Y chromosome variation of mice and men

DNA sequences from the nonrecombining portion of the Y chromosome were compared with autosomal and X-linked sequences from mice and humans to test the neutral prediction that ratios of polymorphism to divergence are the same for different genes. Intraspecific variation within Mus domesticus was compared with divergence between M. domesticus and Mus caroli for Sry, a region 5' to Sry, and four X-linked genes, Hprt, Plp, Amg, and Glra2. None of these comparisons revealed significantly reduced variation on the Y chromosome. Intraspecific variation within humans was compared with divergence between humans and chimpanzees for three Y-linked loci (Zfy, the YAP region, and the Sry region), seven X- linked loci (Il2rg, Plp, Hprt, Gk, Ids, Pdhal, and Dmd), and the beta- globin locus on chromosome 11. In these comparisons, the observed level of variation on the human Y chromosome was slightly lower than expected, but was significantly lower in only one case (Sry region vs. Dmd). These results suggest that the levels of variability on the Y chromosome in mice and humans are close to expected values given the effective population size and mutation rates for these loci. There is at most only a modest reduction in variability that may be attributed to natural selection (either genetic hitchhiking or background selection).      

Animal regeneration: ancestral character or evolutionary novelty?

An old question about regeneration is whether it is an ancestral character which is a general property of living matter, or whether it represents a set of specific adaptations to the different circumstances faced by different types of animal. In this review, some recent results on regeneration are assessed to see if they can throw any new light on this question. Evidence in favour of an ancestral character comes from the role of Wnt and bone morphogenetic protein signalling in controlling the pattern of whole‐body regeneration in acoels, which are a basal group of bilaterian animals. On the other hand, there is some evidence for adaptive acquisition or maintenance of the regeneration of appendages based on the occurrence of severe non‐lethal predation, the existence of some novel genes in regenerating organisms, and differences at the molecular level between apparently similar forms of regeneration. It is tentatively concluded that whole‐body regeneration is an ancestral character although has been lost from most animal lineages. Appendage regeneration is more likely to represent a derived character resulting from many specific adaptations.     

Influence of baroreflex on volume elasticity of heart and aorta in the rabbit

Optimal ventriculoaortic coupling includes tuning of elastic properties. The ratio of effective arterial elastance and left ventricular endsystolic elastance is often taken as a measure for mechanical and energetical efficiency. The present study determined the time course of ventricular and aortic volume elasticity (VE = dp/dV) throughout a complete heartbeat. This was achieved by using changes of eigenfrequency of two catheter-transducer systems under closed chest conditions in rabbits. Short-term VE modulation was studied by a baroreflex response, as induced by pressure changes applied to the carotid sinus. Long-term changes were studied in atherosclerotic rabbits (12 wk of high-cholesterol feeding). The time course and mean values of ventricular and aortic VE were changed by the baroreflex stimulus. Cholesterol feeding diminished the response. The degree of ventriculoaortic coupling, as quantified by VE(Aorta)/VE(Ventricle) ratio, varied during a single ejection period. The large span allows either maximal energetical efficiency or maximal stroke work. Although normal rabbits adjusted their ventriculoaortic coupling during baroreflex input, the cholesterol-fed rabbits failed to do so.     

ImageParser: a tool for finite element generation from three-dimensional medical images

Background

The finite element method (FEM) is a powerful mathematical tool to simulate and visualize the mechanical deformation of tissues and organs during medical examinations or interventions. It is yet a challenge to build up an FEM mesh directly from a volumetric image partially because the regions (or structures) of interest (ROIs) may be irregular and fuzzy.

Methods

A software package, ImageParser, is developed to generate an FEM mesh from 3-D tomographic medical images. This software uses a semi-automatic method to detect ROIs from the context of image including neighboring tissues and organs, completes segmentation of different tissues, and meshes the organ into elements.

Results

The ImageParser is shown to build up an FEM model for simulating the mechanical responses of the breast based on 3-D CT images. The breast is compressed by two plate paddles under an overall displacement as large as 20% of the initial distance between the paddles. The strain and tangential Young's modulus distributions are specified for the biomechanical analysis of breast tissues.

Conclusion

The ImageParser can successfully exact the geometry of ROIs from a complex medical image and generate the FEM mesh with customer-defined segmentation information.

     

The role of Rab27a in the regulation of melanosome distribution within retinal pigment epithelial cells

Melanosomes within the retinal pigment epithelium (RPE) of mammals have long been thought to exhibit no movement in response to light, unlike fish and amphibian RPE. Here we show that the distribution of melanosomes within the mouse RPE undergoes modest but significant changes with the light cycle. Two hours after light onset, there is a threefold increase in the number of melanosomes in the apical processes that surround adjacent photoreceptors. In skin melanocytes, melanosomes are motile and evenly distributed throughout the cell periphery. This distribution is due to the interaction with the cortical actin cytoskeleton mediated by a tripartite complex of Rab27a, melanophilin, and myosin Va. In ashen (Rab27a null) mice RPE, melanosomes are unable to move beyond the adherens junction axis and do not enter apical processes, suggesting that Rab27a regulates melanosome distribution in the RPE. Unlike skin melanocytes, the effects of Rab27a are mediated through myosin VIIa in the RPE, as evidenced by the similar melanosome distribution phenotype observed in shaker-1 mice, defective in myosin VIIa. Rab27a and myosin VIIa are likely to be required for association with and movement through the apical actin cytoskeleton, which is a prerequisite for entry into the apical processes.     

Coupling of left ventricular and aortic volume elasticity in the rabbit

Changes in volume elasticity (VE) of the left ventricle and aorta could be important for blood flow. A procedure is presented to rapidly assess VE of the left ventricle and aorta by analyzing changes in the eigenfrequency. Six control rabbits and 11 rabbits with atheromatosis (12 wk of high-cholesterol feeding) were studied. In control rabbits, during the first half of the systole, left ventricular VE continuously increased to +43% (P < 0.05). Then VE gradually declined to an end-diastolic minimum (20% of the average systolic levels, P < 0.05). Aortic VE changes were in the opposite direction to the ventricle. Aortic VE continuously decreased throughout the systole; the last value was 20% lower than at the beginning of the systole (P < 0.05). Conversely, diastolic VE of the aorta took on greater values. This inverse time course between ventricle and aorta may reduce energy requirements for conveying blood. High cholesterol-fed rabbits did not reveal the inverse behavior of ventricular and aortic VE, e.g., aortic VE increased during the systole (119%, P < 0.05).     

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis

Introduction

The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9β and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum.

Methods

We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9β, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9β or 9β + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use.

Results

GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease.

Conclusions

Differences in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.     

Circulating microRNAs in Patients with Shiga-Toxin-Producing E. coli O104:H4 Induced Hemolytic Uremic Syndrome

Background

In early May 2011, an outbreak of hemorrhagic colitis associated with hemolytic–uremic syndrome (HUS) first developed in Northern Germany and spread to 15 other countries in Europe. The outbreak-strain O104:H4, which combined virulence factors of typical enteroaggregative and Shiga-Toxin–producing E. coli was associated with an unusual high rate of hemolytic uremic syndrome. Also an unexpected high rate of coma and seizures leading to mechanical ventilation and ICU treatment was observed. MicroRNAs are small ribonucleotides orchestrating gene expression. We tested whether circulating microRNAs in serum of HUS patients during the 2011 epidemics are altered in this patient cohort and related to clinical manifestations.

Methodology/Principal Findings

We profiled microRNAs using RNA isolated from serum of patients and healthy age-matched controls. The results were validated in 38 patients at baseline, 29 patients during follow-up and 21 age-matched healthy controls by miRNA-specific quantitative RT-PCR. Circulating levels of miR-24, miR-126 were increased in HUS patients versus controls. There was no association between these microRNAs and renal function or the need for renal replacement therapy. In contrast, levels of miR-126 were associated with neurological symptoms at baseline and during follow-up. In addition, miR-126 (on admission) and miR-24 (on admission and during follow-up) were associated with platelet count.

Conclusions/Significance

Circulating microRNAs are strongly altered in this patient cohort and associated with neurological symptoms as well as platelet count.     

Long-Term In Vivo Imaging of Fibrillar Tau in the Retina of P301S Transgenic Mice

Tauopathies are widespread neurodegenerative disorders characterised by the intracellular accumulation of hyperphosphorylated tau. Especially in Alzheimer''s disease, pathological alterations in the retina are discussed as potential biomarkers to improve early diagnosis of the disease. Using mice expressing human mutant P301S tau, we demonstrate for the first time a straightforward optical approach for the in vivo detection of fibrillar tau in the retina. Longitudinal examinations of individual animals revealed the fate of single cells containing fibrillar tau and the progression of tau pathology over several months. This technique is most suitable to monitor therapeutic interventions aimed at reducing the accumulation of fibrillar tau. In order to evaluate if this approach can be translated to human diagnosis, we tried to detect fibrillar protein aggregates in the post-mortem retinas of patients that had suffered from Alzheimer''s disease or Progressive Supranuclear Palsy. Even though we could detect hyperphosphorylated tau, we did not observe any fibrillar tau or Aß aggregates. In contradiction to previous studies, our observations do not support the notion that Aβ or tau in the retina are of diagnostic value in Alzheimer''s disease.     

The effect of Aβ on IAPP aggregation in the presence of an isolated β-cell membrane

Fibrillar aggregates of the islet amyloid polypeptide (IAPP) and amyloid-β (Aβ) are known to deposit at pancreatic β-cells and neuronal cells and are associated with the cell degenerative diseases type-2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), respectively. Since IAPP is secreted by β-cells and a membrane-damaging effect of IAPP has been discussed as a reason for β-cell dysfunction and the development of T2DM, studies of the interaction of IAPP with the β-cell membrane are of high relevance for gaining a molecular-level understanding of the underlying mechanism. Recently, it has also been shown that patients suffering from T2DM exhibit an increased risk to develop AD and vice versa, and a molecular link between AD and T2DM has been suggested. In this study, membrane lipids from the rat insulinoma-derived INS-1E β-cell line were isolated, and their interaction with the amyloidogenic peptides IAPP and Aβ and a mixture of both peptides has been studied. To yield insight into the associated peptides' conformational changes and their effect on the membrane integrity during aggregation, we have carried out attenuated total reflection Fourier transform infrared spectroscopy, fluorescence microscopy, and atomic force microscopy experiments. The IAPP-Aβ heterocomplexes formed were shown to adsorb, aggregate, and permeabilize the isolated β-cell membrane significantly slower than pure IAPP, however, at a rate that is much faster than that of pure Aβ. In addition, it could be shown that isolated β-cell membranes cause similar effects on the kinetics of IAPP and IAPP-Aβ fibril formation as anionic heterogeneous model membranes.