether these associations were independent of or modified by WM hyperintensity volumes. We found that elevated blood pressure in midlife and late life and elevated glucose in midlife, but not late life, were associated with worse late-life WM microstructural integrity. These associations were independent of the degree of WM hyperintensity, and the association between glucose and WM microstructural integrity appeared stronger for those with the least WM hyperintensity. There was little support for an adverse association between lipids and WM microstructural integrity. CONCLUSIONS:Hypertension in both midlife and late life and elevated glucose in midlife are related to worse WM microstructural integrity in late life.
PMCID:5524102
PMID: 28522676
ISSN: 2047-9980
CID: 5584592
Clinical journal of the American Society of Nephrology : CJASN. 2017:12(5):761-771.DOI: 10.2215/CJN.08560816
Urine Kidney Injury Biomarkers and Risks of Cardiovascular Disease Events and All-Cause Death: The CRIC Study
BACKGROUND AND OBJECTIVES/OBJECTIVE:CKD is an important risk factor for cardiovascular disease (CVD) and death. We investigated whether select urine kidney injury biomarkers were associated with higher risk of heart failure (HF), CVD, and death in persons with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:) all-cause death. RESULTS:d-glucosaminidase/Cr was associated with HF in continuous analyses (aHR per log SD higher 1.18 [95% confidence interval, 1.01 to 1.38]). Only KIM-1/Cr was independently associated with atherosclerotic CVD events (aHR per log SD higher 1.21 [95% confidence interval, 1.02 to 1.41]), whereas both KIM-1/Cr (quintile 5 versus quintile 1 aHR of 1.56 [95% confidence interval, 1.06 to 2.31]) and neutrophil gelatinase-associated lipocalin/Cr (quintile 5 versus quintile 1 aHR of 1.82 [95% confidence interval, 1.19 to 2.8]) were associated with all-cause death. CONCLUSIONS:Selected urine kidney injury biomarkers were independently associated with higher risk of HF, CVD events, and death in CRIC. Among the biomarkers examined, only KIM-1/Cr was associated with each outcome. Further work is needed to determine the utility of these biomarkers to improve risk prediction for these adverse outcomes.
PMCID:5477212
PMID: 28254771
ISSN: 1555-905x
CID: 5584552
Bidirectional relations between executive function and expressive vocabulary in kindergarten and first grade / Relaciones bidireccionales entre la función ejecutiva y el vocabulario expresivo en jardin de infantes y primer grado
: Research suggests that language predicts executive function (EF) in the preschool period; however, the relation between language and EF in the transition to formal schooling has not been previously examined. Given that language and EF are both important for school readiness, it is valuable to examine the ways in which they may be interrelated during the start of formal schooling. Research and theory suggest that expressive language in particular may be bidirectionally related to EF. To test this hypothesis, we analysed data from five- and six-year-old children (N = 347) who completed measures of expressive vocabulary and EF in the fall and spring of kindergarten and the fall of first grade. Path analysis revealed significant cross-lagged paths between EF and expressive vocabulary in kindergarten and from kindergarten into first grade, above and beyond stability in these constructs. The findings are discussed in relation to the current understanding of the relation between language and EF and the best ways in which to support and promote school readiness and early school achievement.
SCOPUS:85016130710
ISSN: 0210-9395
CID: 2806552
Frailty and Advanced Heart Failure in Older Adults
Purpose of Review Advances in medical therapy have resulted in a growing population of older adults with advanced heart failure. Frailty is a clinical syndrome that increases in prevalence with age and is highly prevalent in patients with heart failure. This paper reviews the complex relationship between frailty and advanced systolic heart failure in older adults, including the potential for reversal of frailty following advanced cardiac interventions. Recent Findings Frailty is predictive of adverse outcomes, including rehospitalization and mortality, in heart failure patients. Several small studies have shown that mechanical circulatory support can modify, and possibly reverse, functional impairments and the pathophysiologic changes associated with heart failure-related frailty. Summary Frailty is highly prevalent in patients with advanced heart failure and is a powerful prognostic marker. Routine frailty assessment could allow clinicians to define optimal patient-centered care strategies for older adult patients with advanced heart failure.
ISI:000400129100001
ISSN: 1932-9563
CID: 2617902
Transcatheter aortic valve replacement (TAVR) in older adults improves symptoms but not physical function [Meeting Abstract]
ISI:000402876300362
ISSN: 1532-5415
CID: 2611692
Building a Research Agenda to Support Patient Priority Care (PPC) [Meeting Abstract]
ISI:000402876300409
ISSN: 1532-5415
CID: 2611192
Risk Stratifying Older Heart Failure Patients in the Emergency Department [Meeting Abstract]
ISI:000402876300382
ISSN: 1532-5415
CID: 2611162
Testosterone Replacement Therapy and Risk of Favorable and Aggressive Prostate Cancer
Purpose The association between exposure to testosterone replacement therapy (TRT) and prostate cancer risk is controversial. The objective was to examine this association through nationwide, population-based registry data. Methods We performed a nested case-control study in the National Prostate Cancer Register of Sweden, which includes all 38,570 prostate cancer cases diagnosed from 2009 to 2012, and 192,838 age-matched men free of prostate cancer. Multivariable conditional logistic regression was used to examine associations between TRT and risk of prostate cancer (overall, favorable, and aggressive). Results Two hundred eighty-four patients with prostate cancer (1%) and 1,378 control cases (1%) filled prescriptions for TRT. In multivariable analysis, no association was found between TRT and overall prostate cancer risk (odds ratio [OR], 1.03; 95% CI, 0.90 to 1.17). However, patients who received TRT had more favorable-risk prostate cancer (OR, 1.35; 95% CI, 1.16 to 1.56) and a lower risk of aggressive prostate cancer (OR, 0.50; 95% CI, 0.37 to 0.67). The increase in favorable-risk prostate cancer was already observed within the first year of TRT (OR, 1.61; 95% CI, 1.10 to 2.34), whereas the lower risk of aggressive disease was observed after > 1 year of TRT (OR, 0.44; 95% CI, 0.32 to 0.61). After adjusting for previous biopsy findings as an indicator of diagnostic activity, TRT remained significantly associated with more favorable-risk prostate cancer and lower risk of aggressive prostate cancer. Conclusion The early increase in favorable-risk prostate cancer among patients who received TRT suggests a detection bias, whereas the decrease in risk of aggressive prostate cancer is a novel finding that warrants further investigation.
PMCID:5455459
PMID: 28447913
ISSN: 1527-7755
CID: 3540982
