β2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of β₂-microglobulin (β₂m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which β₂m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of β₂m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that β₂m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between β₂m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of β₂m amyloid-associated osteoarticular tissue destruction in DRA.     

A wheat-based,diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice

Dietary antigens are candidate environmental factors in the pathogenesis of type 1 diabetes. In the non-obese diabetic (NOD) mouse, an animal model of type 1 diabetes, cereal-based diets promote disease development, whereas the diets based on hydrolysed proteins or non-diabetogenic proteins are protective. The hypothesis that diabetogenic diets modulate the cytokine balance in the gut was tested. NOD mice were fed with NTP-2000 (mainly a wheat-based milk-free diet) or Prosobee (a semi-purified hypoallergenic diet based on soy protein isolate) or Prosobee plus casein (milk protein fraction). The mRNA levels of IFN-gamma, IL-10, TNF-alpha, TGF-beta, and inducible NO synthase in the small intestine and the Peyer's patches were determined by semi-quantitative RT-PCR. Mice fed on the cereal-based NTP-2000 diet expressed higher levels of the Th1-type and pro-inflammatory markers IFN-gamma, TNF-alpha, and inducible NO synthase mRNA compared to the Prosobee-fed animals. The expression of the counterregulatory cytokines IL-10 and TGF-beta was unaffected. This resulted in a significant bias of the intestinal cytokine balance towards T helper cell type 1 after feeding NTP-2000. The cytokine mRNA levels in the gut-associated Peyer's patches were not affected. Thus, modulation of gut immunoreactivity by diet may contribute to disease development in NOD mice.     

Allelic variation at the linked AP1 and PhyC loci in hexaploid wheat is associated but not perfectly correlated with vernalization response

Vernalization requirement is an important trait in temperate crop plants such as wheat and must be considered when selecting varieties for cultivation under different climatic conditions. To determine the growth habit of wheat varieties, plants need to be grown under different vernalization regimes, a lengthy but necessary process for breeders involved in crossing winter with spring germplasm. If haplotypes can be associated with growth habit, then molecular marker assays that are reliable, cheap, and quick can be developed to assist in the selection of plants with the desired phenotype. We have analyzed 81 accessions that have different vernalization requirements and putative different origins of spring habit for sequence variation at the Apetala1 (AP1) locus, which underlies Vrn-1, and at the linked Phytochrome C (PhyC) locus. Good correspondence was found between the AP1 genotype and the PhyC haplotype for 77 of the 81 accessions. Two varieties displayed a recombination event between the AP1 and PhyC loci, and one variety carried a recombinant PhyC gene. In addition, one variety carried an apparent AP1 winter allele, but displayed the Vrn-A1 spring habit. The PhyC haplotype for this variety also indicated the presence of a Vrn-A1 spring allele. Our data suggest that both the AP1 promoter region and PhyC SNPs can be used as diagnostic markers for vernalization response at the vrn-A1 locus, but that neither are perfect tags.     

Lifting the lid on Pandora's box: the Bardet-Biedl syndrome

Progress in understanding the cause of the once obscure condition Bardet-Biedl syndrome (BBS) has been rapid since 2003. That BBS is now known to be a disorder of cilia and basal body function has been facilitated by the recent discovery of the novel genes BBS3, 5, 7 and 8 (eight BBS genes in total) and confirmed by the generation of genetic model systems in mice, Chlamydomonas, Caenorhabditis elegans and Drosophila melanogaster. These discoveries have been aided significantly by several elegant comparative genomic exercises, highlighting the utility of such approaches. The high level of species conservation and genetic heterogeneity indicates the fundamental importance of this family of genes and the pathways in which they operate. In the next few years, these pathways will be revealed, and their impact on the development of systems as diverse as the cardiovascular, neurological, endocrinological and skeletal will be realized.     

Zerumbone induced apoptosis in liver cancer cells via modulation of Bax/Bcl-2 ratio

Background  

Zerumbone is a cytotoxic component isolated from Zingiber zerumbet Smith, a herbal plant which is also known as lempoyang. This new anticancer bioactive compound from Z. zerumbet was investigated for its activity and mechanism in human liver cancer cell lines.     

The effect of increased physical load during an active straight leg raise in pain free subjects

PurposeIt has been proposed that pelvic girdle pain (PGP) subjects adopt a high load motor control strategy during the low load task of the active straight leg raise (ASLR). This study investigated this premise by observing the motor control patterns adopted by pain free subjects during a loaded ASLR (ASLR + PL).MethodTrunk muscle activation, intra-abdominal pressure, intra-thoracic pressure, pelvic floor motion, downward pressure of the non-lifted leg and respiratory rate were compared between resting supine, ASLR and ASLR + PL. Additionally, side-to-side comparisons were performed for ASLR + PL.ResultsIncremental increases in muscle activation were observed from resting supine to ASLR to ASLR + PL. During the ASLR + PL there was a simultaneous increase in intra-abdominal pressure with a decrease in intra-thoracic pressure, while respiratory fluctuation of these variables were maintained. The ASLR + PL also resulted in increased pelvic floor descent and greater downward pressure of the non-lifted leg. Trunk muscle activation was comparable between sides during ASLR + PL in all muscles except lower obliquus internus abdominis, which was more active on the leg lift side.ConclusionPain free subjects respond to an ASLR + PL by a general increase in anterior trunk muscle activation, but preserve the pattern of greater activation on the side of the leg lift observed during an unloaded ASLR. This contrasts to findings in PGP subjects who, despite having a high load strategy for performing an ASLR on the symptomatic side of the body, display equal bilateral activation of the anterior abdominal wall during the ASLR. This differentiates PGP subjects from pain free subjects, supporting the notion that PGP subjects have aberrant motor control patterns during an ASLR.     

The effect of resisted inspiration during an active straight leg raise in pain-free subjects

Alterations of respiratory patterns have been observed in pelvic girdle pain subjects during the active straight leg raise (ASLR). This study investigated how pain-free subjects coordinate motor control during an ASLR when this task is complicated by the addition of a respiratory challenge. Trunk muscle activation, intra-abdominal pressure, intra-thoracic pressure, pelvic floor motion, downward pressure of the non-lifted leg and respiratory rate were compared between resting supine, ASLR, breathing with inspiratory resistance (IR) and ASLR+IR. Subjects responded to ASLR+IR with an increase in the motor activation in the abdominal wall and chest wall compared to when ASLR and IR were performed in isolation. Activation of obliquus internus abdominis was greater on the side of the leg lift during the ASLR+IR, in comparison to symmetrical activation observed in the other abdominal wall muscles. The incremental increase of motor activity was associated with greater intra-abdominal pressure baseline shift when lifting the leg during ASLR+IR compared to ASLR. Individual variation was apparent in the form of the motor control patterns, mostly reflected in variable respiratory activation of the abdominal wall. The findings highlight the flexibility of the neuromuscular system in adapting to simultaneous respiratory and stability demands.     

Mainzer-Saldino syndrome is a ciliopathy caused by IFT140 mutations

Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure, and early-onset, severe retinal dystrophy. Through a combination of ciliome resequencing and Sanger sequencing, we identified IFT140 mutations in six MSS families and in a family with the clinically overlapping Jeune syndrome. IFT140 is one of the six currently known components of the intraflagellar transport complex A (IFT-A) that regulates retrograde protein transport in ciliated cells. Ciliary abundance and localization of anterograde IFTs were altered in fibroblasts of affected individuals, a result that supports the pivotal role of IFT140 in proper development and function of ciliated cells.