Discovery and optimization of a series of liver X receptor antagonists

The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/β) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.     

Interactive effects of pH and temperature on the bacteriocin stability by response surface analysis

The combined influence of pH and temperature on bacteriocins produced by three lactic acid bacteria, Pediococcus pentosaceus MMZ26, Enterococcus faecium MMZ17 and Lactococcus lactis MMZ25, isolated from Tunisian traditional dry fermented meat was studied using a second order orthogonal factorial design and response-surface methodology (RSM). This method allows estimating the interactive effects of pH and temperature on the stability of each bacteriocin. The high heat stability of the three bacteriocins was demonstrated, with optimum values at light acidic pH around 5.0, temperature below 90 degrees C and short incubation times. This study contributes to a better understanding of relation between bacteriocins production and stability in order to enhance their, in situ, application as a food and feed biopreservative in fermented and/or heated food products.     

Interactive effects of pH and temperature on the bacteriocin stability by response surface analysis

The combined influence of pH and temperature on bacteriocins produced by three lactic acid bacteria, Pediococcus pentosaceus MMZ26, Enterococcus faecium MMZ17 and Lactococcus lactis MMZ25, isolated from Tunisian traditional dry fermented meat was studied using a second order orthogonal factorial design and response-surface methodology (RSM). This method allows estimating the interactive effects of pH and temperature on the stability of each bacteriocin. The high heat stability of the three bacteriocins was demonstrated, with optimum values at light acidic pH around 5.0, temperature below 90°C and short incubation times. This study contributes to a better understanding of relation between bacteriocins production and stability in order to enhance their, in situ, application as a food and feed biopreservative in fermented and/or heated food products.     

Understanding secondary injury

Secondary injury is a term applied to the destructive and self-propagating biological changes in cells and tissues that lead to their dysfunction or death over hours to weeks after the initial insult (the "primary injury"). In most contexts, the initial injury is usually mechanical. The more destructive phase of secondary injury is, however, more responsible for cell death and functional deficits. This subject is described and reviewed differently in the literature. To biomedical researchers, systemic and tissue-level changes such as hemorrhage, edema, and ischemia usually define this subject. To cell and molecular biologists, "secondary injury" refers to a series of predominately molecular events and an increasingly restricted set of aberrant biochemical pathways and products. These biochemical and ionic changes are seen to lead to death of the initially compromised cells and "healthy" cells nearby through necrosis or apoptosis. This latter process is called "bystander damage." These viewpoints have largely dominated the recent literature, especially in studies of the central nervous system (CNS), often without attempts to place the molecular events in the context of progressive systemic and tissue-level changes. Here we provide a more comprehensive and inclusive discussion of this topic.     

Chaperone receptors: guiding proteins to intracellular compartments

Despite mitochondria and chloroplasts having their own genome, 99% of mitochondrial proteins (Rehling et al., Nat Rev Mol Cell Biol 5:519–530, 2004) and more than 95% of chloroplast proteins (Soll, Curr Opin Plant Biol 5:529–535, 2002) are encoded by nuclear DNA, synthesised in the cytosol and imported post-translationally. Protein targeting to these organelles depends on cytosolic targeting factors, which bind to the precursor, and then interact with membrane receptors to deliver the precursor into a translocase. The molecular chaperones Hsp70 and Hsp90 have been widely implicated in protein targeting to mitochondria and chloroplasts, and receptors capable of recognising these chaperones have been identified at the surface of both these organelles (Schlegel et al., Mol Biol Evol 24:2763–2774, 2007). The role of these chaperone receptors is not fully understood, but they have been shown to increase the efficiency of protein targeting (Young et al., Cell 112:41–50, 2003; Qbadou et al., EMBO J 25:1836–1847, 2006). Whether these receptors contribute to the specificity of targeting is less clear. A class of chaperone receptors bearing tetratricopeptide repeat domains is able to specifically bind the highly conserved C terminus of Hsp70 and/or Hsp90. Interestingly, at least of one these chaperone receptors can be found on each organelle (Schlegel et al., Mol Biol Evol 24:2763–2774, 2007), which suggests a universal role in protein targeting for these chaperone receptors. This review will investigate the role that chaperone receptors play in targeting efficiency and specificity, as well as examining recent in silico approaches to find novel chaperone receptors.     

Epigenetic Inheritance: What News for Evolution?

Whether epigenetic variation is important in adaptive evolution has been contentious. Two recent studies in Arabidopsis thaliana significantly add to our understanding of genome-wide variation and stability of an epigenetic mark, and thus help pave the path for realistically incorporating epigenetics into evolutionary theory.     

Vertically transmitted viral endosymbionts of insects: do sigma viruses walk alone?

Insects are host to a wide range of vertically transmitted bacterial endosymbionts, but we know relatively little about their viral counterparts. Here, we discuss the vertically transmitted viral endosymbionts of insects, firstly examining the diversity of this group, and then focusing on the well-studied sigma viruses that infect dipterans. Despite limited sampling, evidence suggests that vertically transmitted viruses may be common in insects. Unlike bacteria, viruses can be transmitted through sperm and eggs, a trait that allows them to rapidly spread through host populations even when infection is costly to the host. Work on Drosophila melanogaster has shown that sigma viruses and their hosts are engaged in a coevolutionary arms race, in which the spread of resistance genes in the host population is followed by the spread of viral genotypes that can overcome host resistance. In the long-term, associations between sigma viruses and their hosts are unstable, and the viruses persist by occasionally switching to new host species. It therefore seems likely that viral endosymbionts have major impacts on the evolution and ecology of insects.     

Microarray analysis of HIV resistant female sex workers reveal a gene expression signature pattern reminiscent of a lowered immune activation state

To identify novel biomarkers for HIV-1 resistance, including pathways that may be critical in anti-HIV-1 vaccine design, we carried out a gene expression analysis on blood samples obtained from HIV-1 highly exposed seronegatives (HESN) from a commercial sex worker cohort in Nairobi and compared their profiles to HIV-1 negative controls. Whole blood samples were collected from 43 HIV-1 resistant sex workers and a similar number of controls. Total RNA was extracted and hybridized to the Affymetrix HUG 133 Plus 2.0 micro arrays (Affymetrix, Santa Clara CA). Output data was analysed through ArrayAssist software (Agilent, San Jose CA). More than 2,274 probe sets were differentially expressed in the HESN as compared to the control group (fold change ≥1.3; p value ≤0.0001, FDR <0.05). Unsupervised hierarchical clustering of the differentially expressed genes readily distinguished HESNs from controls. Pathway analysis through the KEGG signaling database revealed a majority of the impacted pathways (13 of 15, 87%) had genes that were significantly down regulated. The most down expressed pathways were glycolysis/gluconeogenesis, pentose phosphate, phosphatidyl inositol, natural killer cell cytotoxicity and T-cell receptor signaling. Ribosomal protein synthesis and tight junction genes were up regulated. We infer that the hallmark of HIV-1 resistance is down regulation of genes in key signaling pathways that HIV-1 depends on for infection.     

What you may not see might slow you down anyway: masked images and driving

Many theories of driver behaviour suggest that unconscious or implicit emotions play a functional role in the shaping and control of behaviour. This has not been experimentally tested however. Therefore, in this study the effects of emotive masked images on driver behaviour were examined. While driving a simulator, participants were repeatedly exposed to negative or neutral emotionally laden target images that were sandwich masked by emotionally neutral images. These images were encountered across two different trials each of which consisted of 3-4 minutes of driving on a rural road. The results indicate an effect of the negative target images primarily in reducing the extent of familiarisation occurring between the first and second experimental drives. This is evident in a reduced decrease in heart rate and a reduced increase in high band heart rate variability and actual travelling speed from the first to second drives if the negative target image was presented in the second drive. In addition to these findings there was no clear effect of the target image on subjective ratings of effort or feelings of risk. There was however an effect of gender, with the majority of the effects found in the study being limited to the larger female dataset. These findings suggest that unconscious or implicit emotional stimuli may well influence driver behaviour without explicit awareness.     

Anthrax toxin receptor 2 functions in ECM homeostasis of the murine reproductive tract and promotes MMP activity

Anthrax Toxin Receptor proteins function as receptors for anthrax toxin, however physiological activity remains unclear. To evaluate the biological role of Antxr2, we generated Antxr2-/- mice. Antxr2-/- mice were viable, however Antxr2 is required for parturition in young females and for preserving fertility in older female mice. Histological analysis of the uterus and cervix revealed aberrant deposition of extracellular matrix proteins such as type I collagen, type VI collagen and fibronectin. A marked disruption of both the circular and longitudinal myometrial cell layers was evident in Antxr2-/- mice. These changes progressed as the mice aged, resulting in a thickened, collagen dense, acellular stroma and the disappearance of normal uterine architecture. To investigate the molecular mechanism underlying the uterine fibrosis we performed immunoblotting for MMP2 using uterine lysates and zymography using conditioned medium from Antxr2-/- mouse embryonic fibroblasts and found reduced levels of activated MMP2 in both. This prompted us to investigate MT1-MMP status, as MMP2 processing is regulated by MT1-MMP. We found MT1-MMP activity, as measured by MMP2 processing and activation, was enhanced by expression of either ANTXR1 or ANTXR2. We identified an ANTXR2/MT1-MMP complex and demonstrated that MT1-MMP activity is dependent on ANTXR2 expression levels in cells. Thus, we have discovered that ANTXR1 and ANTXR2 function as positive regulators of MT1-MMP activity.