Faculty Bibliography

Patients with complex chronic diseases usually must make multiple lifestyle changes to limit and manage their conditions. Numerous studies have shown that education alone is insufficient for engaging people in lifestyle behavior change, and that theory-based behavioral approaches also are necessary. However, even the most motivated individual may have difficulty with making lifestyle changes because of the information complexity associated with multiple behavior changes. The goal of the current Healthy Hearts and Kidneys study was to evaluate, different mobile health (mHealth)-delivered intervention approaches for engaging individuals with type 2 diabetes (T2D) and concurrent chronic kidney disease (CKD) in behavior changes. Participants were randomized to 1 of 4 groups, receiving: (1) a behavioral counseling, (2) technology-based self-monitoring to reduce information complexity, (3) combined behavioral counseling and technology-based self-monitoring, or (4) baseline advice. We will determine the impact of randomization assignment on weight loss success and 24-hour urinary excretion of sodium and phosphorus. With this report we describe the study design, methods, and approaches used to assure information security for this ongoing clinical trial. Clinical Trials.gov Identifier: NCT02276742.

BACKGROUND:The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer's disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain has yet to be methodically addressed. OBJECTIVE:To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. METHODS:We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. RESULTS:We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. DISCUSSION/CONCLUSIONS:Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.

Studies of host-associated and environmental microbiomes often incorporate longitudinal sampling or paired samples in their experimental design. Longitudinal sampling provides valuable information about temporal trends and subject/population heterogeneity, offering advantages over cross-sectional and pre-post study designs. To support the needs of microbiome researchers performing longitudinal studies, we developed q2-longitudinal, a software plugin for the QIIME 2 microbiome analysis platform (https://qiime2.org). The q2-longitudinal plugin incorporates multiple methods for analysis of longitudinal and paired-sample data, including interactive plotting, linear mixed-effects models, paired differences and distances, microbial interdependence testing, first differencing, longitudinal feature selection, and volatility analyses. The q2-longitudinal package (https://github.com/qiime2/q2-longitudinal) is open-source software released under a 3-clause Berkeley Software Distribution (BSD) license and is freely available, including for commercial use. IMPORTANCE Longitudinal sampling provides valuable information about temporal trends and subject/population heterogeneity. We describe q2-longitudinal, a software plugin for longitudinal analysis of microbiome data sets in QIIME 2. The availability of longitudinal statistics and visualizations in the QIIME 2 framework will make the analysis of longitudinal data more accessible to microbiome researchers.

Human microbiome is the collection of microbes living in and on the various parts of our body. The microbes living on our body in nature do not live alone. They act as integrated microbial community with massive competing and cooperating and contribute to our human health in a very important way. Most current analyses focus on examining microbial differences at a single time point, which do not adequately capture the dynamic nature of the microbiome data. With the advent of high-throughput sequencing and analytical tools, we are able to probe the interdependent relationship among microbial species through longitudinal study. Here, we propose a multivariate distance-based test to evaluate the association between key phenotypic variables and microbial interdependence utilizing the repeatedly measured microbiome data. Extensive simulations were performed to evaluate the validity and efficiency of the proposed method. We also demonstrate the utility of the proposed test using a well-designed longitudinal murine experiment and a longitudinal human study. The proposed methodology has been implemented in the freely distributed open-source R package and Python code.

Aims/UNASSIGNED:The transformation of the United Arab Emirates (UAE) from a semi-nomadic to a high income society has been accompanied by increasing rates of obesity and Type 2 diabetes mellitus. We examined if the AGE-RAGE (receptor for advanced glycation endproducts) axis is associated with obesity and diabetes mellitus in the pilot phase of the UAE Healthy Futures Study (UAEHFS). Methods/UNASSIGNED:517 Emirati subjects were enrolled and plasma/serum levels of AGE, carboxy methyl lysine (CML)-AGE, soluble (s)RAGE and endogenous secretory (es)RAGE were measured along with weight, height, waist and hip circumference (WC/HC), blood pressure, HbA1c, Vitamin D levels and routine chemistries. The relationship between the AGE-RAGE axis and obesity and diabetes mellitus was tested using proportional odds models and linear regression. Results/UNASSIGNED:After covariate adjustment, AGE levels were significantly associated with diabetes status. Levels of sRAGE and esRAGE were associated with BMI and levels of sRAGE were associated with WC/HC. Conclusions/UNASSIGNED:The AGE-RAGE axis is associated with diabetes status and obesity in this Arab population. Prospective serial analysis of this axis may identify predictive biomarkers of obesity and cardiometabolic dysfunction in the UAEHFS.

Proteasome inhibitors benefit patients with multiple myeloma and B cell-dependent autoimmune disorders but exert toxicity from inhibition of proteasomes in other cells. Toxicity should be minimized by reversible inhibition of the immunoproteasome β5i subunit while sparing the constitutive β5c subunit. Here we report β5i-selective inhibition by asparagine-ethylenediamine (AsnEDA)-based compounds and present the high-resolution cryo-EM structural analysis of the human immunoproteasome. Despite inhibiting noncompetitively, an AsnEDA inhibitor binds the active site. Hydrophobic interactions are accompanied by hydrogen bonding with β5i and β6 subunits. The inhibitors are far more cytotoxic for myeloma and lymphoma cell lines than for hepatocarcinoma or non-activated lymphocytes. They block human B-cell proliferation and promote apoptotic cell death selectively in antibody-secreting B cells, and to a lesser extent in activated human T cells. Reversible, β5i-selective inhibitors may be useful for treatment of diseases involving activated or neoplastic B cells or activated T cells.

BACKGROUND: Increasing evidence shows the importance of the commensal microbe Oxalobacter formigenes in regulating host oxalate homeostasis, with effects against calcium oxalate kidney stone formation, and other oxalate-associated pathological conditions. However, limited understanding of O. formigenes in humans poses difficulties for designing targeted experiments to assess its definitive effects and sustainable interventions in clinical settings. We exploited the large-scale dataset from the American Gut Project (AGP) to study O. formigenes colonization in the human gastrointestinal (GI) tract and to explore O. formigenes-associated ecology and the underlying host-microbe relationships. RESULTS: In >8000 AGP samples, we detected two dominant, co-colonizing O. formigenes operational taxonomic units (OTUs) in fecal specimens. Multivariate analysis suggested that O. formigenes abundance was associated with particular host demographic and clinical features, including age, sex, race, geographical location, BMI, and antibiotic history. Furthermore, we found that O. formigenes presence was an indicator of altered host gut microbiota structure, including higher community diversity, global network connectivity, and stronger resilience to simulated disturbances. CONCLUSIONS: Through this study, we identified O. formigenes colonizing patterns in the human GI tract, potential underlying host-microbe relationships, and associated microbial community structures. These insights suggest hypotheses to be tested in future experiments. Additionally, we proposed a systematic framework to study any bacterial taxa of interest to computational biologists, using large-scale public data to yield novel biological insights.

OBJECTIVE: Diabetic subjects are at higher risk of ischemic peripheral vascular disease. We tested the hypothesis that advanced glycation end products (AGEs) and their receptor (RAGE) block neoangiogenesis and blood flow recovery after hindlimb ischemia induced by femoral artery ligation through modulation of immune/inflammatory mechanisms. APPROACH AND RESULTS: Wild-type mice rendered diabetic with streptozotocin and subjected to unilateral femoral artery ligation displayed increased accumulation and expression of AGEs and RAGE in ischemic muscle. In diabetic wild-type mice, femoral artery ligation attenuated neoangiogenesis and impaired blood flow recovery, in parallel with reduced macrophage content in ischemic muscle and suppression of early inflammatory gene expression, including Ccl2 (chemokine [C-C motif] ligand-2) and Egr1(early growth response gene-1) versus nondiabetic mice. Deletion of Ager (gene encoding RAGE) or transgenic expression of Glo1 (reduces AGEs) restored adaptive inflammation, neoangiogenesis, and blood flow recovery in diabetic mice. In diabetes mellitus, deletion of Ager increased circulating Ly6Chi monocytes and augmented macrophage infiltration into ischemic muscle tissue after femoral artery ligation. In vitro, macrophages grown in high glucose display inflammation that is skewed to expression of tissue damage versus tissue repair gene expression. Further, macrophages grown in high versus low glucose demonstrate blunted macrophage-endothelial cell interactions. In both settings, these adverse effects of high glucose were reversed by Ager deletion in macrophages. CONCLUSIONS: These findings indicate that RAGE attenuates adaptive inflammation in hindlimb ischemia; underscore microenvironment-specific functions for RAGE in inflammation in tissue repair versus damage; and illustrate that AGE/RAGE antagonism may fill a critical gap in diabetic peripheral vascular disease.

The surgical robot, a costly technology for treatment of prostate cancer with equivocal marginal benefit, rapidly diffused into clinical practice. We sought to evaluate the role of teaching in the early adoption phase of the surgical robot. Teaching hospitals were the primary early adopters: data from the Healthcare Cost and Utilization Project showed that surgical robots were acquired by 45.5% of major teaching, 18.0% of minor teaching and 8.0% of non-teaching hospitals during the early adoption phase. However, teaching hospital faculty produced little comparative effectiveness research: By 2008, only 24 published studies compared robotic prostatectomy outcomes to those of conventional techniques. Just ten of these studies (41.7%) were more than minimally powered, and only six (25%) involved cross-institutional collaborations. In adopting the surgical robot, teaching hospitals fulfilled their mission to innovate, but failed to generate corresponding scientific evidence.