2,220 research outputs found
Determination of thermal conductivity of inhomogeneous orthotropic materials from temperature measurements
We consider the two-dimensional inverse determination of the thermal conductivity of inhomogeneous orthotropic materials from internal temperature measurements. The inverse problem is general and is classified as a function estimation since no prior information about the functional form of the thermal conductivity is assumed in the inverse calculation. The least-squares functional minimizing naturally the gap between the measured and computed temperature leads to a set of direct, sensitivity and adjoint problems, which have forms of direct well-posed initial boundary value problems for the heat equation, and new formulas for its gradients are derived. The conjugate gradient method employs recursively the solution of these problems at each iteration. Stopping the iterations according to the discrepancy principle criterion yields a stable solution. The employment of the Sobolev -gradient is shown to result in much more robust and accurate numerical reconstructions than when the standard -gradient is used
Duplication of the EFNB1 Gene in Familial Hypertelorism: Imbalance in Ephrin-B1 Expression and Abnormal Phenotypes in Humans and Mice
Familial hypertelorism, characterized by widely spaced eyes, classically shows autosomal dominant inheritance (Teebi type), but some pedigrees are compatible with X-linkage. No mechanism has been described previously, but clinical similarity has been noted to craniofrontonasal syndrome (CFNS), which is caused by mutations in the X-linked EFNB1 gene. Here we report a family in which females in three generations presented with hypertelorism, but lacked either craniosynostosis or a grooved nasal tip, excluding CFNS. DNA sequencing of EFNB1 was normal, but further analysis revealed a duplication of 937 kb including EFNB1 and two flanking genes: PJA1 and STARD8. We found that the X chromosome bearing the duplication produces ∼1.6-fold more EFNB1 transcript than the normal X chromosome and propose that, in the context of X-inactivation, this difference in expression level of EFNB1 results in abnormal cell sorting leading to hypertelorism. To support this hypothesis, we provide evidence from a mouse model carrying a targeted human EFNB1 cDNA, that abnormal cell sorting occurs in the cranial region. Hence, we propose that X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. Hum Mutat 32:1–9, 2011. © 2011 Wiley-Liss, Inc
The characteristic blue spectra of accretion disks in quasars as uncovered in the infrared
Quasars are thought to be powered by supermassive black holes accreting
surrounding gas. Central to this picture is a putative accretion disk which is
believed to be the source of the majority of the radiative output. It is well
known, however, that the most extensively studied disk model -- an optically
thick disk which is heated locally by the dissipation of gravitational binding
energy -- is apparently contradicted by observations in a few major respects.
In particular, the model predicts a specific blue spectral shape asymptotically
from the visible to the near-infrared, but this is not generally seen in the
visible wavelength region where the disk spectrum is observable. A crucial
difficulty was that, toward the infrared, the disk spectrum starts to be hidden
under strong hot dust emission from much larger but hitherto unresolved scales,
and thus has essentially been impossible to observe. Here we report
observations of polarized light interior to the dust-emiting region that enable
us to uncover this near-infrared disk spectrum in several quasars. The revealed
spectra show that the near-infrared disk spectrum is indeed as blue as
predicted. This indicates that, at least for the outer near-infrared-emitting
radii, the standard picture of the locally heated disk is approximately
correct. The model problems at shorter wavelengths should then be directed
toward a better understanding of the inner parts of the revealed disk. The
newly uncovered disk emission at large radii, with more future measurements,
will also shed totally new light on the unanswered critical question of how and
where the disk ends.Comment: published in Nature, 24 July 2008 issue. Supplementary Information
can be found at
http://www.mpifr-bonn.mpg.de/div/ir-interferometry/suppl_info.pdf Published
version can be accessed from
http://www.nature.com/nature/journal/v454/n7203/pdf/nature07114.pd
'Sifting the significance from the data' - the impact of high-throughput genomic technologies on human genetics and health care.
This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK's Economic and Social Research Council. The meeting was arranged to explore ideas as to the likely future course of human genomics. The achievements of genomics research were reviewed, and the likely constraints on the pace of future progress were explored. New knowledge is transforming biology and our understanding of evolution and human disease. The difficulties we face now concern the interpretation rather than the generation of new sequence data. Our understanding of gene-environment interaction is held back by our current primitive tools for measuring environmental factors, and in addition, there may be fundamental constraints on what can be known about these complex interactions.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
Biallelic CPAMD8 variants are a frequent cause of childhood and juvenile open-angle glaucoma
Purpose: Developmental abnormalities of the ocular anterior segment in some cases can lead to ocular hypertension and glaucoma. CPAMD8 is a gene of unknown function recently associated with ocular anterior segment dysgenesis, myopia, and ectopia lentis. We sought to assess the contribution of biallelic CPAMD8 variants to childhood and juvenile open-angle glaucoma. Design: Retrospective, multicenter case series. Participants: A total of 268 probands and their relatives with a diagnosis of childhood or juvenile open-angle glaucoma. Methods: Patients underwent a comprehensive ophthalmic assessment, with DNA from patients and their relatives subjected to genome, exome, or capillary sequencing. CPAMD8 RNA expression analysis was performed on tissues dissected from cadaveric human eyes. Main outcome measures: Diagnostic yield within a cohort of childhood and juvenile open-angle glaucoma, prevalence and risk of ophthalmic phenotypes, and relative expression of CPAMD8 in the human eye. Results: We identified rare (allele frequency -5) biallelic CPAMD8 variants in 5.7% (5/88) of probands with childhood glaucoma and 2.1% (2/96) of probands with juvenile open-angle glaucoma. When including family members, we identified 11 individuals with biallelic variants in CPAMD8 from 7 unrelated families. Nine of these individuals were diagnosed with glaucoma (9/11, 81.8%), with a mean age at diagnosis of 9.22±14.89 years, and all individuals with glaucoma required 1 or more incisional procedures to control high intraocular pressure. Iris abnormalities were observed in 9 of 11 individuals, cataract was observed in 8 of 11 individuals (72.7%), and retinal detachment was observed in 3 of 11 individuals (27.3%). CPAMD8 expression was highest in neural crest-derived tissues of the adult anterior segment, suggesting that CPAMD8 variation may cause malformation or obstruction of key drainage structures. Conclusions: Biallelic CPAMD8 variation was associated with a highly heterogeneous phenotype and in our cohorts was the second most common inherited cause of childhood glaucoma after CYP1B1 and juvenile open-angle glaucoma after MYOC. CPAMD8 sequencing should be considered in the investigation of both childhood and juvenile open-angle glaucoma, particularly when associated with iris abnormalities, cataract, or retinal detachment
Exploring the Free Energy Landscape: From Dynamics to Networks and Back
The knowledge of the Free Energy Landscape topology is the essential key to
understand many biochemical processes. The determination of the conformers of a
protein and their basins of attraction takes a central role for studying
molecular isomerization reactions. In this work, we present a novel framework
to unveil the features of a Free Energy Landscape answering questions such as
how many meta-stable conformers are, how the hierarchical relationship among
them is, or what the structure and kinetics of the transition paths are.
Exploring the landscape by molecular dynamics simulations, the microscopic data
of the trajectory are encoded into a Conformational Markov Network. The
structure of this graph reveals the regions of the conformational space
corresponding to the basins of attraction. In addition, handling the
Conformational Markov Network, relevant kinetic magnitudes as dwell times or
rate constants, and the hierarchical relationship among basins, complete the
global picture of the landscape. We show the power of the analysis studying a
toy model of a funnel-like potential and computing efficiently the conformers
of a short peptide, the dialanine, paving the way to a systematic study of the
Free Energy Landscape in large peptides.Comment: PLoS Computational Biology (in press
Empathy, engagement, entrainment: the interaction dynamics of aesthetic experience
A recent version of the view that aesthetic experience is based in empathy as inner
imitation explains aesthetic experience as the automatic simulation of actions,
emotions, and bodily sensations depicted in an artwork by motor neurons in the brain. Criticizing the simulation theory for committing to an erroneous concept of empathy and failing to distinguish regular from aesthetic experiences of art, I advance an alternative, dynamic approach and claim that aesthetic experience is enacted and skillful, based in the recognition of others’ experiences as distinct from one’s own. In combining insights from mainly psychology, phenomenology, and cognitive science, the dynamic approach aims to explain the emergence of aesthetic experience in terms of the reciprocal interaction between viewer and artwork. I argue that aesthetic experience emerges by participatory sense-making and revolves around movement as a means for creating meaning. While entrainment merely plays a preparatory part in this, aesthetic engagement constitutes the phenomenological side of coupling to an artwork and provides the context for exploration, and eventually for moving, seeing, and feeling with art. I submit that aesthetic experience emerges from bodily and emotional engagement with works of art via the complementary processes of the perception–action and motion–emotion loops. The former involves the embodied
visual exploration of an artwork in physical space, and progressively structures and organizes visual experience by way of perceptual feedback from body movements made in response to the artwork. The latter concerns the movement qualities and shapes of implicit and explicit bodily responses to an artwork that cue emotion and thereby modulate over-all affect and attitude. The two processes cause the viewer to bodily and emotionally move with and be moved by individual works of art, and consequently to recognize another psychological orientation than her own, which explains how art can cause feelings of insight or awe and disclose aspects of life that are unfamiliar or novel to the viewer
Bayesian paternity analysis and mating patterns in a parasitic nematode, Trichostrongylus tenuis
Mating behaviour is a fundamental aspect of the evolutionary ecology of sexually reproducing species, but one that has been under-researched in parasitic nematodes. We analysed mating behaviour in the parasitic nematode Trichostrongylus tenuis by performing a paternity analysis in a population from a single red grouse host. Paternity of the 150 larval offspring of 25 mothers (sampled from one of the two host caeca) was assigned among 294 candidate fathers (sampled from both caeca). Each candidate father's probability of paternity of each offspring was estimated from 10-locus microsatellite genotypes. Seventy-six (51%) offspring were assigned a father with a probability of >0.8, and the estimated number of unsampled males was 136 (95% credible interval (CI) 77-219). The probability of a male from one caecum fathering an offspring in the other caecum was estimated as 0.024 (95% CI 0.003-0.077), indicating that the junction of the caeca is a strong barrier to dispersal. Levels of promiscuity (defined as the probability of two of an adult's offspring sharing only one parent) were high for both sexes. Variance in male reproductive success was moderately high, possibly because of a combination of random mating and high variance in post-copulatory reproductive success. These results provide the first data on individual mating behaviour among parasitic nematodes
Progressive improvement of impaired visual acuity during the first year after transsphenoidal surgery for non-functioning pituitary macroadenoma
Improvement of visual field defects continues even years after the initial surgical treatment. Because this process of continuing improvement has not been documented for visual acuity, we audited our data to explore the pattern of recovery of visual acuity until 1 year after transsphenoidal surgery for non-functioning pituitary macroadenoma. Retrospective follow-up study. Forty-three patients (mean age 56 +/- 14 years), treated by transsphenoidal surgery for non-functioning pituitary macroadenoma, were included in this analysis. Visual acuity improved significantly within 3 months after transsphenoidal surgery. The mean visual acuity increased from 0.65 +/- 0.37 to 0.75 +/- 0.36 (P <0.01) (right eye), and from 0.60 +/- 0.32 to 0.82 +/- 0.30 (P <0.01) (left eye). Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values. The mean visual acuity increased from 0.75 +/- 0.36 to 0.82 +/- 0.34 (P <0.05) (right eye), and from 0.82 +/- 0.30 to 0.88 +/- 0.27 (P <0.05) (left eye). Visual acuity improves progressively after surgical treatment for non-functioning pituitary macroadenomas, at least within the first year after transsphenoidal surger
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