Exhaustive prediction of disease susceptibility to coding base changes in the human genome

<p>Abstract</p> <p>Background</p> <p>Single Nucleotide Polymorphisms (SNPs) are the most abundant form of genomic variation and can cause phenotypic differences between individuals, including diseases. Bases are subject to various levels of selection pressure, reflected in their inter-species conservation.</p> <p>Results</p> <p>We propose a method that is not dependant on transcription information to score each coding base in the human genome reflecting the disease probability associated with its mutation. Twelve factors likely to be associated with disease alleles were chosen as the input for a support vector machine prediction algorithm. The analysis yielded 83% sensitivity and 84% specificity in segregating disease like alleles as found in the Human Gene Mutation Database from non-disease like alleles as found in the Database of Single Nucleotide Polymorphisms. This algorithm was subsequently applied to each base within all known human genes, exhaustively confirming that interspecies conservation is the strongest factor for disease association. For each gene, the length normalized average disease potential score was calculated. Out of the 30 genes with the highest scores, 21 are directly associated with a disease. In contrast, out of the 30 genes with the lowest scores, only one is associated with a disease as found in published literature. The results strongly suggest that the highest scoring genes are enriched for those that might contribute to disease, if mutated.</p> <p>Conclusion</p> <p>This method provides valuable information to researchers to identify sensitive positions in genes that have a high disease probability, enabling them to optimize experimental designs and interpret data emerging from genetic and epidemiological studies.</p

Characterization of Synaptically Connected Nuclei in a Potential Sensorimotor Feedback Pathway in the Zebra Finch Song System

Birdsong is a learned behavior that is controlled by a group of identified nuclei, known collectively as the song system. The cortical nucleus HVC (used as a proper name) is a focal point of many investigations as it is necessary for song production, song learning, and receives selective auditory information. HVC receives input from several sources including the cortical area MMAN (medial magnocellular nucleus of the nidopallium). The MMAN to HVC connection is particularly interesting as it provides potential sensorimotor feedback to HVC. To begin to understand the role of this connection, we investigated the physiological relation between MMAN and HVC activity with simultaneous multiunit extracellular recordings from these two nuclei in urethane anesthetized zebra finches. As previously reported, we found similar timing in spontaneous bursts of activity in MMAN and HVC. Like HVC, MMAN responds to auditory playback of the bird's own song (BOS), but had little response to reversed BOS or conspecific song. Stimulation of MMAN resulted in evoked activity in HVC, indicating functional excitation from MMAN to HVC. However, inactivation of MMAN resulted in no consistent change in auditory responses in HVC. Taken together, these results indicate that MMAN provides functional excitatory input to HVC but does not provide significant auditory input to HVC in anesthetized animals. We hypothesize that MMAN may play a role in motor reinforcement or coordination, or may provide modulatory input to the song system about the internal state of the animal as it receives input from the hypothalamus

Dual use of Medicare and the Veterans Health Administration: are there adverse health outcomes?

BACKGROUND: Millions of veterans are eligible to use the Veterans Health Administration (VHA) and Medicare because of their military service and age. This article examines whether an indirect measure of dual use based on inpatient services is associated with increased mortality risk. METHODS: Data on 1,566 self-responding men (weighted N = 1,522) from the Survey of Assets and Health Dynamics among the Oldest Old (AHEAD) were linked to Medicare claims and the National Death Index. Dual use was indirectly indicated when the self-reported number of hospital episodes in the 12 months prior to baseline was greater than that observed in the Medicare claims. The independent association of dual use with mortality was estimated using proportional hazards regression. RESULTS: 96 (11%) of the veterans were classified as dual users. 766 men (50.3%) had died by December 31, 2002, including 64.9% of the dual users and 49.3% of all others, for an attributable mortality risk of 15.6% (p < .003). Adjusting for demographics, socioeconomics, comorbidity, hospitalization status, and selection bias at baseline, as well as subsequent hospitalization for ambulatory care sensitive conditions, the independent effect of dual use was a 56.1% increased relative risk of mortality (AHR = 1.561; p = .009). CONCLUSION: An indirect measure of veterans' dual use of the VHA and Medicare systems, based on inpatient services, was associated with an increased risk of death. Further examination of dual use, especially in the outpatient setting, is needed, because dual inpatient and dual outpatient use may be different phenomena

The role of CSF1R-dependent macrophages in control of the intestinal stem cell niche

Colony-stimulating factor 1 (CSF1) controls the growth and differentiation of macrophages.CSF1R signaling has been implicated in the maintenance of the intestinal stem cell niche and differentiation of Paneth cells, but evidence of expression of CSF1R within the crypt is equivocal. Here we show that CSF1R-dependent macrophages influence intestinal epithelial differentiation and homeostasis. In the intestinal lamina propria CSF1R mRNA expression is restricted to macrophages which are intimately associated with the crypt epithelium, and is undetectable in Paneth cells. Macrophage ablation following CSF1R blockade affects Paneth cell differentiation and leads to a reduction of Lgr5 intestinal stem cells. The disturbances to the crypt caused by macrophage depletion adversely affect the subsequent differentiation of intestinal epithelial cell lineages. Goblet cell density is enhanced, whereas the development of M cells in Peyer's patches is impeded. We suggest that modification of the phenotype or abundance of macrophages in the gut wall alters the development of the intestinal epithelium and the ability to sample gut antigens

Magnetotransport in a pseudomorphic GaAs/GaInAs/GaAlAs heterostructure with a Si delta-doping layer

Magnetotransport properties of a pseudomorphic GaAs/Ga0.8In0.2As/Ga0.75Al0.25As heterostructure are investigated in pulsed magnetic fields up to 50 T and at temperatures of T=1.4 K and 4.2 K. The structure studied consists of a Si delta-layer parallel to a Ga0.8In0.2As quantum well (QW). The dark electron density of the structure is n_e=1.67x 10^16 m^-2. By illumination the density can be increased up to a factor of 4; this way the second subband in the Ga0.8In0.2As QW can become populated as well as the Si delta-layer. The presence of electrons in the delta-layer results in drastic changes in the transport data, especially at magnetic fields beyond 30 T. The phenomena observed are interpreted as: 1) magnetic freeze-out of carriers in the delta-layer when a low density of electrons is present in the delta-layer, and 2) quantization of the electron motion in the two dimensional electron gases in both the Ga0.8In0.2As QW and the Si delta-layer in the case of high densities. These conclusions are corroborated by the numerical results of our theoretical model. We obtain a satisfactory agreement between model and experiment.Comment: 23 pages, RevTex, 11 Postscript figures (accepted for Phys. Rev. B

Does urbanization explain differences in interactions between an insect herbivore and its natural enemies and mutualists?

Urbanization can alter the composition of arthropod communities. However, little is known about how urbanization affects ecological interactions. Using experimental colonies of the black bean aphid Aphis fabae Scopoli reared on Vicia faba L, we asked if patterns of predator-prey, host-parasitoid and ant-aphid mutualisms varied along an urbanization gradient across a large town in southern England. We recorded the presence of naturally occurring predators, parasitoid wasps and mutualistic ants together with aphid abundance. We examined how biotic (green areas and plant richness) and abiotic features (impervious surfaces and distance to town center) affected (1) aphid colony size, (2) the likelihood of finding predators, mutualistic ants and aphid mummies (indicating the presence of parasitoids), and (3) how the interplay among these factors affected patterns of parasitoid attack, predator abundance, mutualistic interactions and aphid abundance. The best model to predict aphid abundance was the number of mutualistic ants attending the colonies. Aphid predators responded negatively to both the proportion of impervious surfaces and to the number of mutualistic ants farming the colonies, and positively to aphid population size, whereas parasitized aphids were found in colonies with higher numbers of aphids and ants. The number of mutualistic ants attending was positively associated with aphid colony size and negatively with the number of aphid predators. Our findings suggest that for insect-natural enemy interactions, urbanization may affect some groups, while not influencing others, and that local effects (mutualists, host plant presence) will also be key determinants of how urban ecological communities are formed

Refinement and Pattern Formation in Neural Circuits by the Interaction of Traveling Waves with Spike-Timing Dependent Plasticity

Traveling waves in the developing brain are a prominent source of highly correlated spiking activity that may instruct the refinement of neural circuits. A candidate mechanism for mediating such refinement is spike-timing dependent plasticity (STDP), which translates correlated activity patterns into changes in synaptic strength. To assess the potential of these phenomena to build useful structure in developing neural circuits, we examined the interaction of wave activity with STDP rules in simple, biologically plausible models of spiking neurons. We derive an expression for the synaptic strength dynamics showing that, by mapping the time dependence of STDP into spatial interactions, traveling waves can build periodic synaptic connectivity patterns into feedforward circuits with a broad class of experimentally observed STDP rules. The spatial scale of the connectivity patterns increases with wave speed and STDP time constants. We verify these results with simulations and demonstrate their robustness to likely sources of noise. We show how this pattern formation ability, which is analogous to solutions of reaction-diffusion systems that have been widely applied to biological pattern formation, can be harnessed to instruct the refinement of postsynaptic receptive fields. Our results hold for rich, complex wave patterns in two dimensions and over several orders of magnitude in wave speeds and STDP time constants, and they provide predictions that can be tested under existing experimental paradigms. Our model generalizes across brain areas and STDP rules, allowing broad application to the ubiquitous occurrence of traveling waves and to wave-like activity patterns induced by moving stimuli

Search for neutral MSSM Higgs bosons decaying to a pair of tau leptons in pp collisions

Peer reviewe