Review: quantifying mitochondrial dysfunction in complex diseases of aging.

There is accumulating evidence that mitochondrial respiratory malfunction is associated with aging-associated complex diseases. However, progress in our understanding of these diseases has been hampered by the sensitivity and throughput of systems employed to quantify dysfunction and inherent limitations of the biological systems studied. In this review, we describe and contrast two methodologies that have been developed for measuring mitochondrial function to address the need for improved sensitivity and increased throughput.

TcdB from hypervirulent Clostridium difficile exhibits increased efficiency of autoprocessing.

TcdB, an intracellular bacterial toxin that inactivates small GTPases, is a major Clostridium difficile virulence factor. Recent studies have found that TcdB produced by emerging/hypervirulent strains of C. difficile is more potent than TcdB from historical strains, and in the current work, studies were performed to investigate the underlying mechanisms for this change in TcdB toxicity.

Serum amyloid A protects murine macrophages from lethal toxin-mediated death.

Lethal toxin, a key virulence factor produced by Bacillus anthracis, induces cell death, in part by disrupting numerous signaling pathways, in mouse macrophages. However, exposure to sublethal doses of lethal toxin allows some cells to survive. Because these pro-survival signaling events occur within a few hours after exposure to sublethal doses, we hypothesized that acute phase proteins might influence macrophage survival.

Immunogenicity and safety of re-exposure to recombinant human thrombin in surgical hemostasis.

Background: This Phase 4, open-label study evaluated the immunogenicity and safety of a second exposure to recombinant human thrombin (rThrombin) in adult patients with previous exposure to rThrombin.

Study Design: Topical rThrombin was applied as a hemostatic aid during a surgical procedure (day 1). Adverse events and clinical laboratory abnormalities were monitored to day 29 (study end).

Differential inflammatory responses triggered by toxic small molecules.

Purpose: The aim of this study is to determine whether exposure to hazardous chemicals alters chemokine or cytokine production in macrophages and link these events to changes in intracellular signaling pathways and activation of specific gene promoters.

Methods: RAW 264.7 mouse macrophages were treated with selected toxic industrial chemicals (TICs) and examined for changes in immune function.

Regulation of anthrax toxin-specific antibody titers by natural killer T cell-derived IL-4 and IFNγ.

Activation of Natural Killer-like T cells (NKT) with the CD1d ligand α-GC leads to enhanced production of anthrax toxin protective Ag (PA)-neutralizing Abs, yet the underlying mechanism for this adjuvant effect is not known. In the current study we examined the role of Th1 and Th2 type responses in NKT-mediated enhancement of antibody responses to PA. First, the contribution of IL-4 and IFNγ to the production of PA-specific toxin-neutralizing Abs was examined.

Changing practice to improve patient safety and quality of care in perinatal medicine.

Despite an increased focus on the quality and safety of care, the United States health care system does not reliably deliver safe, high-quality care for all women and infants. In many cases, a gap still exists between best evidence and routine practice and pregnant women and neonates continue to experience preventable harm. Effective change strategies targeting individuals, groups or teams, organizations, and the larger system or environment have been used in the setting of perinatal care to improve quality and safety.

Mitochondrial DNA variants in Drosophila melanogaster are expressed at the level of the organismal phenotype.

A plethora of experimental studies use mtDNA as a marker of demographic processes without questioning the possibility that selection may bias their interpretations. We studied four lines of Drosophila melanogaster that have a standardized nuclear DNA but variable mtDNA. We completed the sequencing of the mitochondrial genomes (excluding the A+T rich region) and compiled the differences.

Glycogen synthase kinase 3 activation is important for anthrax edema toxin-induced dendritic cell maturation and anthrax toxin receptor 2 expression in macrophages.

Anthrax edema toxin (ET) is one of two binary toxins produced by Bacillus anthracis that contributes to the virulence of this pathogen. ET is an adenylate cyclase that generates high levels of cyclic AMP (cAMP), causing alterations in multiple host cell signaling pathways. We previously demonstrated that ET increases cell surface expression of the anthrax toxin receptors (ANTXR) in monocyte-derived cells and promotes dendritic cell (DC) migration toward the lymph node-homing chemokine MIP-3β.

Association between inhibited binding of folic acid to folate receptor alpha in maternal serum and folate-related birth defects in Norway.

Background: Folic acid intake during pregnancy can reduce the risk of neural tube defects (NTDs) and perhaps also oral facial clefts. Maternal autoantibodies to folate receptors can impair folic acid binding. We explored the relationship of these birth defects to inhibition of folic acid binding to folate receptor α (FRα), as well as possible effects of parental demographics or prenatal exposures.

Bone mineral density in Hispanic women: a review of the literature with implications for promoting culturally relevant osteoporosis education.

Osteoporosis is a disease that primarily affects postmenopausal women of all ethnicities. Demographic projections indicate that the number of Hispanics over age 65 in the U.S.

Sumatriptan-naproxen sodium for menstrual migraine and dysmenorrhea: satisfaction, productivity, and functional disability outcomes.

Objective: To evaluate the impact of a sumatriptan/naproxen sodium combination tablet on patient satisfaction, productivity, and functional disability in menstrual migraine treated during the mild pain phase of a single menstrual migraine attack associated with dysmenorrhea.

Background: Menstrual migraineurs with dysmenorrhea represent a unique patient population not previously studied. When health outcomes end points are analyzed alongside traditional efficacy end points in migraine studies, a more comprehensive and robust understanding of the many factors that may influence patients' choice of and adherence to pharmacological treatments for migraine is observed.

Females with a mutation in a nuclear-encoded mitochondrial protein pay a higher cost of survival than do males in Drosophila.

Males and females age at different rates in a variety of species, but the mechanisms underlying the difference is not understood. In this study, we investigated sex-specific costs of a naturally occurring mildly deleterious deletion (DTrp85, DVal86) in cytochrome c oxidase subunit 7A (cox7A) in Drosophila simulans. We observed that females and males homozygous for the mutation had 30% and 26% reduced Cox activity, respectively, compared with wild type.

Adenomatous polyposis coli protein associates with C/EBP beta and increases Bacillus anthracis edema toxin-stimulated gene expression in macrophages.

The production of cAMP from Bacillus anthracis edema toxin (ET) activates gene expression in macrophages through a complex array of signaling pathways, most of which remain poorly defined. In this study, the tumor suppressor protein adenomatous polyposis coli (APC) was found to be important for the up-regulation of previously defined ET-stimulated genes (Vegfa, Ptgs2, Arg2, Cxcl2, Sdc1, and Cebpb). A reduction in the expression of these genes after ET exposure was observed when APC was disrupted in macrophages using siRNA or in bone marrow-derived macrophages obtained from C57BL/6J-Apc(Min) mice, which are heterozygous for a truncated form of APC.

Functional conservatism among Drosophila simulans flies experiencing different thermal regimes and mitochondrial DNA introgression.

Drosophila simulans possesses three different mitochondrial haplotypes (siI, II and III) that are nonrandomly geographically subdivided with a 3% interhaplogroup variation. The aim of this study was to determine whether perturbation of mitochondrial metabolism and ROS management by temperature variation and mtDNA introgression would influence the development of aerobic capacity and the intensity of oxidative stress in D. simulans at different ages.

Thermal sensitivity of mitochondrial functions in permeabilized muscle fibers from two populations of Drosophila simulans with divergent mitotypes.

In ectotherms, the external temperature is experienced by the mitochondria, and the mitochondrial respiration of different genotypes is likely to change as a result. Using high-resolution respirometry with permeabilized fibers (an in situ approach), we tried to identify differences in mitochondrial performance and thermal sensitivity of two Drosophila simulans populations with two different mitochondrial types (siII and siIII) and geographical distributions. Maximal state 3 respiration rates obtained with electrons converging at the Q junction of the electron transport system (ETS) differed between the mitotypes at 24°C.

Anthrax vaccination induced anti-lethal factor IgG: fine specificity and neutralizing capacity.

The efficacy biomarker of the currently licensed anthrax vaccine (AVA) is based on quantity and neutralizing capacity of anti-protective antigen (anti-PA) antibodies. However, animal studies have demonstrated that antibodies to lethal factor (LF) can provide protection against in vivo bacterial spore challenges. Improved understanding of the fine specificities of humoral immune responses that provide optimum neutralization capacity may enhance the efficacy of future passive immune globulin preparations to treat and prevent inhalation anthrax morbidity and mortality.

Ab initio calculations for industrial materials engineering: successes and challenges.

Computational materials science based on ab initio calculations has become an important partner to experiment. This is demonstrated here for the effect of impurities and alloying elements on the strength of a Zr twist grain boundary, the dissociative adsorption and diffusion of iodine on a zirconium surface, the diffusion of oxygen atoms in a Ni twist grain boundary and in bulk Ni, and the dependence of the work function of a TiN-HfO(2) junction on the replacement of N by O atoms. In all of these cases, computations provide atomic-scale understanding as well as quantitative materials property data of value to industrial research and development.

Pyridyl amides as potent inhibitors of T-type calcium channels.

A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.

Autoregulatory characteristics of a Bacillus anthracis serine/threonine kinase.

BA-Stk1 is a serine/threonine kinase (STK) expressed by Bacillus anthracis. In previous studies, we found that BA-Stk1 activity is modulated through dephosphorylation by a partner phosphatase, BA-Stp1. In this study, we identified critical phosphorylation regions of BA-Stk1 and determined the contributions of these phosphodomains to autophosphorylation and substrate phosphorylation.

Early life benefits and later life costs of a two amino acid deletion in Drosophila simulans.

Linking naturally occurring genotypic variation to the organismal phenotype is critical to our understanding of, and ability to, model biological processes such as adaptation to novel environments, disease, and aging. Rarely, however, does a simple mutation cause a single simple observable trait. Rather it is more common for a mutation to elicit an entangled web of responses.

Short-acting T-type calcium channel antagonists significantly modify sleep architecture in rodents.

A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety.

Temporal and geographical genetic variation in the amphipod Melita plumulosa (Crustacea: Melitidae): Link of a localized change in haplotype frequencies to a chemical spill.

Anthropogenic effects such as contamination affect the genetic structure of populations. This study examined the temporal and geographical patterns of genetic diversity among populations of the benthic crustacean amphipod Melita plumulosa in the Parramatta River (Sydney, Australia), following an industrial chemical spill. The spill of an acrylate/methacrylate co-polymer in naphtha solvent occurred in July 2006.