Differential requirement of lipid rafts for FcγRIIA mediated effector activities

Immunoglobulin G (IgG) dependent activities are important in host defense and autoimmune diseases. Various cell types including macrophages and neutrophils contribute to pathogen destruction and tissue damage through binding of IgG to Fcγ receptors (FcγR). One member of this family, FcγRIIA, is a transmembrane glycoprotein known to mediate binding and internalization of IgG-containing targets. FcγRIIA has been observed to translocate into lipids rafts upon binding IgG-containing targets. We hypothesize that lipid rafts participate to different extents in binding and internalizing targets of different sizes. We demonstrate that disruption of lipid rafts with 8 mM methyl-β-cyclodextrin (MβCD) nearly abolishes binding (91% reduction) and phagocytosis (60% reduction) of large IgG-coated targets. Conversely, binding and internalization of small IgG-complexes is less dependent on lipid rafts (49% and 17% inhibition at 8 mM MβCD, respectively). These observations suggest that differences between phagocytosis and endocytosis may arise as early as the initial stages of ligand recognition.     

Unconditional hospitality: HIV, ethics and the refugee 'problem'

Refugees, as forced migrants, have suffered displacement under conditions not of their own choosing. In 2000 there were thought to be 22 million refugees of whom 6 million were HIV positive. While the New Zealand government has accepted a number of HIV positive refugees from sub-Saharan Africa, this hospitality is under threat due to negative public and political opinion. Epidemic conditions raise the social stakes attached to sexual exchanges, contagion becomes a major figure in social relationships and social production, and the fears of the contagious nature of those 'just off the plane' connect refugees to an equally deep-seated fear of racial miscegenation. Jacques Derrida's notion of unconditional hospitality is a dream of a democracy which would have a cosmopolitan form. This means that one cannot decide in advance which refugees one might choose to resettle. This paper will use Derrida's notion of unconditional hospitality to emphasise the fragility of HIV positive refugees' position, caught between becoming newly made New Zealand subjects while at the same time having that subjecthood threatened. For Derrida, both ethics and politics demand both an action and a need for a thoughtful response (a questioning without limit).     

An antifungal and plant growth promoting metabolite from a sterile dark ectotrophic fungus

A sterile dark ectotrophic fungus isolated from roots of an Australian native grass, Neurachne alopecuroidea produces compound 1 in liquid cultures. The structure of the metabolite was determined by spectroscopic and X-ray diffraction studies. The metabolite shows activity against phytopathogens and plant growth promoting activity, properties that are also expressed in vivo by the ectotrophic fungus.     

Sex differences in the rate of fatigue development and recovery

Background

Many musculoskeltal injuries in the workplace have been attributed to the repetitive loading of muscle and soft tissues. It is not disputed that muscular fatigue is a risk factor for musculoskeltal injury, however the disparity between gender with respect to muscular fatigability and rate of recovery is not well understood. Current health and safety guidelines do not account for sex differences in fatiguability and may be predisposing one gender to greater risk. The purpose of this study was to quantify the sex differences in fatigue development and recovery rate of lower and upper body musculature after repeated bouts of sustained isometric contractions.

Methods

Twenty-seven healthy males (n = 12) and females (n = 15) underwent bilateral localized fatigue of either the knee extensors (male: n = 8; female: n = 8), elbow flexors (male: n = 8; female: n = 10), or both muscle groups. The fatigue protocol consisted of ten 30-second sub-maximal isometric contractions. The changes in maximum voluntary contraction (MVC), electrically evoked twitches, and motor unit activation (MUA) were assessed along with the ability to control the sustained contractions (SLP) during the fatigue protocol using a mixed four-factor repeated measures ANOVA (gender × side × muscle × time) design with significance set at p < 0.05.

Results

There was a significant loss of MVC, MUA, and evoked twitch amplitude from pre- to post-fatigue in both the arms and legs. Males had greater relative loss of isometric force, a higher rate of fatigue development, and were less capable of maintaining the fatiguing contractions in the legs when compared to the females.

Conclusion

The nature of the induced fatigue was a combination of central and peripheral fatigue that did not fully recover over a 45-minute period. The results appear to reflect sex differences that are peripheral, and partially support the muscle mass hypothesis for explaining differences in muscular fatigue.

     

Effects of the laryngeal jet on nano- and microparticle transport and deposition in an approximate model of the upper tracheobronchial airways.

The extent to which laryngeal-induced flow features penetrate into the upper tracheobronchial (TB) airways and their related impact on particle transport and deposition are not well understood. The objective of this study was to evaluate the effects of including the laryngeal jet on the behavior and fate of inhaled aerosols in an approximate model of the upper TB region. The upper TB model was based on a simplified numerical reproduction of a replica cast geometry used in previous in vitro deposition experiments that extended to the sixth respiratory generation along some paths. Simulations with and without an approximate larynx were performed. Particle sizes ranging from 2.5 nm to 12 mum were considered using a well-tested Lagrangian tracking model. The model larynx was observed to significantly affect flow dynamics, including a laryngeal jet skewed toward the right wall of the trachea and a significant reverse flow in the left region of the trachea. Inclusion of the laryngeal model increased the tracheal deposition of nano- and micrometer particles by factors ranging from 2 to 10 and significantly reduced deposition in the first three bronchi of the model. Considering localized conditions, inclusion of the laryngeal approximation decreased deposition at the main carina and produced a maximum in local surface deposition density in the lobar-to-segmental bifurcations (G2-G3) for both 40-nm and 4-microm aerosols. These findings corroborate previous experiments and highlight the need to include a laryngeal representation in future computational and in vitro models of the TB region.     

Inhibition of Mitochondrial Complex II by the Anticancer Agent Lonidamine

The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.     

Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.

The SCA7 mutation has been found in 54 patients and 7 at-risk subjects from 17 families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive pigmentary maculopathy. In one isolated case, haplotype reconstruction through three generations confirmed a de novo mutation owing to paternal meiotic instability. Different disease-associated haplotypes segregated among the SCA7-positive kindreds, which indicated a multiple origin of the mutation. One family with the clinical phenotype of ADCA type II did not have the CAG expansion that indicated locus heterogeneity. The distribution of the repeat size in 944 independent normal chromosomes from controls, unaffected at-risk subjects, and one affected individual fell into two ranges. The majority of the alleles were in the first range of 7-19 CAG repeats. A second range could be identified with 28-35 repeats, and we provide evidence that these repeats represent intermediate alleles that are prone to further expansion. The repeat size of the pathological allele, the widest reported for all CAG-repeat disorders, ranged from 37 to approximately 220. The repeat size showed significant negative correlation with both age at onset and age at death. Analysis of the clinical features in the patients with SCA7 confirmed that the most frequently associated features are pigmentary maculopathy, pyramidal tract involvement, and slow saccades. The subjects with <49 repeats tended to have a less complicated neurological phenotype and a longer disease duration, whereas the converse applied to subjects with >/=49 repeats. The degree of instability during meiotic transmission was greater than in all other CAG-repeat disorders and was particularly striking in paternal transmission, in which a median increase in repeat size of 6 and an interquartile range of 12 were observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmission.