Time-dependent response of a zonally averaged ocean–atmosphere–sea ice model to Milankovitch forcing

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Springer-Verlag for personal use, not for redistribution. The definitive version was published in Climate Dynamics 6 (2010): 763-779, doi:10.1007/s00382-010-0790-6.An ocean-atmosphere-sea ice model is developed to explore the time-dependent response of climate to Milankovitch forcing for the time interval 5-3 Myr BP. The ocean component is a zonally averaged model of the circulation in five basins (Arctic, Atlantic, Indian, Pacific, and Southern Oceans). The atmospheric component is a one-dimensional (latitudinal) energy balance model, and the sea-ice component is a thermodynamic model. Two numerical experiments are conducted. The first experiment does not include sea ice and the Arctic Ocean; the second experiment does. Results from the two experiments are used to investigate (i) the response of annual mean surface air and ocean temperatures to Milankovitch forcing, and (ii) the role of sea ice in this response. In both experiments, the response of air temperature is dominated by obliquity cycles at most latitudes. On the other hand, the response of ocean temperature varies with latitude and depth. Deep water formed between 45°N-65°N in the Atlantic Ocean mainly responds to precession. In contrast, deep water formed south of 60°S responds to obliquity when sea ice is not included. Sea ice acts as a time-integrator of summer insolation changes such that annual mean sea-ice conditions mainly respond to obliquity. Thus, in the presence of sea ice, air temperature changes over the sea ice are amplified, and temperature changes in deep water of southern origin are suppressed since water below sea ice is kept near the freezing point.This work was supported by an NSERC Discovery Grant awarded to L.A.M. We also thank GEC3 for a Network Grant

Heterogeneity of human adipose blood flow

BACKGROUND: The long time pharmacokinetics of highly lipid soluble compounds is dominated by blood-adipose tissue exchange and depends on the magnitude and heterogeneity of adipose blood flow. Because the adipose tissue is an infinite sink at short times (hours), the kinetics must be followed for days in order to determine if the adipose perfusion is heterogeneous. The purpose of this paper is to quantitate human adipose blood flow heterogeneity and determine its importance for human pharmacokinetics. METHODS: The heterogeneity was determined using a physiologically based pharmacokinetic model (PBPK) to describe the 6 day volatile anesthetic data previously published by Yasuda et. al. The analysis uses the freely available software PKQuest and incorporates perfusion-ventilation mismatch and time dependent parameters that varied from the anesthetized to the ambulatory period. This heterogeneous adipose perfusion PBPK model was then tested by applying it to the previously published cannabidiol data of Ohlsson et. al. and the cannabinol data of Johansson et. al. RESULTS: The volatile anesthetic kinetics at early times have only a weak dependence on adipose blood flow while at long times the pharmacokinetics are dominated by the adipose flow and are independent of muscle blood flow. At least 2 adipose compartments with different perfusion rates (0.074 and 0.014 l/kg/min) were needed to describe the anesthetic data. This heterogeneous adipose PBPK model also provided a good fit to the cannabinol data. CONCLUSION: Human adipose blood flow is markedly heterogeneous, varying by at least 5 fold. This heterogeneity significantly influences the long time pharmacokinetics of the volatile anesthetics and tetrahydrocannabinol. In contrast, using this same PBPK model it can be shown that the long time pharmacokinetics of the persistent lipophilic compounds (dioxins, PCBs) do not depend on adipose blood flow. The ability of the same PBPK model to describe both the anesthetic and cannabinol kinetics provides direct qualitative evidence that their kinetics are flow limited and that there is no significant adipose tissue diffusion limitation

Come for the looks, stay for the personality? A mixed methods investigation of reacquisition and owner recommendation of Bulldogs, French Bulldogs and Pugs

Brachycephalic breeds are proliferating internationally, with dramatic rises in popularity juxtaposed with common and severe breed-related health problems. Physical appearance is as a dominant factor attracting owners to brachycephalic breeds; however, whether these owners will choose their current breed for future ownership and develop 'breed-loyalty' in the face of health problems is not yet known. The aims of this study were (1) to quantify levels of, and explore factors associated with, brachycephalic dog owners' intentions to: (i) reacquire and/or (ii) recommend their current breed to potential first-time dog owners, and (2) to use qualitative methods to explore why brachycephalic dog owners would or would not recommend their current breed. This large mixed methods study reports on 2168 owners of brachycephalic breeds (Pugs: n = 789; French Bulldog: n = 741; Bulldogs: n = 638). Owners were highly likely to want to own their breed again in the future (93.0%) and recommend their breed to other owners (65.5%). Statistical modelling identified that first-time ownership and increased strength of the dog-owner relationship increased the likelihood of reacquisi-tion and/or recommendation. In contrast, an increased number of health problems, positive perception of their dog's health compared with the rest of their breed, and dog behaviour being worse than expected decreased the likelihood of reacquisition and/or recommendation. Thematic analyses constructed three themes describing why owners recommend their breed: positive behavioural attributes for a companion dog, breed suited to a sedentary lifestyle with limited space, and suitability for households with children. Five themes described why owners recommended against their breed: high prevalence of health problems, expense of ownership, ethical and welfare issues associated with breeding brachycephalic dogs, negative effects upon owner lifestyle and negative behavioural attributes. Understanding how breed-loyalty develops, and whether it can be attenuated, will be key to controlling the current population boom in brachycephalic breeds in the long-term

Muscle weakness and lack of reflex gain adaptation predominate during post-stroke posture control of the wrist

Instead of hyper-reflexia as sole paradigm, post-stroke movement disorders are currently considered the result of a complex interplay between neuronal and muscular properties, modified by level of activity. We used a closed loop system identification technique to quantify individual contributors to wrist joint stiffness during an active posture task. Continuous random torque perturbations applied to the wrist joint by a haptic manipulator had to be resisted maximally. Reflex provoking conditions were applied i.e. additional viscous loads and reduced perturbation signal bandwidth. Linear system identification and neuromuscular modeling were used to separate joint stiffness into the intrinsic resistance of the muscles including co-contraction and the reflex mediated contribution. Compared to an age and sex matched control group, patients showed an overall 50% drop in intrinsic elasticity while their reflexive contribution did not respond to provoking conditions. Patients showed an increased mechanical stability compared to control subjects. Post stroke, we found active posture tasking to be dominated by: 1) muscle weakness and 2) lack of reflex adaptation. This adds to existing doubts on reflex blocking therapy as the sole paradigm to improve active task performance and draws attention to muscle strength and power recovery and the role of the inability to modulate reflexes in post stroke movement disorders.Mechanical, Maritime and Materials Engineerin

A comparison of nicotine dose estimates in smokers between filter analysis, salivary cotinine, and urinary excretion of nicotine metabolites

RATIONALE: Nicotine uptake during smoking was estimated by either analyzing the metabolites of nicotine in various body fluids or by analyzing filters from smoked cigarettes. However, no comparison of the filter analysis method with body fluid analysis methods has been published. OBJECTIVES: Correlate nicotine uptake estimates between filter analysis, salivary cotinine, and urinary excretion of selected nicotine metabolites to determine the suitability of these methods in estimating nicotine absorption in smokers of filtered cigarettes. MATERIALS AND METHODS: A 5-day clinical study was conducted with 74 smokers who smoked 1–19 mg Federal Trade Commission tar cigarettes, using their own brands ad libitum. Filters were analyzed to estimate the daily mouth exposure of nicotine. Twenty-four-hour urine samples were collected and analyzed for nicotine, cotinine, and 3′-hydroxycotinine plus their glucuronide conjugates. Saliva samples were collected daily for cotinine analysis. RESULTS: Each method correlated significantly (p < 0.01) with the other two. The best correlation was between the mouth exposure of nicotine, as estimated by filter analysis, and urinary nicotine plus metabolites. Multiple regression analysis implies that saliva cotinine and urinary output are dependent on nicotine mouth exposure for multiple days. Creatinine normalization of the urinary metabolites degrades the correlation with mouth exposure. CONCLUSIONS: The filter analysis method was shown to correlate with more traditional methods of estimating nicotine uptake. However, because filter analysis is less complicated and intrusive, subjects can collect samples easily and unsupervised. This should enable improvements in study compliance and future study designs

Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases

Current antibiotics tend to be broad spectrum, leading to indiscriminate killing of commensal bacteria and accelerated evolution of drug resistance. Here, we use CRISPR-Cas technology to create antimicrobials whose spectrum of activity is chosen by design. RNA-guided nucleases (RGNs) targeting specific DNA sequences are delivered efficiently to microbial populations using bacteriophage or bacteria carrying plasmids transmissible by conjugation. The DNA targets of RGNs can be undesirable genes or polymorphisms, including antibiotic resistance and virulence determinants in carbapenem-resistant Enterobacteriaceae and enterohemorrhagic Escherichia coli. Delivery of RGNs significantly improves survival in a Galleria mellonella infection model. We also show that RGNs enable modulation of complex bacterial populations by selective knockdown of targeted strains based on genetic signatures. RGNs constitute a class of highly discriminatory, customizable antimicrobials that enact selective pressure at the DNA level to reduce the prevalence of undesired genes, minimize off-target effects and enable programmable remodeling of microbiota.National Institutes of Health (U.S.) (New Innovator Award 1DP2OD008435)National Centers for Systems Biology (U.S.) (Grant 1P50GM098792)United States. Defense Threat Reduction Agency (HDTRA1-14-1-0007)Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies (W911NF13D0001)National Institute of General Medical Sciences (U.S.) (Interdepartmental Biotechnology Training Program 5T32 GM008334)Fonds de la recherche en sante du Quebec (Master's Training Award

Synthetic biology approaches in drug discovery and pharmaceutical biotechnology

Synthetic biology is the attempt to apply the concepts of engineering to biological systems with the aim to create organisms with new emergent properties. These organisms might have desirable novel biosynthetic capabilities, act as biosensors or help us to understand the intricacies of living systems. This approach has the potential to assist the discovery and production of pharmaceutical compounds at various stages. New sources of bioactive compounds can be created in the form of genetically encoded small molecule libraries. The recombination of individual parts has been employed to design proteins that act as biosensors, which could be used to identify and quantify molecules of interest. New biosynthetic pathways may be designed by stitching together enzymes with desired activities, and genetic code expansion can be used to introduce new functionalities into peptides and proteins to increase their chemical scope and biological stability. This review aims to give an insight into recently developed individual components and modules that might serve as parts in a synthetic biology approach to pharmaceutical biotechnology

Identification and Characterization of the Lamprey High-Mobility Group Box 1 Gene

High-mobility group box 1 (HMGB1), a highly conserved DNA-binding protein, plays an important role in maintaining nucleosome structures, transcription, and inflammation. We identified a homolog of HMGB1 in the Japanese lamprey (Lampetra japonica). The Lampetra japonica HMGB1 gene (Lj-HMGB1) has over 70% sequence identity with its homologs in jawed vertebrates. Despite the reasonably high sequence identity with other HMGB1 proteins, Lj-HMGB1 did not group together with these proteins in a phylogenetic analysis. We examined Lj-HMGB1 expression in lymphocyte-like cells, and the kidneys, heart, gills, and intestines of lampreys before and after the animals were challenged with lipopolysaccharide (LPS) and concanavalin A (ConA). Lj-HMGB1 was initially expressed at a higher level in the heart, but after treatment with LPS and ConA only the gills demonstrated a significant up-regulation of expression. The recombinant Lj-HMGB1 (rLj-HMGB1) protein bound double-stranded DNA and induced the proliferation of human adenocarcinoma cells to a similar extent as human HMGB1. We further revealed that Lj-HMGB1 was able to induce the production of tumor necrosis factor-α (TNF-α), a pro-inflammatory mediator, in activated human acute monocytic leukemia cells. These results suggest that lampreys use HMGB1 to activate their innate immunity for the purpose of pathogen defense