The SOD2 C47T polymorphism influences NAFLD fibrosis severity: evidence from case-control and intra-familial allele association studies.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity. METHODS: The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients. RESULTS: In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)). CONCLUSIONS: Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH

Reconstruction of a function from its spherical (circular) means with the centers lying on the surface of certain polygons and polyhedra

We present explicit filtration/backprojection-type formulae for the inversion of the spherical (circular) mean transform with the centers lying on the boundary of some polyhedra (or polygons, in 2D). The formulae are derived using the double layer potentials for the wave equation, for the domains with certain symmetries. The formulae are valid for a rectangle and certain triangles in 2D, and for a cuboid, certain right prisms and a certain pyramid in 3D. All the present inversion formulae yield exact reconstruction within the domain surrounded by the acquisition surface even in the presence of exterior sources.Comment: 9 figure

Uniqueness of reconstruction and an inversion procedure for thermoacoustic and photoacoustic tomography

The paper contains a simple approach to reconstruction in Thermoacoustic and Photoacoustic Tomography. The technique works for any geometry of point detectors placement and for variable sound speed satisfying a non-trapping condition. A uniqueness of reconstruction result is also obtained

On the injectivity of the circular Radon transform arising in thermoacoustic tomography

The circular Radon transform integrates a function over the set of all spheres with a given set of centers. The problem of injectivity of this transform (as well as inversion formulas, range descriptions, etc.) arises in many fields from approximation theory to integral geometry, to inverse problems for PDEs, and recently to newly developing types of tomography. The article discusses known and provides new results that one can obtain by methods that essentially involve only the finite speed of propagation and domain dependence for the wave equation.Comment: To appear in Inverse Problem

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-offunction mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n¼40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC

Thermoacoustic tomography arising in brain imaging

We study the mathematical model of thermoacoustic and photoacoustic tomography when the sound speed has a jump across a smooth surface. This models the change of the sound speed in the skull when trying to image the human brain. We derive an explicit inversion formula in the form of a convergent Neumann series under the assumptions that all singularities from the support of the source reach the boundary

Developing an intervention to facilitate family communication about inherited genetic conditions, and training genetic counsellors in its delivery.

Many families experience difficulty in talking about an inherited genetic condition that affects one or more of them. There have now been a number of studies identifying the issues in detail, however few have developed interventions to assist families. The SPRinG collaborative have used the UK Medical Research Council's guidance on Developing and Evaluating Complex Interventions, to work with families and genetic counsellors (GCs) to co-design a psycho-educational intervention to facilitate family communication and promote better coping and adaptation to living with an inherited genetic condition for parents and their children (<18 years). The intervention is modelled on multi-family discussion groups (MFDGs) used in psychiatric settings. The MFDG was developed and tested over three phases. First focus groups with parents, young people, children and health professionals discussed whether MFDG was acceptable and proposed a suitable design. Using evidence and focus group data, the intervention and a training manual were developed and three GCs were trained in its delivery. Finally, a prototype MFDG was led by a family therapist and co-facilitated by the three GCs. Data analysis showed that families attending the focus groups and intervention thought MFDG highly beneficial, and the pilot sessions had a significant impact on their family' functioning. We also demonstrated that it is possible to train GCs to deliver the MFDG intervention. Further studies are now required to test the feasibility of undertaking a definitive randomised controlled trial to evaluate its effectiveness in improving family outcomes before implementing into genetic counselling practice.The National Institute of Health Research funded the study but any views expressed do not necessarily reflect those of the Authority. Funded by NIHR reference number: RP-DG-1211-10015

Lymphangiogenesis in myocardial remodelling after infarction

Ishikawa Y, Akishima-Fukasawa Y, Ito K, Akasaka Y, Tanaka M, Shimokawa R, Kimura-Matsumoto M, Morita H, Sato S, Kamata I & Ishii T (2007) Histopathology51, 345–35

An empirical algorithm for light absorption by ocean water based on color

Empirical algorithms for the total absorption coefficient and absorption coefficient by pigments for surface waters at 440 nm were developed by applying a quadratic formula that combines two spectral ratios of remote-sensing reflectance. For total absorption coefficients ranging from 0.02 to 2.0 m⁻¹, a goodness of fit was achieved between the measured and modeled data with a root-mean-squared difference between the measured and modeled values for log10 scale(RMSDₗₒ₁₀) of 0.062 (15.3% for linear scale, number of samples N = 63), while RMSDₗₒ₁₀ is 0.111 ( 29.1% for linear scale, N = 126) for pigment absorption (ranging from 0.01 to 1.0 m⁻¹). As alternatives to pigment concentration algorithms, the absorption algorithms developed can be applied to the coastal zone color scanner and sea-viewing wide-field-of-view sensor data to derive inherent optical properties of the ocean. For the same data sets, we also directly related the chlorophyll a concentrations to the spectral ratios and obtained an RMSDₗₒ₁₀ value of 0.218 (65.2% for linear scale, N = 120) for concentrations ranging from 0.06 to 50.0 mg m⁻³. These results indicate that it is more accurate to estimate the absorption coefficients than the pigment concentrations from remotely sensed data. This is likely due to the fact that for the broad range of waters studied the pigment-specific absorption coefficient at 440nm ranged from 0.02 to 0.2 m² (mg chl)⁻¹. As an indirect test of the algorithms developed, the chlorophyll a concentration algorithm is applied to an independent global dataset and an RMSDₗₒ₁₀ of 0.191( 55.2% for linear scale, N = 919) is obtained. There is no independent global absorption data set available as yet to test the absorption algorithms