Human immunodeficiency virus type 1 fitness is a determining factor in viral rebound and set point in chronic infection.

Human immunodeficiency virus type 1 (HIV-1) isolates from 20 chronically infected patients who participated in a structured treatment interruption (STI) trial were studied to determine whether viral fitness influences reestablishment of viremia. Viruses derived from individuals who spontaneously controlled viremia had significantly lower in vitro replication capacities than viruses derived from individuals that did not control viremia after interruption of antiretroviral therapy (ART), and replication capacities correlated with pre-ART and post-STI viral set points. Of note, no clinically relevant improvement of viral loads upon STI occurred. Virus isolates from controlling and noncontrolling patients were indistinguishable in terms of coreceptor usage, genetic subtype, and sensitivity to neutralizing antibodies. In contrast, viruses from controlling patients exhibited increased sensitivity to inhibition by chemokines. Sensitivity to inhibition by RANTES correlated strongly with slower replication kinetics of the virus isolates, suggesting a marked dependency of these virus isolates on high coreceptor densities on the target cells. In summary, our data indicate that viral fitness is a driving factor in determining the magnitude of viral rebound and viral set point in chronic HIV-1 infection, and thus fitness should be considered as a parameter influencing the outcome of therapeutic intervention in chronic infection.

Natural classification of knots

The principal objective of the knot theory is to provide a simple way of classifying and ordering all the knot types. Here, we propose a natural classification of knots based on their intrinsic position in the knot space that is defined by the set of knots to which a given knot can be converted by individual intersegmental passages. In addition, we characterize various knots using a set of simple quantum numbers that can be determined upon inspection of minimal crossing diagram of a knot. These numbers include: crossing number; average three-dimensional writhe; number of topological domains; and the average relaxation value

Construction and electrophoretic migration of single-stranded DNA knots and catenanes.

In recent years there has been growing interest in the question of how the particular topology of polymeric chains affects their overall dimensions and physical behavior. The majority of relevant studies are based on numerical simulation methods or analytical treatment; however, both these approaches depend on various assumptions and simplifications. Experimental verification is clearly needed but was hampered by practical difficulties in obtaining preparative amounts of knotted or catenated polymers with predefined topology and precisely set chain length. We introduce here an efficient method of production of various single-stranded DNA knots and catenanes that have the same global chain length. We also characterize electrophoretic migration of the produced single-stranded DNA knots and catenanes with increasing complexity.

Comparative gene finding in chicken indicates that we are closing in on the set of multi-exonic widely expressed human genes.

The recent availability of the chicken genome sequence poses the question of whether there are human protein-coding genes conserved in chicken that are currently not included in the human gene catalog. Here, we show, using comparative gene finding followed by experimental verification of exon pairs by RT-PCR, that the addition to the multi-exonic subset of this catalog could be as little as 0.2%, suggesting that we may be closing in on the human gene set. Our protocol, however, has two shortcomings: (i) the bioinformatic screening of the predicted genes, applied to filter out false positives, cannot handle intronless genes; and (ii) the experimental verification could fail to identify expression at a specific developmental time. This highlights the importance of developing methods that could provide a reliable estimate of the number of these two types of genes.

Resting-state temporal synchronization networks emerge from connectivity topology and heterogeneity.

Spatial patterns of coherent activity across different brain areas have been identified during the resting-state fluctuations of the brain. However, recent studies indicate that resting-state activity is not stationary, but shows complex temporal dynamics. We were interested in the spatiotemporal dynamics of the phase interactions among resting-state fMRI BOLD signals from human subjects. We found that the global phase synchrony of the BOLD signals evolves on a characteristic ultra-slow (<0.01Hz) time scale, and that its temporal variations reflect the transient formation and dissolution of multiple communities of synchronized brain regions. Synchronized communities reoccurred intermittently in time and across scanning sessions. We found that the synchronization communities relate to previously defined functional networks known to be engaged in sensory-motor or cognitive function, called resting-state networks (RSNs), including the default mode network, the somato-motor network, the visual network, the auditory network, the cognitive control networks, the self-referential network, and combinations of these and other RSNs. We studied the mechanism originating the observed spatiotemporal synchronization dynamics by using a network model of phase oscillators connected through the brain's anatomical connectivity estimated using diffusion imaging human data. The model consistently approximates the temporal and spatial synchronization patterns of the empirical data, and reveals that multiple clusters that transiently synchronize and desynchronize emerge from the complex topology of anatomical connections, provided that oscillators are heterogeneous.

Exporting Contours to DICOM-RT Structure Set

This paper presents an ITK implementation for exportingthe contours of the automated segmentation results toDICOM-RT Structure Set format. The âeurooeradiotherapystructure setâeuro (RTSTRUCT) object of the DICOM standard isused for the transfer of patient structures and relateddata, between the devices found within and outside theradiotherapy department. It mainly contains theinformation of regions of interest (ROIs) and points ofinterest (E.g. dose reference points). In many cases,rather than manually drawing these ROIs on the CT images,one can indeed benefit from the automated segmentationalgorithms already implemented in ITK. But at present, itis not possible to export the ROIs obtained from ITK toRTSTRUCT format. In order to bridge this gap, we havedeveloped a framework for exporting contour data toRTSTRUCT. We provide here the complete implementation ofRTSTRUCT exporter and present the details of the pipelineused. Results on a 3-D CT image of the Head and Neck(H&N) region are presented.

DNA topology: feeling the pulse of a topoisomerase.

The action of individual type II DNA topoisomerases has been followed in real time by observing the elastic response of single DNA molecules to sequential strand passage events. Micromanipulation methods provide a complementary approach to biochemical studies for investigating the mechanism of DNA topoisomerases.

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients.

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.

Extreme prematurity and intra uterine growth restriction effects in brain network topology at school age

Higher risk for long-term behavioral and emotional sequelae, with attentional problems (with or without hyperactivity) is now becoming one of the hallmarks of extreme premature (EP) birth and birth after pregancy conditions leading to poor intra uterine growth restriction (IUGR) [1,2]. However, little is know so far about the neurostructural basis of these complexe brain functional abnormalities that seem to have their origins in early critical periods of brain development. The development of cortical axonal pathways happens in a series of sequential events. The preterm phase (24-36 post conecptional weeks PCW) is known for being crucial for growth of the thalamocortical fiber bundles as well as for the development of long projectional, commisural and projectional fibers [3]. Is it logical to expect, thus, that being exposed to altered intrauterine environment (altered nutrition) or to extrauterine environment earlier that expected, lead to alterations in the structural organization and, consequently, alter the underlying white matter (WM) structure. Understanding rate and variability of normal brain development, and detect differences from typical development may offer insight into the neurodevelopmental anomalies that can be imaged at later stages. Due to its unique ability to non-invasively visualize and quantify in vivo white matter tracts in the brain, in this study we used diffusion MRI (dMRI) tractography to derive brain graphs [4,5,6]. This relatively simple way of modeling the brain enable us to use graph theory to study topological properties of brain graphs in order to study the effects of EP and IUGR on childrens brain connectivity at age 6 years old.

Plastid genome characterisation in Brassica and Brassicaceae using a new set of nine SSRs.

We report a new set of nine primer pairs specifically developed for amplification of Brassica plastid SSR markers. The wide utility of these markers is demonstrated for haplotype identification and detection of polymorphism in B. napus, B. nigra, B. oleracea, B. rapa and in related genera Arabidopsis, Camelina, Raphanus and Sinapis. Eleven gene regions (ndhB-rps7 spacer, rbcL-accD spacer, rpl16 intron, rps16 intron, atpB-rbcL spacer, trnE-trnT spacer, trnL intron, trnL-trnF spacer, trnM-atpE spacer, trnR-rpoC2 spacer, ycf3-psaA spacer) were sequenced from a range of Brassica and related genera for SSR detection and primer design. Other sequences were obtained from GenBank/EMBL. Eight out of nine selected SSR loci showed polymorphism when amplified using the new primers and a combined analysis detected variation within and between Brassica species, with the number of alleles detected per locus ranging from 5 (loci MF-6, MF-1) to 11 (locus MF-7). The combined SSR data were used in a neighbour-joining analysis (SMM, D (DM) distances) to group the samples based on the presence and absence of alleles. The analysis was generally able to separate plastid types into taxon-specific groups. Multi-allelic haplotypes were plotted onto the neighbour joining tree. A total number of 28 haplotypes were detected and these differentiated 22 of the 41 accessions screened from all other accessions. None of these haplotypes was shared by more than one species and some were not characteristic of their predicted type. We interpret our results with respect to taxon differentiation, hybridisation and introgression patterns relating to the 'Triangle of U'.

A set of indicators for decomposing the secular increase of life expectancy.

ABSTRACT: BACKGROUND: The ongoing increase in life expectancy in developed countries is associated with changes in the shape of the survival curve. These changes can be characterized by two main, distinct components: (i) the decline in premature mortality, i.e., the concentration of deaths around some high value of the mean age at death, also termed rectangularization of the survival curve; and (ii) the increase of this mean age at death, i.e., longevity, which directly reflects the reduction of mortality at advanced ages. Several recent observations suggest that both mechanisms are simultaneously taking place. METHODS: We propose a set of indicators aiming to quantify, disentangle, and compare the respective contribution of rectangularization and longevity increase to the secular increase of life expectancy. These indicators, based on a nonparametric approach, are easy to implement. RESULTS: We illustrate the method with the evolution of the Swiss mortality data between 1876 and 2006. Using our approach, we are able to say that the increase in longevity and rectangularization explain each about 50% of the secular increase of life expectancy. CONCLUSION: Our method may provide a useful tool to assess whether the contribution of rectangularization to the secular increase of life expectancy will remain around 50% or whether it will be increasing in the next few years, and thus whether concentration of mortality will eventually take place against some ultimate biological limit.

Mapping the Membrane Topology of Hepatitis C Virus Nonstructural Protein 4B

BACKGROUND: Nonstructural protein 4B (NS4B) plays an essential role in the formation of the hepatitis C virus (HCV) replication complex. It is an integral membrane protein that has only poorly been characterized to date. In particular, a precise membrane topology is thus far elusive. Here, we explored a novel strategy to map the membrane topology of HCV NS4B. METHODS: Selective permeabilization of the plasma membrane, maleimide-polyethyleneglycol (mPEG) labeling of natural or engineered cysteine residues and immunoblot analyses were combined to map the membrane topology of NS4B. Cysteine substitutions were introduced at carefully selected positions within NS4B and their impact on HCV RNA replication and infectious virus production analyzed in cell culture. RESULTS: We established a panel of viable HCV mutants with cysteine substitutions at strategic positions within NS4B. These mutants are infectious and replicate to high levels in cell culture. In parallel, we adapted and optimized the selective permeabilization and mPEG labeling techniques to Huh-7 human hepatocellular carcinoma cells which can support HCV infection and replication. CONCLUSIONS: The newly established experimental tools and techniques should allow us to refine the membrane topology of HCV NS4B in a physiological context. The expected results should enhance our understanding of the functional architecture of the HCV replication complex and may provide new opportunities for antiviral intervention in the future.