ALBERT

Description: Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1 -knockout ( Ppt1 -KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4 + T-helper 17 (T H 17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1 -KO mice, (ii) if so, do T H 17-lymphocytes underlie this complication, and (iii) how might T H 17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1 -KO mice and that T H 17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T H 17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1 -KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4 + T lymphocytes to IL-17A-positive T H 17 cells. Our findings uncover a mechanism by which T H 17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T H 17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL.

Description: Mammalian genomes are replete with millions of polymorphic sites, among which those genetic variants that are colocated on the same chromosome and exist close to one another form blocks of closely linked mutations known as haplotypes. The linkage within haplotypes is constantly disrupted due to meiotic recombination events. Whole ensembles of such numerous haplotypes are subjected to evolutionary pressure, where mutations influence each other and should be considered as a whole entity—a gigantic matrix, unique for each individual genome. This idea was implemented into a computational approach, named Genome Evolution by Matrix Algorithms (GEMA) to model genomic changes taking into account all mutations in a population. GEMA has been tested for modeling of entire human chromosomes. The program can precisely mimic real biological processes that have influence on genome evolution such as: 1) Authentic arrangements of genes and functional genomic elements, 2) frequencies of various types of mutations in different nucleotide contexts, and 3) nonrandom distribution of meiotic recombination events along chromosomes. Computer modeling with GEMA has demonstrated that the number of meiotic recombination events per gamete is among the most crucial factors influencing population fitness. In humans, these recombinations create a gamete genome consisting on an average of 48 pieces of corresponding parental chromosomes. Such highly mosaic gamete structure allows preserving fitness of population under the intense influx of novel mutations (40 per individual) even when the number of mutations with deleterious effects is up to ten times more abundant than those with beneficial effects.

Description: The original intensity interferometers were instruments built in the 1950s and 1960s by Hanbury Brown and collaborators, achieving milliarcsec resolutions in visible light without optical-quality mirrors. They exploited a then-novel physical effect, nowadays known as HBT correlation after the experiments of Hanbury Brown and Twiss, and considered fundamental in quantum optics. Now a new generation of intensity interferometers is being designed, raising the possibility of measuring intensity correlations with three or more detectors. Quantum optics predicts two interesting features in many-detector HBT: (i) the signal contains spatial information about the source (such as the bispectrum or closure phase) not present in standard HBT and (ii) correlation increases combinatorially with the number of detectors. The signal-to-noise ratio (SNR) depends crucially on the number of photons – in practice always 〈〈1 – detected per coherence time. A simple SNR formula is derived for thermal sources, indicating that three-detector HBT is feasible for bright stars. The many-detector enhancement of HBT would be much more difficult to measure, but seems plausible for bright masers.

Description: We have made mass maps of three strong-lensing clusters, Abell 3827, Abell 2218 and Abell 1689, in order to test for mass–light offsets. The technique used is GRALE, which enables lens reconstruction with minimal assumptions, and specifically with no information about the cluster light being given. In the first two of these clusters, we find local mass peaks in the central regions that are displaced from the nearby galaxies by a few to several kpc. These offsets could be due to line-of-sight structure unrelated to the clusters, but that is very unlikely, given the typical levels of chance line-of-sight coincidences in cold dark matter simulations – for Abell 3827 and Abell 2218 the offsets appear to be intrinsic. In the case of Abell 1689, we see no significant offsets in the central region, but we do detect a possible line-of-sight structure: it appears only when sources at z 3 are used for reconstructing the mass. We discuss possible origins of the mass–galaxy offsets in Abell 3827 and Abell 2218: these include pure gravitational effects like dynamical friction, but also non-standard mechanisms like self-interacting dark matter.

Description: Analysis of chromatin-immunoprecipitation followed by sequencing (ChIP-seq) usually disregards sequence reads that do not map within binding positions (peaks). Using an unbiased approach, we analysed all reads, both that mapped and ones that were not included as part of peaks. ChIP-seq experiments were performed in human lung adenocarcinoma and fibrosarcoma cells for the metastasis suppressor non-metastatic 2 (NME2). Surprisingly, we identified sequence reads that uniquely represented human telomere ends in both cases. In vivo presence of NME2 at telomere ends was validated using independent methods and as further evidence we found intranuclear association of NME2 and the telomere repeat binding factor 2. Most remarkably, results demonstrate that NME2 associates with telomerase and reduces telomerase activity in vitro and in vivo , and sustained NME2 expression resulted in reduced telomere length in aggressive human cancer cells. Anti-metastatic function of NME2 has been demonstrated in human cancers, however, mechanisms are poorly understood. Together, findings reported here suggest a novel role for NME2 as a telomere binding protein that can alter telomerase function and telomere length. This presents an opportunity to investigate telomere-related interactions in metastasis suppression.

Description: Motivation: Scholarly biomedical publications report on the findings of a research investigation. Scientists use a well-established discourse structure to relate their work to the state of the art, express their own motivation and hypotheses and report on their methods, results and conclusions. In previous work, we have proposed ways to explicitly annotate the structure of scientific investigations in scholarly publications. Here we present the means to facilitate automatic access to the scientific discourse of articles by automating the recognition of 11 categories at the sentence level, which we call Core Scientific Concepts (CoreSCs). These include: Hypothesis, Motivation, Goal, Object, Background, Method, Experiment, Model, Observation, Result and Conclusion. CoreSCs provide the structure and context to all statements and relations within an article and their automatic recognition can greatly facilitate biomedical information extraction by characterizing the different types of facts, hypotheses and evidence available in a scientific publication. Results: We have trained and compared machine learning classifiers (support vector machines and conditional random fields) on a corpus of 265 full articles in biochemistry and chemistry to automatically recognize CoreSCs. We have evaluated our automatic classifications against a manually annotated gold standard, and have achieved promising accuracies with ‘Experiment’, ‘Background’ and ‘Model’ being the categories with the highest F 1-scores (76%, 62% and 53%, respectively). We have analysed the task of CoreSC annotation both from a sentence classification as well as sequence labelling perspective and we present a detailed feature evaluation. The most discriminative features are local sentence features such as unigrams, bigrams and grammatical dependencies while features encoding the document structure, such as section headings, also play an important role for some of the categories. We discuss the usefulness of automatically generated CoreSCs in two biomedical applications as well as work in progress. Availability: A web-based tool for the automatic annotation of articles with CoreSCs and corresponding documentation is available online at http://www.sapientaproject.com/software http://www.sapientaproject.com also contains detailed information pertaining to CoreSC annotation and links to annotation guidelines as well as a corpus of manually annotated articles, which served as our training data. Contact: liakata@ebi.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Description: The S stars near the Galactic Centre and any pulsars that may be on similar orbits can be modelled in a unified way as clocks orbiting a black hole, and hence are potential probes of relativistic effects, including black hole spin. The high eccentricities of many S stars mean that relativistic effects peak strongly around pericentre; for example, orbit precession is not a smooth effect but almost a kick at pericentre. We argue that concentration around pericentre will be an advantage when analysing redshift or pulse-arrival data to measure relativistic effects, because cumulative precession will be drowned out by Newtonian perturbations from other mass in the Galactic Centre region. Wavelet decomposition may be a way to disentangle relativistic effects from Newton perturbations. Assuming a plausible model for Newtonian perturbations on S2, relativity appears to be strongest in a two-year interval around pericentre, in wavelet modes of time-scale 6 months.

Description: The interferometers of Hanbury Brown and collaborators in the 1950s and 1960s, and their modern descendants now being developed (intensity interferometers) measure the spatial power spectrum of the source from intensity correlations at two points. The quantum optical theory of the Hanbury Brown and Twiss effect shows that more is possible, in particular the phase information can be recovered by correlating intensities at three points (bispectrum). In this paper we argue that such three-point measurements are possible for bright stars such as Sirius and Betelgeuse using off the shelf single photon counters with collecting areas of the order of 100 m 2 . It seems possible to map individual features on the stellar surface. Simple diameter measurements would be possible with amateur class telescopes.

Description: In a previous study, we found that 2-deoxyribonolactone is effectively generated in the specific 5-bromouracil ( Br U)-substituted sequence 5'-(G/C)[A] n = 1,2 Br U Br U-3' and proposed that a formed uracil-5-yl radical mainly abstracts the C1' hydrogen from the 5'-side of Br U Br U under 302-nm irradiation condition. In the present work, we performed photoirradiation of Br U-substituted DNA in the presence of a hydrogen donor, tetrahydrofuran, to quench the uracil-5-yl radical to uracil and then subjected the sample to uracil DNA glycosylase digestion. Slab gel sequence analysis indicated that uracil residues were formed at the hot-spot sequence of 5'-(G/C)[A] n = 1,2 Br U Br U-3' in 302-nm irradiation of Br U-substituted DNA. Furthermore, we found that the uracil residue was also formed at the reverse sequence 5'- Br U Br U[A] n = 1,2 (G/C)-3', which suggests that both 5'-(G/C)[A] n = 1,2 Br U Br U-3' and 5'- Br U Br U[A] n = 1,2 (G/C)-3' are hot-spot sequences for the formation of the uracil-5-yl radical.

Description: We use a new non-parametric gravitational modelling tool – glass – to determine what quality of data (strong lensing, stellar kinematics, and/or stellar masses) are required to measure the circularly averaged mass profile of a lens and its shape. glass uses an underconstrained adaptive grid of mass pixels to model the lens, searching through thousands of models to marginalize over model uncertainties. Our key findings are as follows: (i) for pure lens data, multiple sources with wide redshift separation give the strongest constraints as this breaks the well-known mass-sheet or steepness degeneracy; (ii) a single quad with time delays also performs well, giving a good recovery of both the mass profile and its shape; (iii) stellar masses – for lenses where the stars dominate the central potential – can also break the steepness degeneracy, giving a recovery for doubles almost as good as having a quad with time-delay data, or multiple source redshifts; (iv) stellar kinematics provide a robust measure of the mass at the half-light radius of the stars r 1/2 that can also break the steepness degeneracy if the Einstein radius r E != r 1/2 ; and (v) if r E  ~  r 1/2 , then stellar kinematic data can be used to probe the stellar velocity anisotropy β – an interesting quantity in its own right. Where information on the mass distribution from lensing and/or other probes becomes redundant, this opens up the possibility of using strong lensing to constrain cosmological models.