Human 13N-ammonia PET studies: the importance of measuring 13N-ammonia metabolites in blood

Dynamic 13N-ammonia PET is used to assess ammonia metabolism in brain, liver and muscle based on kinetic modeling of metabolic pathways, using arterial blood 13N-ammonia as input function. Rosenspire et al. (1990) introduced a solid phase extraction procedure for fractionation of 13N-content in blood into 13N-ammonia, 13N-urea, 13N-glutamine and 13N-glutamate. Due to a radioactive half-life for 13N of 10 min, the procedure is not suitable for blood samples taken beyond 5–7 min after tracer injection. By modifying Rosenspire’s method, we established a method enabling analysis of up to 10 blood samples in the course of 30 min. The modified procedure was validated by HPLC and by 30-min reproducibility studies in humans examined by duplicate 13N-ammonia injections with a 60-min interval. Blood data from a 13N-ammonia brain PET study (from Keiding et al. 2006) showed: (1) time courses of 13N-ammonia fractions could be described adequately by double exponential functions; (2) metabolic conversion of 13N-ammonia to 13N-metabolites were in the order: healthy subjects > cirrhotic patients without HE > cirrhotic patients with HE; (3) kinetics of initial tracer distribution in tissue can be assessed by using total 13N-concentration in blood as input function, whereas assessment of metabolic processes requires 13N-ammonia measurements

Influence of environmental parameters on movements and habitat utilization of humpback whales (Megaptera novaeangliae) in the Madagascar breeding ground

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Royal Society Open Science 3 (2016): 160616, doi:10.1098/rsos.160616.Assessing the movement patterns and key habitat features of breeding humpback whales is a prerequisite for the conservation management of this philopatric species. To investigate the interactions between humpback whale movements and environmental conditions off Madagascar, we deployed 25 satellite tags in the northeast and southwest coast of Madagascar. For each recorded position, we collated estimates of environmental variables and computed two behavioural metrics: behavioural state of ‘transiting’ (consistent/directional) versus ‘localized’ (variable/non-directional), and active swimming speed (i.e. speed relative to the current). On coastal habitats (i.e. bathymetry < 200 m and in adjacent areas), females showed localized behaviour in deep waters (191 ± 20 m) and at large distances (14 ± 0.6 km) from shore, suggesting that their breeding habitat extends beyond the shallowest waters available close to the coastline. Males' active swimming speed decreased in shallow waters, but environmental parameters did not influence their likelihood to exhibit localized movements, which was probably dominated by social factors instead. In oceanic habitats, both males and females showed localized behaviours in shallow waters and favoured high chlorophyll-a concentrations. Active swimming speed accounts for a large proportion of observed movement speed; however, breeding humpback whales probably exploit prevailing ocean currents to maximize displacement. This study provides evidence that coastal areas, generally subject to strong human pressure, remain the core habitat of humpback whales off Madagascar. Our results expand the knowledge of humpback whale habitat use in oceanic habitat and response to variability of environmental factors such as oceanic current and chlorophyll level.Funding was provided by Total Foundation to NeuroPSI, and by individuals and foundations to the WCS Ocean Giants Program

Prenatal Diagnosis of Oculocutaneous Albinism by Electron Microscopy of Fetal Skin

Oculocutaneous albinism was diagnosed prenatally by electron microscopic examination of fetal skin samples taken during fetoscopy at 20 weeks of gestation. Melanosome development in hair bulb melanocytes progressed no further than stage II, indicating a lack of melanin synthesis. In 4 age-matched control fetuses, numerous stage IV melanosomes, signifying active melanin synthesis, were identified. The diagnosis was confirmed after the pregnancy was terminated at 22 weeks. Examination of the fetal eye showed absence of pigment in the retinal epithelium and uvea at a stage when ocular melanogenesis would normally be active. This study shows that oculocutaneous albinism can be detected in the second trimester using similar techniques to those employed in the prenatal diagnosis of epidermolysis bullosa and ichthyosis

A systems approach to identifying correlated gene targets for the loss of colour pigmentation in plants

<p>Abstract</p> <p>Background</p> <p>The numerous diverse metabolic pathways by which plant compounds can be produced make it difficult to predict how colour pigmentation is lost for different tissues and plants. This study employs mathematical and <it>in silico </it>methods to identify correlated gene targets for the loss of colour pigmentation in plants from a whole cell perspective based on the full metabolic network of <it>Arabidopsis</it>. This involves extracting a self-contained flavonoid subnetwork from the AraCyc database and calculating feasible metabolic routes or elementary modes (EMs) for it. Those EMs leading to anthocyanin compounds are taken to constitute the anthocyanin biosynthetic pathway (ABP) and their interplay with the rest of the EMs is used to study the minimal cut sets (MCSs), which are different combinations of reactions to block for eliminating colour pigmentation. By relating the reactions to their corresponding genes, the MCSs are used to explore the phenotypic roles of the ABP genes, their relevance to the ABP and the impact their eliminations would have on other processes in the cell.</p> <p>Results</p> <p>Simulation and prediction results of the effect of different MCSs for eliminating colour pigmentation correspond with existing experimental observations. Two examples are: i) two MCSs which require the simultaneous suppression of genes DFR and ANS to eliminate colour pigmentation, correspond to observational results of the same genes being co-regulated for eliminating floral pigmentation in <it>Aquilegia </it>and; ii) the impact of another MCS requiring CHS suppression, corresponds to findings where the suppression of the early gene CHS eliminated nearly all flavonoids but did not affect the production of volatile benzenoids responsible for floral scent.</p> <p>Conclusions</p> <p>From the various MCSs identified for eliminating colour pigmentation, several correlate to existing experimental observations, indicating that different MCSs are suitable for different plants, different cells, and different conditions and could also be related to regulatory genes. Being able to correlate the predictions with experimental results gives credence to the use of these mathematical and <it>in silico </it>analyses methods in the design of experiments. The methods could be used to prioritize target enzymes for different objectives to achieve desired outcomes, especially for less understood pathways.</p

The genetic mating system of a sea spider with male-biased sexual size dimorphism: evidence for paternity skew despite random mating success

Male-biased size dimorphism is usually expected to evolve in taxa with intense male–male competition for mates, and it is hence associated with high variances in male mating success. Most species of pycnogonid sea spiders exhibit female-biased size dimorphism, and are notable among arthropods for having exclusive male parental care of embryos. Relatively little, however, is known about their natural history, breeding ecology, and mating systems. Here we first show that Ammothella biunguiculata, a small intertidal sea spider, exhibits male-biased size dimorphism. Moreover, we combine genetic parentage analysis with quantitative measures of sexual selection to show that male body size does not appear to be under directional selection. Simulations of random mating revealed that mate acquisition in this species is largely driven by chance factors, although actual paternity success is likely non-randomly distributed. Finally, the opportunity for sexual selection (Is), an indirect metric for the potential strength of sexual selection, in A. biunguiculata males was less than half of that estimated in a sea spider with female-biased size dimorphism, suggesting the direction of size dimorphism may not be a reliable predictor of the intensity of sexual selection in this group. We highlight the suitability of pycnogonids as model systems for addressing questions relating parental investment and sexual selection, as well as the current lack of basic information on their natural history and breeding ecology

Precision medicine driven by cancer systems biology

Molecular insights from genome and systems biology are influencing how cancer is diagnosed and treated. We critically evaluate big data challenges in precision medicine. The melanoma research community has identified distinct subtypes involving chronic sun-induced damage and the mitogen-activated protein kinase driver pathway. In addition, despite low mutation burden, non-genomic mitogen-activated protein kinase melanoma drivers are found in membrane receptors, metabolism, or epigenetic signaling with the ability to bypass central mitogen-activated protein kinase molecules and activating a similar program of mitogenic effectors. Mutation hotspots, structural modeling, UV signature, and genomic as well as non-genomic mechanisms of disease initiation and progression are taken into consideration to identify resistance mutations and novel drug targets. A comprehensive precision medicine profile of a malignant melanoma patient illustrates future rational drug targeting strategies. Network analysis emphasizes an important role of epigenetic and metabolic master regulators in oncogenesis. Co-occurrence of driver mutations in signaling, metabolic, and epigenetic factors highlights how cumulative alterations of our genomes and epigenomes progressively lead to uncontrolled cell proliferation. Precision insights have the ability to identify independent molecular pathways suitable for drug targeting. Synergistic treatment combinations of orthogonal modalities including immunotherapy, mitogen-activated protein kinase inhibitors, epigenetic inhibitors, and metabolic inhibitors have the potential to overcome immune evasion, side effects, and drug resistance

The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration

Apoptosis is a programmed cell death that plays a critical role during the development of the nervous system and in many chronic neurodegenerative diseases, including Alzheimer's disease (AD). This pathology, characterized by a progressive degeneration of cholinergic function resulting in a remarkable cognitive decline, is the most common form of dementia with high social and economic impact. Current therapies of AD are only symptomatic, therefore the need to elucidate the mechanisms underlying the onset and progression of the disease is surely needed in order to develop effective pharmacological therapies. Because of its pivotal role in neuronal cell death, apoptosis has been considered one of the most appealing therapeutic targets, however, due to the complexity of the molecular mechanisms involving the various triggering events and the many signaling cascades leading to cell death, a comprehensive understanding of this process is still lacking. Modular systems biology is a very effective strategy in organizing information about complex biological processes and deriving modular and mathematical models that greatly simplify the identification of key steps of a given process. This review aims at describing the main steps underlying the strategy of modular systems biology and briefly summarizes how this approach has been successfully applied for cell cycle studies. Moreover, after giving an overview of the many molecular mechanisms underlying apoptosis in AD, we present both a modular and a molecular model of neuronal apoptosis that suggest new insights on neuroprotection for this disease