ImAge quantitates aging and rejuvenation.

For efficient, cost-effective and personalized healthcare, biomarkers that capture aspects of functional, biological aging, thus predicting disease risk and lifespan more accurately and reliably than chronological age, are essential. We developed an imaging-based chromatin and epigenetic age (ImAge) that captures intrinsic age-related trajectories of the spatial organization of chromatin and epigenetic marks in single nuclei, in mice. We show that such trajectories readily emerge as principal changes in each individual dataset without regression on chronological age, and that ImAge can be computed using several epigenetic marks and DNA labeling.

Detection of Superheated Steam during Sterilization Using Biological Indicators.

Saturated steam (SS) is used for sterilizing many medical devices. Exposure to SS for appropriate temperature/time combinations creates a microbicidal environment that renders product sterile. Superheated steam (SHS) has been heated beyond its saturation point and is less microbicidal, compromising process efficacy.

Increased Incidence of Pseudotumor Cerebri Syndrome Among Users of Tetracycline Antibiotics.

Background: To determine whether the use of a tetracycline-class antibiotic is associated with an increased risk of developing pseudotumor cerebri syndrome (PTCS).

Methods: We identified patients in the University of Utah Health system who were prescribed a tetracycline-class antibiotic and determined what percentage of those individuals were subsequently diagnosed with PTCS secondary to tetracycline use. We compared this calculation to the number of patients with PTCS unrelated to tetracycline use.

Strategic partnerships for outreach and enrollment: Filling in insurance gaps for Florida's military children and families.

Military-provided health insurance does not adequately cover children with special needs and children of veterans. Medicaid and the Children's Health Insurance Program (CHIP) can help eliminate insurance gaps, if promoted within the military community. This manuscript describes a Military Outreach Program to educate and reach Florida military families about insurance.

Three classes of response elements for human PRC2 and MLL1/2-Trithorax complexes.

Polycomb group (PcG) and Trithorax group (TrxG) proteins are essential for maintaining epigenetic memory in both embryonic stem cells and differentiated cells. To date, how they are localized to hundreds of specific target genes within a vertebrate genome had remained elusive. Here, by focusing on short cis-acting DNA elements of single functions, we discovered three classes of response elements in human genome: Polycomb response elements (PREs), Trithorax response elements (TREs) and Polycomb/Trithorax response elements (P/TREs).

An Estimation of the Risk of Pseudotumor Cerebri among Users of the Levonorgestrel Intrauterine Device.

Because of a previous association of pseudotumor cerebri (PTC) with levonorgestrel, we wished to evaluate the use of levonorgestrel-eluting intrauterine devices ("levonorgestrel intrauterine systems", LNG-IUS) in our University of Utah and Rigshospitalet PTC patients. In our retrospective series, PTC prevalence was approximately 0.18% and 0.

Developing a Framework to Promote Children's Health Insurance Enrollment in Florida.

Florida Covering Kids & Families (FL-CKF) at the University of South Florida's Chiles Center for Healthy Mothers and Babies advocates for uninsured children and promotes outreach and enrollment in the state's children's health insurance program, Florida KidCare. FL-CKF facilitates the development of local coalitions to reach children and families throughout the state. Coalitions are provided with one-on-one training and a wide array of tools to increase effectiveness such as coalition-building resources, membership guides, and assistance in building strong local partnerships.

Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration.

To assess whether Tie2-mediated vascular stabilization ameliorates neovascular age-related macular degeneration (AMD), we investigated the impact of adeno-associated virus-mediated gene therapy with cartilage oligomeric matrix protein angiopoietin-1 (AAV2.COMP-Ang1) on choroidal neovascularization (CNV), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF) in a mouse model of the disease. We treated mice with subretinal injections of AAV2.

Multiple mechanisms in Pd(II)-catalyzed S(N)2' reactions of allylic alcohols.

Density functional calculations and experiments were used to examine mechanisms of Pd(II) catalyzed intramolecular cyclization and dehydration in acyclic and bicyclic monoallylic diols, a formal S(N)2' reaction. In contrast to the previously proposed syn-oxypalladation mechanism for acyclic monoallylic diols, calculations and experiments strongly suggest that hydrogen bonding templates a hydroxyl group and Pd addition across the alkene and provides a low energy pathway via anti-addition (anti-oxypalladation) followed by intramolecular proton transfer and anti-elimination of water. This anti-addition, anti-elimination pathway also provides a simple rationale for the observed stereospecificity.

MUC1* ligand, NM23-H1, is a novel growth factor that maintains human stem cells in a more naïve state.

We report that a single growth factor, NM23-H1, enables serial passaging of both human ES and iPS cells in the absence of feeder cells, their conditioned media or bFGF in a fully defined xeno-free media on a novel defined, xeno-free surface. Stem cells cultured in this system show a gene expression pattern indicative of a more "naïve" state than stem cells grown in bFGF-based media. NM23-H1 and MUC1* growth factor receptor cooperate to control stem cell self-replication.

The importance of hydrogen bonding to stereoselectivity and catalyst turnover in gold-catalyzed cyclization of monoallylic diols.

Density functional calculations and experiment were used to examine the mechanism, reactivity, and origin of chirality transfer in monophosphine Au-catalyzed monoallylic diol cyclization reactions. The lowest energy pathway for cyclization involves a two-step sequence that begins with intramolecular C-O bond formation by anti-addition of the non-allylic hydroxyl group to the Au-coordinated alkene followed by concerted hydrogen transfer/anti-elimination to liberate water. Concerted S(N)2'-type transition states were found to be significantly higher in energy.

Genome-wide polycomb target gene prediction in Drosophila melanogaster.

As key epigenetic regulators, polycomb group (PcG) proteins are responsible for the control of cell proliferation and differentiation as well as stem cell pluripotency and self-renewal. Aberrant epigenetic modification by PcG is strongly correlated with the severity and invasiveness of many types of cancers. Unfortunately, the molecular mechanism of PcG-mediated epigenetic regulation remained elusive, partly due to the extremely limited pool of experimentally confirmed PcG target genes.

Diversifying selective pressure on influenza B virus hemagglutinin.

Influenza B virus hemagglutinin (HA) is a major surface glycoprotein with frequent amino acid substitutions. However, the roles of antibody selection in the amino acid substitutions of HA were still poorly understood. In order to gain insights into this important issue, an analysis was conducted on a total of 271 HA1 sequences of influenza B virus strains isolated during 1940-2007.

Novel algorithms reveal streptococcal transcriptomes and clues about undefined genes.

Bacteria-host interactions are dynamic processes, and understanding transcriptional responses that directly or indirectly regulate the expression of genes involved in initial infection stages would illuminate the molecular events that result in host colonization. We used oligonucleotide microarrays to monitor (in vitro) differential gene expression in group A streptococci during pharyngeal cell adherence, the first overt infection stage. We present neighbor clustering, a new computational method for further analyzing bacterial microarray data that combines two informative characteristics of bacterial genes that share common function or regulation: (1) similar gene expression profiles (i.

4-aminophenylalanine and 4-aminocyclohexylalanine derivatives as potent, selective, and orally bioavailable inhibitors of dipeptidyl peptidase IV.

A novel series of 4-aminophenylalanine and 4-aminocyclohexylalanine derivatives were designed and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4). The phenylalanine series afforded compounds such as 10 that were potent and selective (DPP-4, IC(50)=28nM), but exhibited limited oral bioavailability. The corresponding cyclohexylalanine derivatives such as 25 afforded improved PK exposure and efficacy in a murine OGTT experiment.

Direct observation (NMR) of the efficacy of glucagon receptor antagonists in murine liver expressing the human glucagon receptor.

The demonstration of pharmacodynamic efficacy of novel chemical entities represents a formidable challenge in the early exploration of synthetic lead classes. Here, we demonstrate a technique to validate the biological efficacy of novel antagonists of the human glucagon receptor (hGCGR) in the surgically removed perfused liver prior to the optimization of the pharmacokinetic properties of the compounds. The technique involves the direct observation by (13)C NMR of the biosynthesis of [(13)C]glycogen from [(13)C]pyruvate via the gluconeogenic pathway.

Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor.

A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).

Novel HIV-1 protease inhibitors active against multiple PI-resistant viral strains: coadministration with indinavir.

HIV-1 protease inhibitors (PI) with an N-arylpyrrole moiety in the P(3) position afforded excellent antiviral potency and substantially improved aqueous solubility over previously reported variants. The rapid in vitro clearance of these compounds in human liver microsomes prompted oral coadministration with indinavir to hinder their metabolism by the cyctochrome P450 3A4 isozyme and allow for in vivo PK assessment.

HIV-1 protease inhibitors with picomolar potency against PI-resistant HIV-1 by modification of the P1' substituent.

Transposition of the pyridyl nitrogen from the P(3) substituent to the P(1)' substituent in HIV-1 protease inhibitors (PI) affords compounds such as 3 with an improved inhibitory profile against multiple P450 isoforms. These compounds also displayed increased potency, with 3 inhibiting viral spread (CIC(95)) at <8 nM for every strain of PI-resistant HIV-1 tested. The poor to modest bioavailability of these compounds may correlate in part to their aqueous solubility.

Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains.

Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.

Single nucleotide polymorphism seeking long term association with complex disease.

Successful investigation of common diseases requires advances in our understanding of the organization of the genome. Linkage disequilibrium provides a theoretical basis for performing candidate gene or whole-genome association studies to analyze complex disease. However, to constructively interrogate SNPs for these studies, technologies with sufficient throughput and sensitivity are required.

An endonuclease/ligase based mutation scanning method especially suited for analysis of neoplastic tissue.

Knowledge of inherited and sporadic mutations in known and candidate cancer genes may influence clinical decisions. We have developed a mutation scanning method that combines thermostable EndonucleaseV (Endo V) and DNA ligase. Variant and wild-type PCR amplicons are generated using fluorescently labeled primers, and heteroduplexed.