961 research outputs found
Using epigenomic studies in monozygotic twins to improve our understanding of cancer
No full textCancer is a set of diseases that exhibit not only genetic mutations but also a profoundly distorted epigenetic landscape. Over the last two decades, great advances have been made in identifying these alterations and their importance in the initiation and progression of cancer. Epigenetic changes can be seen from the very early stages in tumorigenesis and dysregulation of the epigenome has an increasingly acknowledged pathogenic role. Epigenomic twin studies have great potential to contribute to our understanding of complex diseases, such as cancer. This is because the use of monozygotic twins discordant for cancer enables epigenetic variation analysis without the confounding influence of the constitutive genetic background, age or cohort effects. It therefore allows the identification of susceptibility loci that may be sensitive to modification by the environment. These studies into cancer etiology will potentially lead to robust epigenetic markers for the detection and risk assessment of cance
Birthweight, vitamin D receptor genotype and the programming of osteoporosis
No full textStudies of the association between polymorphisms of the gene for the vitamin D receptor (VDR) and adult bone mass have been inconsistent, pointing to the possibility that gene–environment interactions may vary in different populations. We have demonstrated previously an association between weight in infancy (a marker of the intrauterine and early post-natal environment) and each of adult bone mass and VDR genotype. We therefore sought to extend these observations in an elderly UK cohort and to investigate the possibility of an interaction between these genetic and early environmental markers of later osteoporosis risk. One hundred and sixty-five men and 126 women aged 61–73 years for whom birth records were available underwent bone mass measurements at baseline and follow-up 4 years later. Whole-blood samples were obtained, DNA extracted using standard techniques and polymorphisms in the VDR and collagen type I?1 (Col IA1) genes identified. In the cohort as a whole, there were no significant associations between either birthweight or VDR genotype and bone mineral density (BMD) or bone loss rate at either site. However, the relationship between lumbar spine BMD and VDR genotype varied according to birthweight. Among individuals in the lowest third of birthweight, spine BMD was higher (P = 0.01) in individuals of genotype ‘BB’ after adjustment for age, sex and weight at baseline. In contrast, spine BMD was reduced (P = 0.04) in individuals of the same genotype who were in the highest third of the birthweight distribution. A significant (P = 0.02) statistical interaction was also found between VDR genotype and birthweight as determinants of BMD. Similar but slightly weaker associations were seen between lumbar spine bone mineral content (BMC) and VDR genotype in the lowest birthweight tertile. When examining the relationship between Col1A1 genotype and bone mass, lumbar spine BMC was higher in individuals of genotype ‘Ss’ or ‘ss’ in the lowest birthweight tertile (P = 0.02) after adjustment for age, sex and weight at baseline. These results suggest that genetic influences on adult bone size and mineral density may be modified by undernutrition in utero
Effects of biochemical and mechanical stimulation of articular chondrocytes in collagen-GAG scaffolds : extracellular matrix biosynthesis and scaffold stiffness
No full textThesis (S.M.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2004.Includes bibliographical references (p. 55-59).As the incidence of osteoarthritis and other degenerative joint conditions continues to grow, rehabilitation via tissue engineering is becomingly increasingly attractive as an alternative to traditional surgical interventions. Chapters 2 and 3 of this thesis are specifically concerned with cartilage tissue engineering, while chapter 4 is relevant to bone and osteochondral tissue engineering. The cartilage tissue engineering sections focus on the effects of two different classes of regulators of chondrocyte behavior: chemical growth factors and mechanical loading. In chapter 2, FGF-2, a chemical regulator, was supplied to chondrocyte-seeded constructs over a 4 week culture period. Afterward, these constructs were subjected to sequential ramp and hold compressive strains on a Dynastat mechanical testing apparatus, and the unconfined elastic moduli were calculated. These data were compared to the values for scaffolds receiving no FGF. The results indicate that FGF-2 induced a significant increase in the modulus of chondrocyte-seeded scaffolds. Numerous reports indicate that certain types of mechanical loading can increase chondrocytes' ECM biosynthesis in particular cell-scaffold systems in vitro. Few if any loading experiments have been done, however, with type II collagen-GAG scaffolds cultured in serum-free medium. Chapter 3 describes a series of experiments in which chondrocyte-seeded scaffolds were subjected to dynamic compression and the effects of this treatment on the proliferation of the chondrocytes, their synthesis of ECM, and the stiffness of the scaffolds were measured. The results of these experiments were inconclusive. Analysis indicated that very few chondrocytes were retained in the scaffolds.(cont.) A post hoc investigation of the scaffolds revealed that they were biologically inactive due to their oversize pores. The low cell density was reflected in unusually low biosynthesis values and no significant differences in stiffness post-loading. The mechanical properties of implantable constructs such as stiffness and compressive strength are likely to significantly affect the clinical outcome. The fourth chapter describes measurements of the elastic modulus and ultimate compressive strength of a bone scaffold material. Five different scaffold formulations were tested, and the mechanical properties correlated with the variations in their composition.by Timothy D. Gordon.S.M
Congruence of additive and non-additive effects on gene expression estimated from pedigree and SNP data
No full textThere is increasing evidence that heritable variation in gene expression underlies genetic variation in susceptibility to disease. Therefore, a comprehensive understanding of the similarity between relatives for transcript variation is warranted-in particular, dissection of phenotypic variation into additive and non-additive genetic factors and shared environmental effects. We conducted a gene expression study in blood samples of 862 individuals from 312 nuclear families containing MZ or DZ twin pairs using both pedigree and genotype information. From a pedigree analysis we show that the vast majority of genetic variation across 17,994 probes is additive, although non-additive genetic variation is identified for 960 transcripts. For 180 of the 960 transcripts with non-additive genetic variation, we identify expression quantitative trait loci (eQTL) with dominance effects in a sample of 339 unrelated individuals and replicate 31% of these associations in an independent sample of 139 unrelated individuals. Over-dominance was detected and replicated for a trans association between rs12313805 and ETV6, located 4MB apart on chromosome 12. Surprisingly, only 17 probes exhibit significant levels of common environmental effects, suggesting that environmental and lifestyle factors common to a family do not affect expression variation for most transcripts, at least those measured in blood. Consistent with the genetic architecture of common diseases, gene expression is predominantly additive, but a minority of transcripts display non-additive effects
Mechanisms of top-down facilitation in perception of visual objects studied by fMRI
No full textPrior knowledge regarding the possible identity of an object facilitates its recognition from a degraded visual input, though the underlying mechanisms are unclear. Previous work implicated ventral visual cortex but did not disambiguate whether activity-changes in these regions are causal to or merely reflect an effect of facilitated recognition. We used functional magnetic resonance imaging to study top-down influences on processing of gradually revealed objects, by preceding each object with a name that was congruent or incongruent with the object. Congruently primed objects were recognized earlier than incongruently primed, and this was paralleled by shifts in activation profiles for ventral visual, parietal, and prefrontal cortices. Prior to recognition, defined on a trial-by-trial basis, activity in ventral visual cortex rose gradually but equivalently for congruently and incongruently primed objects. In contrast, prerecognition activity was greater with congruent priming in lateral parietal, retrosplenial, and lateral prefrontal cortices, whereas functional coupling between parietal and ventral visual (and also left lateral prefrontal and parietal) cortices was enhanced in the same context. Thus, when controlling for recognition point and stimulus information, activity in ventral visual cortex mirrors recognition success, independent of condition. Facilitation by top-down cues involves lateral parietal cortex interacting with ventral visual areas, potentially explaining why parietal lesions can lead to deficits in recognizing degraded objects even in the context of top-down knowledge
Determinants of pressure pain threshold in adult twins: evidence that shared environmental influences predominate
No full textThe objective of this study was to examine the relative contribution of genetic and environmental factors in determining pain perception in a classical twin study. Dolorimeter measurements of pressure pain threshold (PPT) were recorded in 609 healthy female-female twin pairs of whom 269 pairs were monozygotic (MZ) and 340 were dizygotic (DZ). There was a strong correlation (R) in PPT in both MZ and DZ pairs (R(MZ) = 0.57, 95% confidence interval (CI): [0.49, 0.65]; R(DZ) = 0.51, 95% CI: [0.42, 0.59]). The slight excess in intraclass correlation observed in MZ when compared with DZ twins corresponds to a heritability for PPT of only 10% and is not statistically significant. Neither estimate of intraclass correlation was substantially altered after adjusting for a range of potential confounding variables including age, current tobacco and alcohol use, current analgesic use, psychological status assessed by the general health questionnaire, and social class. The dolorimeter measurements were shown to be reliable (between observer agreement R = 0.66; within observer agreement R = 0.70-0.76) and stable over time. In conclusion, these data suggest that there is no significant genetic contribution to the strong correlation in PPT that is observed in twin pairs. These findings reinforce the view that learned patterns of behaviour within families are an important determinant of perceived sensitivity to pain.</p
A noninequality for the fractional gradient
No full textIn this paper we give a streamlined proof of an inequality recently obtained by the author: For every α∈(0,1) there exists a constant C=C(α,d)>0 such that
[Formula: see text]
for all u∈Lq(Rd) for some 1≤q<d/(1−α) such that Dαu:=∇I1−αu∈L1(Rd;Rd). We also give a counterexample which shows that in contrast to the case α=1, the fractional gradient does not admit an L1 trace inequality, i.e. [Formula: see text] cannot control the integral of u with respect to the Hausdorff content [Formula: see text]. The main substance of this counterexample is a result of interest in its own right, that even a weak-type estimate for the Riesz transforms fails on the space [Formula: see text], β∈[1,d). It is an open question whether this failure of a weak-type estimate for the Riesz transforms extends to β∈(0,1).journal articl
A sparse resolution of the DiPerna-Majda gap problem for D Euler equations
No full textA central question which originates in the celebrated work in the 1980\u27s of DiPerna and Majda asks what is the optimal decay such that uniform rates of the vorticity maximal functions guarantee strong convergence without concentrations of approximate solutions to energy-conserving weak solutions of the D Euler equations with vortex sheet initial data. A famous result of Majda (1993) shows , as a sufficient condition for the lack of concentrations, while the expected gap remains as an open question. In this paper we resolve the DiPerna-Majda D gap problem: In striking contrast to the well-known case of distinguished sign vortex sheets, we identify as the optimal regularity for mixed sign vortex sheets that rules out concentrations.
For the proof, we propose a novel method to construct explicitly solutions with mixed sign to the D Euler equations in such a way that wild behaviour creates within the relevant geometry of \emph{sparse} cubes (i.e., these cubes are not necessarily pairwise disjoint, but their possible overlappings can be controlled in a sharp fashion). Such a strategy is inspired by the recent work of the first author and Milman \cite{DM} where strong connections between energy conservation and sparseness are established.24 page
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