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Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences.
Colbran LL, Gamazon ER, Zhou D, Evans P, Cox NJ, Capra JA
(2019) Nat Ecol Evol :
Show Abstract · Added October 12, 2019
Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes' regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone.
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Impact of Acipimox Therapy on Free Fatty Acid Efflux and Endothelial Function in the Metabolic Syndrome: A Randomized Trial.
Aday AW, Goldfine AB, Gregory JM, Beckman JA
(2019) Obesity (Silver Spring) :
Show Abstract · Added October 2, 2019
OBJECTIVE - Insulin resistance is associated with increased lipolysis and elevated concentrations of free fatty acids (FFA), which in turn contribute to impaired vascular function. It was hypothesized that lowering FFA with acipimox, a nicotinic acid derivative that impairs FFA efflux, would improve endothelial function, measured by flow-mediated dilation (FMD), in individuals with metabolic syndrome.
METHODS - A total of 18 participants with metabolic syndrome and 17 healthy controls were enrolled and treated with acipimox 250 mg orally every 6 hours or placebo for 7 days in a randomized, double-blind, crossover trial.
RESULTS - Acipimox reduced FFA concentrations among individuals with metabolic syndrome to near normal levels (P = 0.01), but there was no change among healthy controls (P = 0.17). Acipimox did not improve endothelial-dependent FMD in either group (metabolic syndrome: P = 0.42; healthy controls: P = 0.16), although endothelial-independent nitroglycerin-mediated dilation among those with metabolic syndrome tended to increase (20.3%, P = 0.06). There were no changes in blood lipids or markers of inflammation following therapy. There was minimal correlation between change in FMD and baseline measures of BMI ( ρ = -0.09) or waist circumference ( ρ = -0.15).
CONCLUSIONS - In groups with normal or elevated baseline FFA, short-term reductions do not improve endothelial function assessed by FMD.
© 2019 The Obesity Society.
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Sample Preparation and Analysis of Single Cells Using High Performance MALDI FTICR Mass Spectrometry.
Yang B, Tsui T, Caprioli RM, Norris JL
(2020) Methods Mol Biol 2064: 125-134
Show Abstract · Added October 15, 2019
Imaging mass spectrometry is a powerful technology that combines the molecular measurements of mass spectrometry with the spatial information inherent to microscopy. This unique combination of capabilities is ideally suited for the analysis of metabolites and lipids from single cells. This chapter describes a methodology for the sample preparation and analysis of single cells using high performance MALDI FTICR MS. Using this approach, we are able to generate profiles of lipid and metabolite expression from single cells that characterize cellular heterogeneity. This approach also enables the detection of variations in the expression profiles of lipids and metabolites induced by chemical stimulation of the cells. These results demonstrate that MALDI IMS provides an insightful view of lipid and metabolite expression useful in the characterization of a number of biological systems at the single cell level.
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Women with overactive bladder exhibit more unhealthy toileting behaviors: a cross-sectional study.
Daily AM, Kowalik CG, Delpe SD, Kaufman MR, Dmochowski RR, Reynolds WS
(2019) Urology :
Show Abstract · Added September 16, 2019
OBJECTIVE - To determine whether women overactive bladder symptoms would report more frequent unhealthy toileting behaviors.
METHODS - A community-based sample of adult women were electronically recruited to complete the Toileting Behavior Scale and the International Consultation on Incontinence Questionnaire - Overactive Bladder module, as well as clinical and demographic questionnaires. The associations between overactive bladder and toileting behavior subscales were assessed as continuous variables using Spearman's rank correlation and as dichotomous variables with multivariable logistic regression.
RESULTS - Of the 6,562 adult women included in the analytic sample, 1,059 (16.1%) were classified as having overactive bladder. Of the toileting behavior subscales, convenience voiding had the highest, positive association with overactive bladder score (r = 0.301, p < 0.0001). On multivariable logistic regression, women with OAB were more likely to report behaviors of convenience voiding (OR 1.13, CI 1.11-1.15), delayed voiding (OR 1.05, CI 1.02-1.08), straining to void (OR 1.05, CI 1.03-1.07), and position preference (OR 1.13, CI 1.08-1.18).
CONCLUSIONS - OAB symptoms were associated with specific toileting behaviors of convenience voiding, delayed voiding, straining to void, and position preference. Further investigation is needed to determine if toileting behaviors are a risk factor for OAB or a compensatory adaptation to mitigate symptoms.
Copyright © 2019. Published by Elsevier Inc.
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Targeted mobilization of Lrig1 gastric epithelial stem cell populations by a carcinogenic type IV secretion system.
Wroblewski LE, Choi E, Petersen C, Delgado AG, Piazuelo MB, Romero-Gallo J, Lantz TL, Zavros Y, Coffey RJ, Goldenring JR, Zemper AE, Peek RM
(2019) Proc Natl Acad Sci U S A 116: 19652-19658
Show Abstract · Added September 27, 2019
-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within -infected gastric mucosa. Lineage tracing was induced in (Lrig1/YFP) mice that were uninfected or subsequently infected with or an isogenic mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the mutant. WT -infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic infection stimulates Lrig1-expressing progenitor cells in a -dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.
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Combining Salt Doping and Matrix Sublimation for High Spatial Resolution MALDI Imaging Mass Spectrometry of Neutral Lipids.
Dufresne M, Patterson NH, Norris JL, Caprioli RM
(2019) Anal Chem :
Show Abstract · Added October 15, 2019
The combination of sodium salt doping of a tissue section along with the sublimation of the matrix 2,5-dihydrobenzoic acid (DHB) was found to be an effective coating for the simultaneous detection of neutral lipids and phospholipids using matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry in positive ionization mode. Lithium, sodium, and potassium acetate were initially screened for their ability to cationize difficult to analyze neutral lipids such as cholesterol esters, cerebrosides, and triglycerides directly from a tissue section. The combination of sodium salt and DHB sublimation was found to be an effective cation/matrix combination for detection of neutral lipids. Further experimental optimizations revealed that sodium carbonate or sodium phosphate followed by DHB sublimation increases the signal intensity of the neutral lipids studied depending on the specific lipid family and tissue type by 10-fold to 140-fold compared with that of previously published methods. Application of sodium carbonate tissue doping and DHB sublimation resulted in crystal sizes ≤2 μm. We were thus able to image a mouse brain cerebellum at a high spatial resolution and detected 37 cerebrosides in a single run using a MALDI-TOF instrument. The combination of sodium doping and DHB sublimation offer a targeted and sensitive approach for the detection of neutral lipids that do not typically ionize well under normal MALDI conditions.
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Aerobic exercise training improves hepatic and muscle insulin sensitivity, but reduces splanchnic glucose uptake in obese humans with type 2 diabetes.
Gregory JM, Muldowney JA, Engelhardt BG, Tyree R, Marks-Shulman P, Silver HJ, Donahue EP, Edgerton DS, Winnick JJ
(2019) Nutr Diabetes 9: 25
Show Abstract · Added September 3, 2019
BACKGROUND - Aerobic exercise training is known to have beneficial effects on whole-body glucose metabolism in people with type 2 diabetes (T2D). The responses of the liver to such training are less well understood. The purpose of this study was to determine the effect of aerobic exercise training on splanchnic glucose uptake (SGU) and insulin-mediated suppression of endogenous glucose production (EGP) in obese subjects with T2D.
METHODS - Participants included 11 obese humans with T2D, who underwent 15 ± 2 weeks of aerobic exercise training (AEX; n = 6) or remained sedentary for 15 ± 1 weeks (SED; n = 5). After an initial screening visit, each subject underwent an oral glucose load clamp and an isoglycemic/two-step (20 and 40 mU/m/min) hyperinsulinemic clamp (ISO-clamp) to assess SGU and insulin-mediated suppression of EGP, respectively. After the intervention period, both tests were repeated.
RESULTS - In AEX, the ability of insulin to suppress EGP was improved during both the low (69 ± 9 and 80 ± 6% suppression; pre-post, respectively; p < 0.05) and high (67 ± 6 and 82 ± 4% suppression, respectively; p < 0.05) insulin infusion periods. Despite markedly improved muscle insulin sensitivity, SGU was reduced in AEX after training (22.9 ± 3.3 and 9.1 ± 6.0 g pre-post in AEX, respectively; p < 0.05).
CONCLUSIONS - In obese T2D subjects, exercise training improves whole-body glucose metabolism, in part, by improving insulin-mediated suppression of EGP and enhancing muscle glucose uptake, which occur despite reduced SGU during an oral glucose challenge.
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Physical Activity and Stress Incontinence in Women.
Chisholm L, Delpe S, Priest T, Reynolds WS
(2019) Curr Bladder Dysfunct Rep 14: 174-179
Show Abstract · Added September 16, 2019
Purpose of Review - This review aims to discuss the current literature addressing associations between physical activity and stress urinary incontinence in women.
Recent Findings - Multiple cross-sectional studies utilize survey questionnaires to determine prevalence of stress urinary incontinence, impact of various types and intensities of physical activity on stress urinary incontinence, and explain differences in urinary symptoms among active women.
Summary - Although there is evidence for increased rates of stress incontinence among women who are physically active, pathophysiology is not fully understood and there is a need for additional research exploring changes to the pelvic floor during exercise. Future research focusing on the mechanism in which physical activity contributes to urinary symptoms can guide development of primary preventions for stress urinary incontinence.
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Detrusor underactivity in women: A current understanding.
Hartigan SM, Reynolds WS, Dmochowski RR
(2019) Neurourol Urodyn :
Show Abstract · Added September 16, 2019
AIMS - To examine the current understanding and management of detrusor underactivity (DUA) and underactive bladder (UAB) in women.
METHODS - A review of the current literature was performed with a specific focus on new management strategies and treatment options for women with DUA and UAB.
RESULTS - DUA has become an area of increased interest in recent years. Affecting up to 45% of older women undergoing urodynamic evaluation for non-neurogenic lower urinary tract symptoms, DUA is common. There are a variety of possible etiologies including neurogenic or myogenic dysfunction. As there is currently no cure for DUA and no way to restore the ability of the detrusor muscle to contract, management of DUA in women is mostly focused on effective bladder drainage by urinary catheterization. Clean intermittent catheterization is the gold standard for bladder drainage however for a variety of reasons, women with DUA often are managed with indwelling urethral catheter or suprapubic tube. Medications, sacral neuromodulation, and the inFlow urinary prosthesis are also treatment alternatives or additions to catheterization. Novel therapies using stem cells and gene therapy are also under investigation for the treatment of DUA and UAB.
CONCLUSIONS - DUA is likely more prevalent than recognized and undertreated in women. It is vital that further research in treatment options beyond catheterization be developed for these patients to offer patients a variety of treatment options.
© 2019 Wiley Periodicals, Inc.
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