ABSTRACT
Once a patient is in septic shock, survival rates drop by 7.6% for every hour of delay in antibiotic therapy. Biomarkers based on the molecular mechanism of sepsis are important for timely diagnosis and triage. Here, we study the potential roles of a panel of cellular and viral miRNAs as sepsis biomarkers. We performed genome-wide microRNA (miRNA) expression profiling in leukocytes from septic patients and nonseptic controls, combined with quantitative RT-PCR in plasmas from two cohorts of septic patients, two cohorts of nonseptic surgical patients and healthy volunteers. Enzyme-linked immunosorbent assay, miRNA transfection and chromatin immunoprecipitation were used to study the effects of Kaposi sarcoma herpes virus (KSHV) miRNAs on interleukin's secretion. Differences related to sepsis etiology were noted for plasma levels of 10 cellular and 2 KSHV miRNAs (miR-K-10b and miR-K-12-12*) between septic and nonseptic patients. All the sepsis groups had high KSHV miRNAs levels compared with controls; Afro-American patients had higher levels of KSHV-miR-K12-12* than non-Afro-American patients. Both KSHV miRNAs were increased on postoperative day 1, but returned to baseline on day 7; they acted as direct agonists of Toll-like receptor 8 (TLR8), which might explain the increased secretion of the IL-6 and IL-10. Cellular and KSHV miRNAs are differentially expressed in sepsis and early postsurgical patients and may be exploited for diagnostic and therapeutic purposes. Increased miR-K-10b and miR-K12-12* are functionally involved in sepsis as agonists of TLR8, forming a positive feedback that may lead to cytokine dysregulation.
Subject(s)
Herpesvirus 8, Human/genetics , MicroRNAs/genetics , Sarcoma, Kaposi/genetics , Sepsis/genetics , Toll-Like Receptor 8/genetics , Wounds and Injuries/genetics , APACHE , Black or African American , Aged , Case-Control Studies , Feedback, Physiological , Female , Gene Expression Profiling , Gene Expression Regulation , Humans , Interleukin-6/blood , Interleukin-6/genetics , Interleukin-8/blood , Interleukin-8/genetics , Leukocytes, Mononuclear/metabolism , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology , Male , MicroRNAs/blood , Middle Aged , Sarcoma, Kaposi/blood , Sarcoma, Kaposi/ethnology , Sarcoma, Kaposi/mortality , Sepsis/blood , Sepsis/ethnology , Sepsis/mortality , Signal Transduction , Survival Analysis , Toll-Like Receptor 8/blood , Wounds and Injuries/blood , Wounds and Injuries/ethnology , Wounds and Injuries/mortalitySubject(s)
Embolism/etiology , Foreign Bodies/complications , Heart Diseases/etiology , Polymethyl Methacrylate , Postoperative Complications/etiology , Spinal Fractures/surgery , Embolism/diagnostic imaging , Female , Foreign Bodies/diagnostic imaging , Heart Diseases/diagnostic imaging , Humans , Middle Aged , Postoperative Complications/diagnostic imaging , Radiography , Spinal Fractures/diagnostic imaging , Vertebroplasty/adverse effectsABSTRACT
An investigation into the endo/exo selectivity and pi-diastereofacial selectivity of ester-tethered intramolecular Diels-Alder reactions is reported. High levels of exo selectivity are realized with terminally substituted dienophiles, and high lk pi-diastereofacial selectivities are induced by the presence of a bulky dioxolanyl substituent at the allylic position of the tether. Precursors 19S, 20S, and 21S, readily prepared from glucose, provide densely functionalized bicyclic lactones of predictable stereochemistry in high yields in enantiomerically pure form upon thermolysis at 110 degrees C. B3LYP/6-31G(d) theory provides good descriptions of transition structures for these reactions and allows an understanding of the formation of the major cycloadducts.
ABSTRACT
Sensitised excitation of the DMN[3]DCME donor[bridge]acceptor system allows population of a triplet CT state with a microsecond lifetime in polar solvents. This is more than five orders of magnitude longer than the lifetime of the corresponding singlet CT state which is populated exclusively upon direct excitation. The picture indicates the spin-forbidden nature of the charge recombination between the acceptor (red) to donor (green) moieties.
ABSTRACT
Theoretical investigations of the transition structures of additions and cycloadditions reveal details about the geometries of bond-forming processes that are not directly accessible by experiment. The conformational analysis of transition states has been developed from theoretical generalizations about the preferred angle of attack by reagents on multiple bonds and predictions of conformations with respect to partially formed bonds. Qualitative rules for the prediction of the stereochemistries of organic reactions have been devised, and semi-empirical computational models have also been developed to predict the stereoselectivities of reactions of large organic molecules, such as nucleophilic additions to carbonyls, electrophilic hydroborations and cycloadditions, and intramolecular radical additions and cycloadditions.