Choking phenomena in a lung-like model

A simple, continuous, one-dimensional model for the geometry and structure of the bronchial airways is used for the analysis of fluid flow patterns which have been observed in forced expiration maneuvers. Various phenomena within the conducting system associated with flow limitation are investigated: the conditions in which a "choke" (flow limitation) can occur in a compliant system; theoretical flows that are physically impossible; the possibility of having elastic jumps downstream of the choke point; perturbations in the physical parameters of the conducting system.     

Characterization of Respiratory and Cardiac Motion from Electro-Anatomical Mapping Data for Improved Fusion of MRI to Left Ventricular Electrograms

Accurate fusion of late gadolinium enhancement magnetic resonance imaging (MRI) and electro-anatomical voltage mapping (EAM) is required to evaluate the potential of MRI to identify the substrate of ventricular tachycardia. However, both datasets are not acquired at the same cardiac phase and EAM data is corrupted with respiratory motion limiting the accuracy of current rigid fusion techniques. Knowledge of cardiac and respiratory motion during EAM is thus required to enhance the fusion process. In this study, we propose a novel approach to characterize both cardiac and respiratory motion from EAM data using the temporal evolution of the 3D catheter location recorded from clinical EAM systems. Cardiac and respiratory motion components are extracted from the recorded catheter location using multi-band filters. Filters are calibrated for each EAM point using estimates of heart rate and respiratory rate. The method was first evaluated in numerical simulations using 3D models of cardiac and respiratory motions of the heart generated from real time MRI data acquired in 5 healthy subjects. An accuracy of 0.6–0.7 mm was found for both cardiac and respiratory motion estimates in numerical simulations. Cardiac and respiratory motions were then characterized in 27 patients who underwent LV mapping for treatment of ventricular tachycardia. Mean maximum amplitude of cardiac and respiratory motion was 10.2±2.7 mm (min = 5.5, max = 16.9) and 8.8±2.3 mm (min = 4.3, max = 14.8), respectively. 3D Cardiac and respiratory motions could be estimated from the recorded catheter location and the method does not rely on additional imaging modality such as X-ray fluoroscopy and can be used in conventional electrophysiology laboratory setting.     

PCA-correlated SNPs for structure identification in worldwide human populations

Existing methods to ascertain small sets of markers for the identification of human population structure require prior knowledge of individual ancestry. Based on Principal Components Analysis (PCA), and recent results in theoretical computer science, we present a novel algorithm that, applied on genomewide data, selects small subsets of SNPs (PCA-correlated SNPs) to reproduce the structure found by PCA on the complete dataset, without use of ancestry information. Evaluating our method on a previously described dataset (10,805 SNPs, 11 populations), we demonstrate that a very small set of PCA-correlated SNPs can be effectively employed to assign individuals to particular continents or populations, using a simple clustering algorithm. We validate our methods on the HapMap populations and achieve perfect intercontinental differentiation with 14 PCA-correlated SNPs. The Chinese and Japanese populations can be easily differentiated using less than 100 PCA-correlated SNPs ascertained after evaluating 1.7 million SNPs from HapMap. We show that, in general, structure informative SNPs are not portable across geographic regions. However, we manage to identify a general set of 50 PCA-correlated SNPs that effectively assigns individuals to one of nine different populations. Compared to analysis with the measure of informativeness, our methods, although unsupervised, achieved similar results. We proceed to demonstrate that our algorithm can be effectively used for the analysis of admixed populations without having to trace the origin of individuals. Analyzing a Puerto Rican dataset (192 individuals, 7,257 SNPs), we show that PCA-correlated SNPs can be used to successfully predict structure and ancestry proportions. We subsequently validate these SNPs for structure identification in an independent Puerto Rican dataset. The algorithm that we introduce runs in seconds and can be easily applied on large genome-wide datasets, facilitating the identification of population substructure, stratification assessment in multi-stage whole-genome association studies, and the study of demographic history in human populations.     

Ablation of ceramide synthase 2 strongly affects biophysical properties of membranes

Little is known about the effects of altering sphingolipid (SL) acyl chain structure and composition on the biophysical properties of biological membranes. We explored the biophysical consequences of depleting very long acyl chain (VLC) SLs in membranes prepared from lipid fractions isolated from a ceramide synthase 2 (CerS2)-null mouse, which is unable to synthesize C22-C24 ceramides. We demonstrate that ablation of CerS2 has different effects on liver and brain, causing a significant alteration in the fluidity of the membrane and affecting the type and/or extent of the phases present in the membrane. These changes are a consequence of the depletion of VLC and unsaturated SLs, which occurs to a different extent in liver and brain. In addition, ablation of CerS2 causes changes in intrinsic membrane curvature, leading to strong morphological alterations that promote vesicle adhesion, membrane fusion, and tubule formation. Together, these results show that depletion of VLC-SLs strongly affects membrane biophysical properties, which may compromise cellular processes that critically depend on membrane structure, such as trafficking and sorting.     

Limonoid compounds inhibit sphingomyelin biosynthesis by preventing CERT protein-dependent extraction of ceramides from the endoplasmic reticulum

To identify novel inhibitors of sphingomyelin (SM) metabolism, a new and selective high throughput microscopy-based screening based on the toxicity of the SM-specific toxin, lysenin, was developed. Out of a library of 2011 natural compounds, the limonoid, 3-chloro-8β-hydroxycarapin-3,8-hemiacetal (CHC), rendered cells resistant to lysenin by decreasing cell surface SM. CHC treatment selectively inhibited the de novo biosynthesis of SM without affecting glycolipid and glycerophospholipid biosynthesis. Pretreatment with brefeldin A abolished the limonoid-induced inhibition of SM synthesis suggesting that the transport of ceramide (Cer) from the endoplasmic reticulum to the Golgi apparatus is affected. Unlike the Cer transporter (CERT) inhibitor HPA-12, CHC did not change the transport of a fluorescent short chain Cer analog to the Golgi apparatus or the formation of fluorescent and short chain SM from the corresponding Cer. Nevertheless, CHC inhibited the conversion of de novo synthesized Cer to SM. We show that CHC specifically inhibited the CERT-mediated extraction of Cer from the endoplasmic reticulum membranes in vitro. Subsequent biochemical screening of 21 limonoids revealed that some of them, such as 8β-hydroxycarapin-3,8-hemiacetal and gedunin, which exhibits anti-cancer activity, inhibited SM biosynthesis and CERT-mediated extraction of Cer from membranes. Model membrane studies suggest that 8β-hydroxycarapin-3,8-hemiacetal reduced the miscibility of Cer with membrane lipids and thus induced the formation of Cer-rich membrane domains. Our study shows that certain limonoids are novel inhibitors of SM biosynthesis and suggests that some biological activities of these limonoids are related to their effect on the ceramide metabolism.     

Effects of subinhibitory concentrations of menthol on adaptation, morphological, and gene expression changes in enterohemorrhagic Escherichia coli

Menthol (C(10)H(20)O) possesses antibacterial activity; nevertheless, bacterial adaptation to this compound has never been studied. Here we report that precultivation of enterohemorrhagic Escherichia coli (EHEC) strains in increasing subinhibitory (SI) concentrations of menthol significantly elevates (4- to 16-fold) their resistance to menthol. Concomitant morphological alterations included the appearance of mucoid colonies and reduced biofilm production. Scanning electron microscopy (SEM) examination revealed suppressed curli formation in menthol-adapted cells. Expression of the gene cpsB10 (encoding one of the enzymes responsible for colanic acid production) was elevated in response to SI concentrations of menthol in a laboratory E. coli strain, whereas expression in an rcsC null mutant was reduced, implicating a partial role for the Rcs phosphorelay system in mediating the menthol signal. Adaptation to menthol also reduced expression of the locus of enterocyte effacement-encoded regulator (Ler). This reduction, together with reduced curli and biofilm formation and elevated mucoidity, suggests a general reduction in bacterial virulence following adaptation to menthol. Our results thus suggest menthol as a potential lead in the recently emerging alternative strategy of targeting bacterial virulence factors to develop new types of anti-infective agents.     

A generic theoretical model for biological control of foliar plant diseases

We have developed a generic modelling framework to understand the dynamics of foliar pathogen and biocontrol agent (BCA) populations in order to predict the likelihood of successful biocontrol in relation to the mechanisms involved. The model considers biocontrol systems for foliar pathogens only and, although it is most applicable to fungal BCA systems, does not address a specific biocontrol system. Four biocontrol mechanisms (competition, antibiosis, mycoparasitism and induced resistance) were included within the model rubric. Because of the wide range of mechanisms involved we use Trichoderma/Botrytis as an exemplar system. Qualitative analysis of the model showed that the rates of a BCA colonising diseased and/or healthy plant tissues and the time that the BCA remains active are two of the more important factors in determining the final outcome of a biocontrol system. Further evaluation of the model indicated that the dynamic path to the steady-state population levels also depends critically on other parameters such as the host-pathogen infection rate. In principle, the model can be extended to include other potential mechanisms, including spatio-temporal heterogeneity, fungicide effects, non-fungal BCA and strategies for BCA application, although with a cost in model tractability and ease of interpretation.     

Evaluating the survival and environmental fate of the biocontrol agent Trichoderma atroviride SC1 in vineyards in northern Italy

Aims:  To study the survival in the soil and the dispersion in the environment of Trichoderma atroviride SC1 after soil applications in a vineyard.
Methods and Results:  Trichoderma atroviride SC1 was introduced into soil in two consecutive years. The levels of T. atroviride populations at different spatial and temporal points following inoculation were assessed by counting the colony-forming units and by a specific quantitative real-time PCR. A high concentration of T. atroviride SC1 was still observed at the 18th week after inoculation. The vertical migration of the fungus to a soil depth of 0·4 m was already noticeable during the first week after inoculation. The fungus spread up to 4 m (horizontally) from the point of inoculation and its concentration decreased with the increasing distance (horizontal and vertical). It was able to colonize the rhizosphere and was also found on grapevine leaves. One year after soil inoculation, T. atroviride SC1 could still be recovered in the treated areas.
Conclusions:  Trichoderma atroviride SC1 survived and dispersed becoming an integrant part of the local microbial community under the tested conditions.
Significance and Impact of the Study:  The persistence and rapid spread of T. atroviride SC1 represent good qualities for its future use as biocontrol agent against soilborne pathogens.     

Ancestry-related assortative mating in Latino populations

Background

While spouse correlations have been documented for numerous traits, no prior studies have assessed assortative mating for genetic ancestry in admixed populations.

Results

Using 104 ancestry informative markers, we examined spouse correlations in genetic ancestry for Mexican spouse pairs recruited from Mexico City and the San Francisco Bay Area, and Puerto Rican spouse pairs recruited from Puerto Rico and New York City. In the Mexican pairs, we found strong spouse correlations for European and Native American ancestry, but no correlation in African ancestry. In the Puerto Rican pairs, we found significant spouse correlations for African ancestry and European ancestry but not Native American ancestry. Correlations were not attributable to variation in socioeconomic status or geographic heterogeneity. Past evidence of spouse correlation was also seen in the strong evidence of linkage disequilibrium between unlinked markers, which was accounted for in regression analysis by ancestral allele frequency difference at the pair of markers (European versus Native American for Mexicans, European versus African for Puerto Ricans). We also observed an excess of homozygosity at individual markers within the spouses, but this provided weaker evidence, as expected, of spouse correlation. Ancestry variance is predicted to decline in each generation, but less so under assortative mating. We used the current observed variances of ancestry to infer even stronger patterns of spouse ancestry correlation in previous generations.

Conclusions

Assortative mating related to genetic ancestry persists in Latino populations to the current day, and has impacted on the genomic structure in these populations.