Higher moment singularities explored by the net proton non-statistical fluctuations

We use the non-statistical fluctuation instead of the full one to explore the higher moment singularities of net proton event distributions in the relativistic Au+Au collisions at $\sqrt{s_{NN}}$ from 11.5 to 200 GeV calculated by the parton and hadron cascade model PACIAE. The PACIAE results of mean ($M$), variance ($\sigma^2$), skewness ($S$), and kurtosis ($\kappa$) are consistent with the corresponding STAR data. Non-statistical moments are calculated as the difference between the moments derived from real events and the ones from mixed events, which are constructed by combining particles randomly selected from different real events. An evidence of singularity at $\sqrt{s_{NN}}\sim$ 60 GeV is first seen in the energy dependent non-statistical $S$ and $S\sigma$.Comment: 5 pages,5 figure

Commentary: Tracing the fate of metabolic substrates during changes in whole-body energy expenditure in mice

For small mammals, such as mice, cannulation procedures can be quite challenging, limiting research associated with tracing isotopically labelled substrates at the whole-animal level. When cannulation in mice is possible, assessment of substrate use is further limited to when mice are either under anesthesia or are at rest, as there are no studies directly quantifying substrate use during exercise in mice. The use of isotopic tracer techniques has greatly advanced our knowledge in understanding how metabolic substrates (carbohydrates, amino acids, and fatty acids) contribute to whole-body metabolism. However, research regarding tissue-specific fuel use contributions to whole-body energy expenditure in mice at varying metabolic intensities (i.e., exercise) is lacking, despite the popularity of using mice in a variety of metabolic models. In this commentary, we briefly discuss the methodologies, advantages, and disadvantages of using radiolabelled, positron emission, and stable isotopes with a specific focus on fatty acids. We highlight recent mouse studies that have used creative experimental designs employing the use of isotopic tracer techniques and we briefly discuss how these methodologies can be further pursued to deepen our understanding of substrate use during exercise. Lastly, we show findings of a recent study we performed using a radiolabelled fatty acid tracer (14C-bromopalmitic acid) to determine fatty acid uptake in 16 muscles, two brown and two white adipose tissue depots during submaximal exercise in deer mice

Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue

During maximal cold challenge (cold-induced V̇O2,max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and probably plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V̇O2,max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab-born and -raised highland and lowland deer mice, acclimated to either thermoneutral (30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V̇O2,max, CH-acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to thermoneutral highlanders, a response that was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and β-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher levels of fatty acid translocase CD36 (FAT/CD36) in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to chronic cold hypoxia, and combined with higher rates of tissue delivery, this contributes to their survival in the cold high alpine environment

Thermogenesis is supported by high rates of circulatory fatty acid and triglyceride delivery in highland deer mice

Highland native deer mice (Peromyscus maniculatus) have greater rates of lipid oxidation during maximal cold challenge in hypoxia (hypoxic cold-induced V̇O2,max) compared with their lowland conspecifics. Lipid oxidation is also increased in deer mice acclimated to simulated high altitude (cold hypoxia), regardless of altitude ancestry. The underlying lipid metabolic pathway traits responsible for sustaining maximal thermogenic demand in deer mice is currently unknown. The objective of this study was to characterize key steps in the lipid oxidation pathway in highland and lowland deer mice acclimated to control (23°C, 21 kPa O2) or cold hypoxic (5°C, 12 kPa O2) conditions. We hypothesized that capacities for lipid delivery and tissue uptake will be greater in highlanders and further increase with cold hypoxia acclimation. With the transition from rest to hypoxic cold-induced V̇O2,max, both highland and lowland deer mice showed increased plasma glycerol concentrations and fatty acid availability. Interestingly, acclimation to cold hypoxia led to increased plasma triglyceride concentrations at cold-induced V̇O2,max, but only in highlanders. Highlanders also had significantly greater delivery rates of circulatory free fatty acids and triglycerides due to higher plasma flow rates at cold-induced V̇O2,max. We found no population or acclimation differences in fatty acid translocase (FAT/CD36) abundance in the gastrocnemius or brown adipose tissue, suggesting that fatty acid uptake across membranes is not limiting during thermogenesis. Our data indicate that circulatory lipid delivery plays a major role in supporting the high thermogenic rates observed in highland versus lowland deer mice

Fuel Use in Mammals: Conserved Patterns and Evolved Strategies for Aerobic Locomotion and Thermogenesis

SYNOPSIS: Effective aerobic locomotion depends on adequate delivery of oxygen and an appropriate allocation of metabolic substrates. The use of metabolic substrates during exercise follows a predictive pattern of lipid and carbohydrate oxidation that is similar in lowland native cursorial mammals. We have found that in two highland lineages of mice (Phyllotis and Peromyscus) the fuel use pattern is shifted to a greater reliance on carbohydrates compared to their lowland conspecifics and congenerics. However, there is variation between lineages in the importance of phenotypic plasticity in the expression of this metabolic phenotype. Moreover, this metabolic phenotype is independent of running aerobic capacity and can also be independent of thermogenic capacity. For example, wild-caught mice from a highland population of deer mice (Peromyscus maniculatus) housed in warm normoxic laboratory conditions maintain higher maximum cold-induced oxygen consumption in acute hypoxia than lowland congenerics, but shivering and non-shivering thermogenesis is supported by high rates of lipid oxidation. This is reflected in the consistently higher activities of oxidative and fatty acid oxidation enzymes in the gastrocnemius of highland deer mice compared to lowlanders, which are resistant to hypoxia acclimation. While a fixed trait in muscle aerobic capacity may reflect the pervasive and unremitting low PO2 at high altitudes, muscle capacities for substrate oxidation may be more flexible to match appropriate substrate use with changing energetic demands. How shivering thermogenesis and locomotion potentially interact in the matching of muscle metabolic capacities to appropriate substrate use is unclear. Perhaps it is possible that shivering serves as "training" to ensure muscles have the capacity to support locomotion or visa-versa

Histone Acetylation-Mediated Regulation of the Hippo Pathway

The Hippo pathway is a signaling cascade recently found to play a key role in tumorigenesis therefore understanding the mechanisms that regulate it should open new opportunities for cancer treatment. Available data indicate that this pathway is controlled by signals from cell-cell junctions however the potential role of nuclear regulation has not yet been described. Here we set out to verify this possibility and define putative mechanism(s) by which it might occur. By using a luciferase reporter of the Hippo pathway, we measured the effects of different nuclear targeting drugs and found that chromatin-modifying agents, and to a lesser extent certain DNA damaging drugs, strongly induced activity of the reporter. This effect was not mediated by upstream core components (i.e. Mst, Lats) of the Hippo pathway, but through enhanced levels of the Hippo transducer TAZ. Investigation of the underlying mechanism led to the finding that cancer cell exposure to histone deacetylase inhibitors induced secretion of growth factors and cytokines, which in turn activate Akt and inhibit the GSK3 beta associated protein degradation complex in drug-affected as well as in their neighboring cells. Consequently, expression of EMT genes, cell migration and resistance to therapy were induced. These processes were suppressed by using pyrvinium, a recently described small molecule activator of the GSK 3 beta associated degradation complex. Overall, these findings shed light on a previously unrecognized phenomenon by which certain anti-cancer agents may paradoxically promote tumor progression by facilitating stabilization of the Hippo transducer TAZ and inducing cancer cell migration and resistance to therapy. Pharmacological targeting of the GSK3 beta associated degradation complex may thus represent a unique approach to treat cancer. © 2013 Basu et al

Spatially valid proprioceptive cues improve the detection of a visual stimulus

Vision and proprioception are the main sensory modalities that convey hand location and direction of movement. Fusion of these sensory signals into a single robust percept is now well documented. However, it is not known whether these modalities also interact in the spatial allocation of attention, which has been demonstrated for other modality pairings. The aim of this study was to test whether proprioceptive signals can spatially cue a visual target to improve its detection. Participants were instructed to use a planar manipulandum in a forward reaching action and determine during this movement whether a near-threshold visual target appeared at either of two lateral positions. The target presentation was followed by a masking stimulus, which made its possible location unambiguous, but not its presence. Proprioceptive cues were given by applying a brief lateral force to the participant’s arm, either in the same direction (validly cued) or in the opposite direction (invalidly cued) to the on-screen location of the mask. The d′ detection rate of the target increased when the direction of proprioceptive stimulus was compatible with the location of the visual target compared to when it was incompatible. These results suggest that proprioception influences the allocation of attention in visual spac

Living with severe allergy: an Anaphylaxis Campaign national survey of young people

<p>Abstract</p> <p>Background</p> <p>The transition to adulthood can be particularly challenging for young people with severe allergies, who must learn to balance personal safety with independent living. Information and support for young people and their families are crucial to successfully managing this transition. We sought to: gather insights into the impact of severe allergies on the lives of young people; explore where young people go for information about anaphylaxis and what information they want and need; identify areas where further support is needed.</p> <p>Methods</p> <p>An online questionnaire survey of young people aged 15–25 years with severe allergies in the United Kingdom (UK) was conducted on behalf of the Anaphylaxis Campaign, the main patient support organisation. Participants were recruited mainly from the Anaphylaxis Campaign membership database and also via allergy clinics and social media. The study was funded by the Anaphylaxis Campaign’s In Memoriam Fund.</p> <p>Results</p> <p>A total of 520 young people responded to the survey. The majority had lived with severe allergies since they were young children; 59% reported having attended Accident and Emergency units as a consequence of their allergies. Only 66% of respondents reported always carrying their epinephrine auto-injectors; only 23% had ever used these. Few were currently receiving specialist allergy care; younger respondents were more likely to be under specialist care (34%) than those 18 years and above (23%). Respondents wanted more information about eating out (56%), travelling (54%) and food labelling (43%). Almost a quarter of respondents (23%) reported needing more information on managing their allergies independently without parental help. Managing allergies in the context of social relationships was a concern for 22% of respondents.</p> <p>Conclusions</p> <p>This survey has identified the information and support needs and gaps in service provision for young people with severe allergies. Healthcare professionals and patient support organisations, with the support of the food industry, can help to meet these needs.</p