Synthesis and bacterial biofilm inhibition studies of ethyl N-(2-phenethyl) carbamate derivatives

This is the published version. Copyright Royal Society of ChemistryAn 88 member library based upon the marine bacterial metabolite ethyl N-(2-phenethyl) carbamate was evaluated for bacterial biofilm inhibition against a panel of medically relevant strains. These studies culminated in the discovery of a new class of molecules capable of inhibiting the formation of S. aureus biofilms with low micromolar IC50 values

A Feynman-Kac Formula for Anticommuting Brownian Motion

Motivated by application to quantum physics, anticommuting analogues of Wiener measure and Brownian motion are constructed. The corresponding Ito integrals are defined and the existence and uniqueness of solutions to a class of stochastic differential equations is established. This machinery is used to provide a Feynman-Kac formula for a class of Hamiltonians. Several specific examples are considered.Comment: 21 page

Concentration of Listeria monocytogenes in Skim Milk and Soft Cheese through Microplate Immunocapture

Microplate immunocapture is an inexpensive method for the concentration of foodborne pathogens using an antibody-coated microplate. The objective of this study was to determine the efficacy of microplate immunocapture as an alternative to traditional enrichment for concentrating Listeria monocytogenes to levels detectable with selective plating or real-time PCR. L. monocytogenes isolates serologically characterized as Type 1 (1/2a) and Type 4 (untypeable) were grown overnight and diluted to 100 to 106 colony-forming units (CFU)/mL. The isolates were used to optimize microplate immunocapture in tryptic soy broth with 0.6% yeast extract (TSBYE), skim milk, and queso fresco samples. Following microplate immunocapture, the bacteria were streaked onto polymyxin-acriflavine-LiCl-ceftazidime-aesculin-mannitol (PALCAM) agar, followed by incubation at 37 °C for 24 ± 2 h. The bacteria also underwent real-time polymerase chain reaction (PCR). The optimized microplate immunocapture method was tested in triplicate for its ability to capture L. monocytogenes in broth and food samples. Overall recovery rates for L. monocytogenes in food samples at cell populations of 100, 102, and 104 CFU/25 g using microplate immunocapture with real-time PCR were 88.9%, 94.4%, and 100%, respectively. Recovery in these matrices using microplate immunocapture with selective plating was comparatively lower, at 0%, 44.4%, and 100%, respectively. Conventional culture method showed 100% detection at each inoculation level. Microplate immunocapture combined with real-time PCR shows high potential to reduce the time required for detection, with concentration of L. monocytogenes to detectable levels within 1–4 h. The incorporation of a short enrichment step may improve recovery rates at low cell levels

The Addition of the Charlson Comorbidity Index to the GRACE Risk Prediction Index Improves Prediction of Outcomes in Acute Coronary Syndrome

Patients with cardiovascular disease have increased risk of poor outcomes when coexisting illnesses are present. Clinicians, administrators, and health services researchers utilize risk adjustment indices to stratify patients for various outcomes. The GRACE Risk Prediction Index (GRPI) was developed to risk stratify patients who experienced an acute coronary syndrome (ACS) event. GRPI does not account for the presence of comorbid conditions. The objective of this study was to compare the ability of the GRPI and the Charlson Comorbidity Index (CCI), used independently or combined, to predict mortality or secondary coronary events in patients admitted for ACS. Data were obtained from an academic health system's ACS registry. Outcomes included inpatient and 6-month postdischarge mortality and occurrence of secondary cardiovascular events or revascularization procedures. Logistic regression derived C statistics for CCI, GRPI, and CCI-GRPI predictive models for each outcome. Likelihood ratio tests determined the contribution of CCI when added to GRPI models. Complete data were available for 1202 patients. The GRPI model had the greatest C statistic when predicting inpatient mortality (0.73); the GRPI-CCI combined model C statistic was 0.81 when predicting death during the follow-up period; and C statistics for all 3 models were similar in predicting secondary events (0.57?0.60). The likelihood ratio analysis demonstrated that adding CCI to GRPI models was beneficial primarily for predicting secondary events. CCI is a useful addition to GRPI when predicting future cardiac-related events or mortality after an ACS event. It is an acceptable alternative to the GRPI model if data to construct GRPI are not available. (Population Health Management 2014;17:54?59)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140179/1/pop.2012.0117.pd

Structural and Functional Evaluation of Clinically Relevant Inhibitors of Steroidogenic Cytochrome P450 17A1

Human steroidogenic cytochrome P450 17A1 (CYP17A1) is a bifunctional enzyme that performs both hydroxylation and lyase reactions, with the latter required to generate androgens that fuel prostate cancer proliferation. The steroid abiraterone, the active form of the only CYP17A1 inhibitor approved by the Food and Drug Administration, binds the catalytic heme iron, nonselectively impeding both reactions and ultimately causing undesirable corticosteroid imbalance. Some nonsteroidal inhibitors reportedly inhibit the lyase reaction more than the preceding hydroxylase reaction, which would be clinically advantageous, but the mechanism is not understood. Thus, the nonsteroidal inhibitors seviteronel and orteronel and the steroidal inhibitors abiraterone and galeterone were compared with respect to their binding modes and hydroxylase versus lyase inhibition. Binding studies and X-ray structures of CYP17A1 with nonsteroidal inhibitors reveal coordination to the heme iron like the steroidal inhibitors. (S)-seviteronel binds similarly to both observed CYP17A1 conformations. However, (S)-orteronel and (R)-orteronel bind to distinct CYP17A1 conformations that differ in a region implicated in ligand entry/exit and the presence of a peripheral ligand. To reconcile these binding modes with enzyme function, side-by-side enzymatic analysis was undertaken and revealed that neither the nonsteroidal seviteronel nor the (S)-orteronel inhibitors demonstrated significant lyase selectivity, but the less potent (R)-orteronel was 8- to 11-fold selective for lyase inhibition. While active-site iron coordination is consistent with competitive inhibition, conformational selection for binding of some inhibitors and the differential presence of a peripheral ligand molecule suggest the possibility of CYP17A1 functional modulation by features outside the active site

Inhibition of Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa biofilm formation with a class of TAGE-triazole conjugates

This is the published version. Copyright Royal Society of ChemistryA chemically diverse library of TAGE-triazole conjugates was synthesized utilizing click chemistry on the TAGE scaffold. This library of small molecules was screened for anti-biofilm activity and found to possess the ability of inhibiting biofilm formation against Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa. One such compound in this library demonstrated the most potent inhibitory effect against Staphylococcus aureus biofilm formation that has been displayed by any 2-aminoimidazole derivative