A novel splice variant of the DNA-PKcs gene is associated with clinical and cellular radiosensivity in a patient with xeroderma pigmentosum

Background: Radiotherapy-induced DNA double-strand breaks (DSBs) are critical cytotoxic lesions. Inherited defects in DNA DSB repair pathways lead to hypersensitivity to ionising radiation, immunodeficiency and increased cancer incidence. A patient with xeroderma pigmentosum complementation group C, with a scalp angiosarcoma, exhibited dramatic clinical radiosensitivity following radiotherapy, resulting in death. A fibroblast cell line from non-affected skin (XP14BRneo17) was hypersensitive to ionising radiation and defective in DNA DSB repair. Aim: To determine the genetic defect causing cellular radiation hypersensitivity in XP14BRneo17 cells. Methods: Functional genetic complementation whereby copies of human chromosomes containing genes involved in DNA DSB repair (chromosomes 2, 5, 8 10, 13 and 22) were individually transferred to XP14BRneo17 cells in an attempt to correct the radiation hypersensitivity. Clonogenic survival assays and g-H2AX immunofluorescence were conducted to measure radiation sensitivity and repair of DNA DSBs. DNA sequencing of defective DNA repair genes was performed. Results: Transfer of chromosome 8 (location of DNAPKcs gene) and transfection of a mammalian expression construct containing the DNA-PKcs cDNA restored normal ionising radiation sensitivity and repair of DNA DSBs in XP14BRneo17 cells. DNA sequencing of the DNA-PKcs coding region revealed a 249-bp deletion (between base pairs 3656 and 3904) encompassing exon 31 of the gene. Conclusion: We provide evidence of a novel splice variant of the DNA-PKcs gene associated with radiosensitivity in a patient with xeroderma pigmentosum and report the first double mutant in distinct DNA repair pathways being consistent with viability

Animal Models of Bone Loss in Inflammatory Arthritis: from Cytokines in the Bench to Novel Treatments for Bone Loss in the Bedside—a Comprehensive Review

Throughout life, bone is continuously remodelled. Bone is formed by osteoblasts, from mesenchymal origin, while osteoclasts induce bone resorption. This process is tightly regulated. During inflammation, several growth factors and cytokines are increased inducing osteoclast differentiation and activation, and chronic inflammation is a condition that initiates systemic bone loss. Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that is characterised by active synovitis and is associated with early peri-articular bone loss. Peri-articular bone loss precedes focal bone erosions, which may progress to bone destruction and disability. The incidence of generalised osteoporosis is associated with the severity of arthritis in RA and increased osteoporotic vertebral and hip fracture risk. In this review, we will give an overview of different animal models of inflammatory arthritis related to RA with focus on bone erosion and involvement of pro-inflammatory cytokines. In addition, a humanised endochondral ossification model will be discussed, which can be used in a translational approach to answer osteoimmunological questions

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density

Studies on the interaction between the estrogen and vitamin D endocrine system

Estrogen deficiency and vitamin D deficiency play key roles in the pathogenesis of postmenopausal osteoporosis. Aim of the studies in this thesis is to extend our knowledge on the interaction between E2 and 1,25-(0H)2D3 and thereby to provide more insight into the significance of E, for 1,25-(0H)2D3 mediated processes in calcium and bone metabolism. Furthermore the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR genotypes in relation to BMD and fracture risk are studied. The first part of the thesis focuses on the effect of E2 on 1,25-(0H)2D3 mediated processes. In chapters 2 and 3 the effect of E, deficiency and E2 repletion on 1,25-(0H),D, synthesis and 1,25-(0H)2D3 mediated intestinal calcium absorption in a rat model for postmenopausal osteoporosis is described. An important bone anabolic factor is IGF-1. Both 1,25-(0H)2D3 as well as Ez have been shown to regulate IGF-I expression in vitro. Chapter 4 describes the effect of E, deficiency and E2 repletion on IGF-I levels in bone in vivo in relation to bone metabolism. The effect of E2 on bone mineralization is discussed in Chapter 5. The second part of the thesis considers the significance of VDR genotypes for the biological response to 1,25-(0H)2D3 and the interaction between ERa and VDR gene polymorphisms in relation to BMD and fracture risk. Chapter 6 describes a pilot study addressed to whether differences in rates of bone turnover between women with either extremely low or extremely high BMD can be ascribed to genetic variations of the VDR. Furthermore, the biochemical response to short-term substitution of 1,25-(0H)2D3 in both BMD groups was related to VDR gene polymorphisms. In chapter 7 functional consequences of VDR gene polymorphisms in vitro are studied. Chapter 8 discusses the association between ERa gene polymorphism and fracture risk in postmenopausal women. Moreover, the interaction between ERa gene and VDR gene polymorphisms on fracture risk is described. In chapter 9 the results are discussed and suggestions for future research are made. Finally, the main findings are summarized in Chapter 10

Interaction between vitamin D receptor genotype and estrogen receptor alpha genotype influences vertebral fracture risk

In view of the interactions of vitamin D and the estrogen endocrine system, we studied the combined influence of polymorphisms in the estrogen receptor (ER) alpha gene and the vitamin D receptor (VDR) gene on the susceptibility to osteoporotic vertebral fractures in 634 women aged 55 yr and older. Three VDR haplotypes (1, 2, and 3) of the BsmI, ApaI, and TaqI restriction fragment length polymorphisms and three ERalpha haplotypes (1, 2, and 3) of the PvuII and XbaI restriction fragment length polymorphisms were identified. We captured 131 nonvertebral and 85 vertebral fracture cases during a mean follow-up period of 7 yr. ERalpha haplotype 1 was dose-dependently associated with increased vertebral fracture risk (P < 0.001) corresponding to an odds ratio of 1.9 [95% confidence interval (CI), 0.9-4.1] per copy of the risk allele. VDR haplotype 1 was overrepresented in vertebral fracture cases. There was a significant interaction (P = 0.01) between ERalpha haplotype 1 and VDR haplotype 1 in determining vertebral fracture risk. The association of ERalpha haplotype 1 with vertebral fracture risk was only present in homozygous carriers of VDR haplotype 1. The risk of fracture was 2.5 (95% CI, 0.6-9.9) for heterozygous and 10.3 (95% CI, 2.7-40) for homozygous carriers of ERalpha haplotype 1. These associations were independent of bone mineral density. In conclusion, interaction between ERalpha and VDR gene polymorphisms leads to increased risk of osteoporotic vertebral fractures in women, largely independent of bone mineral density

Higher serum vitamin D3 levels are associated with better cognitive test performance in patients with Alzheimer's disease

Background/Aims: Recent studies suggest that vitamin D metabolites may be important for preserving cognitive function via specific neuroprotective effects. No large studies have examined the association between vitamin D status and cognition. Methods: In this cross-sectional study, we analyzed the serum 25-hydroxyvitamin D3levels and Mini-Mental State Examination (MMSE) test scores of 225 older outpatients who were diagnosed as having probable Alzheimer's disease (AD). In addition to the 25-hydroxyvitamin D3levels, we analyzed the serum vitamin B1, B6and B12levels. Results: An association was found between MMSE test scores and serum 25-hydroxyvitamin D3levels, with a β-coefficient of 0.05 (p = 0.01). Vitamin-D-sufficient patients had significantly higher MMSE scores as compared to vitamin-D-insufficient ones. No association was found with the other serum vitamin levels. Conclusions: These data support the idea that a relationship exists between vitamin D status and cognition in patients with probable AD. However, given the cross-sectional design of this study, no causality can be concluded. Further prospective studies are needed to specify the contribution of vitamin D status to the onset and course of cognitive decline and AD. Copyrigh

Methodological framework for World Health Organization estimates of the global burden of foodborne disease

Background: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization to estimate the global burden of foodborne diseases (FBDs). This paper describes the methodological framework developed by FERG's Computational Task Force to transform epidemiological information into FBD burden estimates. Methods and Findings: The global and regional burden of 31 FBDs was quantified, along with limited estimates for 5 other FBDs, using Disability-Adjusted Life Years in a hazard- and incidence-based approach. To accomplish this task, the following workflow was defined: outline of disease models and collection of epidemiological data; design and completion of a database template; development of an imputation model; identification of disability weights; probabilistic burden assessment; and estimating the proportion of the disease burden by each hazard that is attributable to exposure by food (i.e., source attribution). All computations were performed in R and the different functions were compiled in the R package 'FERG'. Traceability and transparency were ensured by sharing results and methods in an interactive way with all FERG members throughout the process. Conclusions: We developed a comprehensive framework for estimating the global burden of FBDs, in which methodological simplicity and transparency were key elements. All the tools developed have been made available and can be translated into a user-friendly national toolkit for studying and monitoring food safety at the local level

Nearshore movement ecology of a medium-bodied shark, the creek whaler Carcharhinus fitzroyensis

Background: The movement and habitat use patterns of medium-bodied nearshore sharks are poorly understood. However, these species face some of the highest levels of exposure to anthropogenic development. The habitat and space use strategies species exhibit affect their role within communities and how they respond to environmental change. The present study used passive acoustic telemetry to evaluate the residency, space use, and habitat use patterns of the creek whaler Carcharhinus fitzroyensis in a nearshore embayment in Queensland, Australia. Results: Individuals were monitored for approximately 18 months. Half of the monitored population were highly resident to the bay. In contrast, several individuals spent less than 2 weeks in the bay, suggesting that broader movements may occur in a portion of the population. Size had no effect on residency. Activity space size varied between months and time of day but was also not affected by animal size. All C. fitzroyensis spent the majority of time in seagrass habitat (70%) and deep water (>5 m) mud substrate (20%). Shallow mudflat, sandy inshore, and reef habitats were rarely used (7%). Although the sample size of immature individuals was relatively small, results indicated immature and mature C. fitzroyensis shared space and habitats. Conclusions: Overall, C. fitzroyensis used a combination of nearshore movement patterns typically exhibited by small- and large-bodied species. The movement patterns exhibited by C. fitzroyensis suggest that this species has a moderately high degree of seagrass habitat specialisation. Seagrass habitat is typically highly productive and may be an important foraging habitat for this species. Given the consistent use of seagrass habitat, C. fitzroyensis are likely vulnerable to population decline as a result of seagrass habitat loss. Future research should continue to investigate the unique movements of medium-bodied sharks

Interface state contribution to the photovoltaic effect in organic phototransistors:Photocapacitance measurements and optical sensing

Made available in DSpace on 2018-12-11T16:50:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2018-01-01Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Instituto Nacional de Ciência e Tecnologia em Eletrônica OrgânicaWe report the results of an investigation into the contribution that trapping in interface states makes to the photovoltaic effect observed in organic phototransistors. To isolate this effect from other processes that occur in the transistor structure when under illumination, we focus attention on the photo-response of metal-insulator-semiconductor (MIS) capacitors - the core structure of transistors. The capacitors comprised poly(3-hexylthiophene), (P3HT), as the active semiconductor in combination with one of three insulators, namely, poly(amide-imide), (PAI), SU-8 photoresist and polysilsesquioxane (PSQ). Following initial characterization in the dark, the capacitor response was measured both during and after irradiation with light in the wavelength range 400–700 nm. Three different approaches were employed to study the photo-response, each providing a different insight into the processes occurring. Capacitance-voltage sweeps before, during and after illumination provided direct evidence supporting the view that the photovoltaic effect occurred as a result of electron trapping in interface states of density up to ∼2 × 1012 cm−2 in the P3HT/PAI combination but lower for SU-8 and PSQ. The dynamic photo-response, in which device capacitance was held constant by changing the applied bias, showed a fast component related to optically induced photoconduction in the semiconductor and a slower component reflecting the dynamics of interface electron trapping. Finally, photo-induced capacitance changes occurring with constant applied voltage were used to demonstrate a simple 3 × 3 imaging array.School of Electronic Engineering Bangor University, Dean StreetBrazilian Nanotechnology National Laboratory (LNNano) Brazilian Centre of Research in Energy and Materials (CNPEM)Department of Physics São Paulo State University (UNESP), PO Box 266Institute of Physics of São Carlos University of São Paulo (USP), PO Box 369Catarinense Federal Institute of Education Science and Technology, PO Box 21Department of Physics São Paulo State University (UNESP), PO Box 26