Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis

Common fragile sites (cfs) are specific regions in the human genome that are particularly prone to genomic instability under conditions of replicative stress. Several investigations support the view that common fragile sites play a role in carcinogenesis. We discuss a genome-wide approach based on graph theory and Gene Ontology vocabulary for the functional characterization of common fragile sites and for the identification of genes that contribute to tumour cell biology. CFS were assembled in a network based on a simple measure of correlation among common fragile site patterns of expression. By applying robust measurements to capture in quantitative terms the non triviality of the network, we identified several topological features clearly indicating departure from the Erdos-Renyi random graph model. The most important outcome was the presence of an unexpected large connected component far below the percolation threshold. Most of the best characterized common fragile sites belonged to this connected component. By filtering this connected component with Gene Ontology, statistically significant shared functional features were detected. Common fragile sites were found to be enriched for genes associated to the immune response and to mechanisms involved in tumour progression such as extracellular space remodeling and angiogenesis. Our results support the hypothesis that fragile sites serve a function; we propose that fragility is linked to a coordinated regulation of fragile genes expression.Comment: 18 pages, accepted for publication in BMC Bioinformatic

Liver Progenitor Cell Line HepaRG Differentiated in a Bioartificial Liver Effectively Supplies Liver Support to Rats with Acute Liver Failure

A major roadblock to the application of bioartificial livers is the need for a human liver cell line that displays a high and broad level of hepatic functionality. The human bipotent liver progenitor cell line HepaRG is a promising candidate in this respect, for its potential to differentiate into hepatocytes and bile duct cells. Metabolism and synthesis of HepaRG monolayer cultures is relatively high and their drug metabolism can be enhanced upon treatment with 2% dimethyl sulfoxide (DMSO). However, their potential for bioartificial liver application has not been assessed so far. Therefore, HepaRG cells were cultured in the Academic Medical Center bioartificial liver (AMC-BAL) with and without DMSO and assessed for their hepatic functionality in vitro and in a rat model of acute liver failure. HepaRG-AMC-BALs cultured without DMSO eliminated ammonia and lactate, and produced apolipoprotein A-1 at rates comparable to freshly isolated hepatocytes. Cytochrome P450 3A4 transcript levels and activity were high with 88% and 37%, respectively, of the level of hepatocytes. DMSO treatment of HepaRG-AMC-BALs reduced the cell population and the abovementioned functions drastically. Therefore, solely HepaRG-AMC-BALs cultured without DMSO were tested for efficacy in rats with acute liver failure (n = 6). HepaRG-AMC-BAL treatment increased survival time of acute liver failure rats ∼50% compared to acellular-BAL treatment. Moreover, HepaRG-AMC-BAL treatment decreased the progression of hepatic encephalopathy, kidney failure, and ammonia accumulation. These results demonstrate that the HepaRG-AMC-BAL is a promising bioartificial liver for clinical application

The functional anatomy of semantic retrieval is influenced by gender, menstrual cycle, and sex hormones

This study examines the neurobiology of semantic retrieval and describes the influence of gender, menstrual cycle, and sex hormones on semantic networks. Healthy right-handed subjects (12 men, 12 women) were investigated with 3T-fMRI during synonym generation. Behavioral performance and sex hormone levels were assessed. Women were examined during the early follicular and midluteal cycle phase. The activation pattern in all groups involved left frontal and temporal as well as bilateral medial frontal, cingulate, occipital, basal ganglia, and cerebellar regions. Men showed greater left frontal activation than women in both menstrual cycle phases. Women yielded high correlations of left prefrontal activation with estradiol in the midluteal phase and with progesterone in both phases. Testosterone levels correlated highly with left prefrontal activation in all three groups. In all, we describe a cerebral network involved in semantic processing and demonstrate that it is significantly affected by gender and sex steroid hormones

A Synthesis of Tagging Studies Examining the Behaviour and Survival of Anadromous Salmonids in Marine Environments

This paper synthesizes tagging studies to highlight the current state of knowledge concerning the behaviour and survival of anadromous salmonids in the marine environment. Scientific literature was reviewed to quantify the number and type of studies that have investigated behaviour and survival of anadromous forms of Pacific salmon (Oncorhynchus spp.), Atlantic salmon (Salmo salar), brown trout (Salmo trutta), steelhead (Oncorhynchus mykiss), and cutthroat trout (Oncorhynchus clarkii). We examined three categories of tags including electronic (e.g. acoustic, radio, archival), passive (e.g. external marks, Carlin, coded wire, passive integrated transponder [PIT]), and biological (e.g. otolith, genetic, scale, parasites). Based on 207 papers, survival rates and behaviour in marine environments were found to be extremely variable spatially and temporally, with some of the most influential factors being temperature, population, physiological state, and fish size. Salmonids at all life stages were consistently found to swim at an average speed of approximately one body length per second, which likely corresponds with the speed at which transport costs are minimal. We found that there is relatively little research conducted on open-ocean migrating salmonids, and some species (e.g. masu [O. masou] and amago [O. rhodurus]) are underrepresented in the literature. The most common forms of tagging used across life stages were various forms of external tags, coded wire tags, and acoustic tags, however, the majority of studies did not measure tagging/handling effects on the fish, tag loss/failure, or tag detection probabilities when estimating survival. Through the interdisciplinary application of existing and novel technologies, future research examining the behaviour and survival of anadromous salmonids could incorporate important drivers such as oceanography, tagging/handling effects, predation, and physiology

Long-Term Climate Forcing in Loggerhead Sea Turtle Nesting

The long-term variability of marine turtle populations remains poorly understood, limiting science and management. Here we use basin-scale climate indices and regional surface temperatures to estimate loggerhead sea turtle (Caretta caretta) nesting at a variety of spatial and temporal scales. Borrowing from fisheries research, our models investigate how oceanographic processes influence juvenile recruitment and regulate population dynamics. This novel approach finds local populations in the North Pacific and Northwest Atlantic are regionally synchronized and strongly correlated to ocean conditions—such that climate models alone explain up to 88% of the observed changes over the past several decades. In addition to its performance, climate-based modeling also provides mechanistic forecasts of historical and future population changes. Hindcasts in both regions indicate climatic conditions may have been a factor in recent declines, but future forecasts are mixed. Available climatic data suggests the Pacific population will be significantly reduced by 2040, but indicates the Atlantic population may increase substantially. These results do not exonerate anthropogenic impacts, but highlight the significance of bottom-up oceanographic processes to marine organisms. Future studies should consider environmental baselines in assessments of marine turtle population variability and persistence

Histone methyltransferase Dot1 and Rad9 inhibit single-stranded DNA accumulation at DSBs and uncapped telomeres

Cells respond to DNA double-strand breaks (DSBs) and uncapped telomeres by recruiting checkpoint and repair factors to the site of lesions. Single-stranded DNA (ssDNA) is an important intermediate in the repair of DSBs and is produced also at uncapped telomeres. Here, we provide evidence that binding of the checkpoint protein Rad9, through its Tudor domain, to methylated histone H3-K79 inhibits resection at DSBs and uncapped telomeres. Loss of DOT1 or mutations in RAD9 influence a Rad50-dependent nuclease, leading to more rapid accumulation of ssDNA, and faster activation of the critical checkpoint kinase, Mec1. Moreover, deletion of RAD9 or DOT1 partially bypasses the requirement for CDK1 in DSB resection. Interestingly, Dot1 contributes to checkpoint activation in response to low levels of telomere uncapping but is not essential with high levels of uncapping. We suggest that both Rad9 and histone H3 methylation allow transmission of the damage signal to checkpoint kinases, and keep resection of damaged DNA under control influencing, both positively and negatively, checkpoint cascades and contributing to a tightly controlled response to DNA damage

Evaluation of a health promotion program in children: Study protocol and design of the cluster-randomized Baden-Württemberg primary school study [DRKS-ID: DRKS00000494]

<p>Abstract</p> <p>Background</p> <p>Increasing prevalences of overweight and obesity in children are known problems in industrialized countries. Early prevention is important as overweight and obesity persist over time and are related with health problems later in adulthood. "Komm mit in das gesunde Boot - Grundschule" is a school-based program to promote a healthier lifestyle. Main goals of the intervention are to increase physical activity, decrease the consumption of sugar-sweetened beverages, and to decrease time spent sedentary by promoting active choices for healthy lifestyle. The program to date is distributed by 34 project delivery consultants in the state of Baden-Württemberg and is currently implemented in 427 primary schools. The efficacy of this large scale intervention is examined via the Baden-Württemberg Study.</p> <p>Methods/Design</p> <p>The Baden-Württemberg Study is a prospective, stratified, cluster-randomized, and longitudinal study with two groups (intervention group and control group). Measurements were taken at the beginning of the academic years 2010/2011 and 2011/2012. Efficacy of the intervention is being assessed using three main outcomes: changes in waist circumference, skinfold thickness and 6 minutes run. Stratified cluster-randomization (according to class grade level) was performed for primary schools; pupils, teachers/principals, and parents were investigated. An approximately balanced number of classes in intervention group and control group could be reached by stratified randomization and was maintained at follow-up.</p> <p>Discussion</p> <p>At present, "Komm mit in das Gesunde Boot - Grundschule" is the largest school-based health promotion program in Germany. Comparative objective main outcomes are used for the evaluation of efficacy. Simulations showed sufficient power with the existing sample size. Therefore, the results will show whether the promotion of a healthier lifestyle in primary school children is possible using a relatively low effort within a school-based program involving children, teachers and parents. The research team anticipates that not only efficacy will be proven in this study but also expects many other positive effects of the program.</p> <p>Trial registration</p> <p>German Clinical Trials Register (DRKS), DRKS-ID: DRKS00000494</p

Non-pharmacological management of osteoporosis: a consensus of the Belgian Bone Club

This consensus article reviews the various aspects of the non-pharmacological management of osteoporosis, including the effects of nutriments, physical exercise, lifestyle, fall prevention, and hip protectors. Vertebroplasty is also briefly reviewed. Non-pharmacological management of osteoporosis is a broad concept. It must be viewed as an essential part of the prevention of fractures from childhood through adulthood and the old age. The topic also includes surgical procedures for the treatment of peripheral and vertebral fractures and the post-fracture rehabilitation. The present document is the result of a consensus, based on a systematic review and a critical appraisal of the literature. Diets deficient in calcium, proteins or vitamin D impair skeletal integrity. The effect of other nutriments is less clear, although an excessive consumption of sodium, caffeine, or fibres exerts negative effects on calcium balance. The deleterious effects of tobacco, excessive alcohol consumption and a low BMI are well accepted. Physical activity is of primary importance to reach optimal peak bone mass but, if numerous studies have shown the beneficial effects of various types of exercise on bone mass, fracture data as an endpoint are scanty. Fall prevention strategies are especially efficient in the community setting, but less evidence is available about their effectiveness in preventing fall-related injuries and fractures. The efficacy of hip protectors remains controversial. This is also true for vertebroplasty and kyphoplasty. Several randomized controlled studies had reported a short-term advantage of vertebroplasty over medical treatment for pain relief, but these findings have been questioned by recent sham-controlled randomized clinical studies