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Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology


Ketone bodies are the most energy-efficient fuel and yield more ATP per mole of substrate than pyruvate and increase the free energy released from ATP hydrolysis. Elevation of circulating ketones via high-fat, low-carbohydrate diets has been used for the treatment of drug-refractory epilepsy and for neurodegenerative diseases, such as Parkinson’s disease. Ketones may also be beneficial for muscle and brain in times of stress, such as endurance exercise. The challenge has been to raise circulating ketone levels by using a palatable diet without altering lipid levels. We found that blood ketone levels can be increased and cholesterol and triglycerides decreased by feeding rats a novel ketone ester diet: chow that is supplemented with ®-3-hydroxybutyl ®-3-hydroxybutyrate as 30% of calories. For 5 d, rats on the ketone diet ran 32% further on a treadmill than did control rats that ate an isocaloric diet that was supplemented with either corn starch or palm oil (P < 0.05). Ketone-fed rats completed an 8-arm radial maze test 38% faster than did those on the other diets, making more correct decisions before making a mistake (P < 0.05). Isolated, perfused hearts from rats that were fed the ketone diet had greater free energy available from ATP hydrolysis during increased work than did hearts from rats on the other diets as shown by using [(31)P]-NMR spectroscopy. The novel ketone diet, therefore, improved physical performance and cognitive function in rats, and its energy-sparing properties suggest that it may help to treat a range of human conditions with metabolic abnormalities.-Murray, A. J., Knight, N. S., Cole, M. A., Cochlin, L. E., Carter, E., Tchabanenko, K., Pichulik, T., Gulston, M. K., Atherton, H. J., Schroeder, M. A., Deacon, R. M. J., Kashiwaya, Y., King, M. T., Pawlosky, R., Rawlins, J. N. P., Tyler, D. J., Griffin, J. L., Robertson, J., Veech, R. L., Clarke, K. Novel ketone diet enhances physical and cognitive performance.

Concepts: Metabolism, Nutrition, Adenosine triphosphate, Fatty acid, Lipid, Ketone, Ketone bodies, Carbohydrate


There is strong diurnal variation in the symptoms and severity of chronic inflammatory diseases, such as rheumatoid arthritis. In addition, disruption of the circadian clock is an aggravating factor associated with a range of human inflammatory diseases. To investigate mechanistic links between the biological clock and pathways underlying inflammatory arthritis, mice were administered collagen (or saline as a control) to induce arthritis. The treatment provoked an inflammatory response within the limbs, which showed robust daily variation in paw swelling and inflammatory cytokine expression. Inflammatory markers were significantly repressed during the dark phase. Further work demonstrated an active molecular clock within the inflamed limbs and highlighted the resident inflammatory cells, fibroblast-like synoviocytes (FLSs), as a potential source of the rhythmic inflammatory signal. Exposure of mice to constant light disrupted the clock in peripheral tissues, causing loss of the nighttime repression of local inflammation. Finally, the results show that the core clock proteins CRYPTOCHROMES 1 and 2 repressed inflammation within the FLSs, and provide novel evidence that a CRYPTOCHROME activator has anti-inflammatory properties in human cells. We conclude that under chronic inflammatory conditions, the clock actively represses inflammatory pathways during the dark phase. This interaction has exciting potential as a therapeutic avenue for treatment of inflammatory disease.-Hand, L. E., Hopwood, T. W., Dickson, S. H., Walker, A. L., Loudon, A. S. I., Ray D. W., Bechtold, D. A., Gibbs, J. E. The circadian clock regulates inflammatory arthritis.

Concepts: Inflammation, Interleukin 1, Asthma, Rheumatoid arthritis, Vasculitis, Anti-inflammatory, Circadian rhythm, C-reactive protein


Mucins are the main components of the gastrointestinal mucus layer. Mucin glycosylation is critical to most intermolecular and intercellular interactions. However, due to the highly complex and heterogeneous mucin glycan structures, the encoded biological information remains largely encrypted. Here we have developed a methodology based on force spectroscopy to identify biologically accessible glycoepitopes in purified porcine gastric mucin (pPGM) and purified porcine jejunal mucin (pPJM). The binding specificity of lectins Ricinus communis agglutinin I (RCA), peanut (Arachis hypogaea) agglutinin (PNA), Maackia amurensis lectin II (MALII), and Ulex europaeus agglutinin I (UEA) was utilized in force spectroscopy measurements to quantify the affinity and spatial distribution of their cognate sugars at the molecular scale. Binding energy of 4, 1.6, and 26 aJ was determined on pPGM for RCA, PNA, and UEA. Binding was abolished by competition with free ligands, demonstrating the validity of the affinity data. The distributions of the nearest binding site separations estimated the number of binding sites in a 200-nm mucin segment to be 4 for RCA, PNA, and UEA, and 1.8 for MALII. Binding site separations were affected by partial defucosylation of pPGM. Furthermore, we showed that this new approach can resolve differences between gastric and jejunum mucins.-Gunning, A. P., Kirby, A. R., Fuell, C., Pin, C., Tailford L. E., Juge, N. Mining the “glycocode”-exploring the spatial distribution of glycans in gastrointestinal mucin using force spectroscopy.

Concepts: DNA, Proteins, Mass, Ricin, Peanut, Faboideae, Glycomics, Ulex europaeus


Tendons are often injured and heal poorly. Whether this is caused by a slow tissue turnover is unknown, since existing data provide diverging estimates of tendon protein half-life that range from 2 mo to 200 yr. With the purpose of determining life-long turnover of human tendon tissue, we used the (14)C bomb-pulse method. This method takes advantage of the dramatic increase in atmospheric levels of (14)C, produced by nuclear bomb tests in 1955-1963, which is reflected in all living organisms. Levels of (14)C were measured in 28 forensic samples of Achilles tendon core and 4 skeletal muscle samples (donor birth years 1945-1983) with accelerator mass spectrometry (AMS) and compared to known atmospheric levels to estimate tissue turnover. We found that Achilles tendon tissue retained levels of (14)C corresponding to atmospheric levels several decades before tissue sampling, demonstrating a very limited tissue turnover. The tendon concentrations of (14)C approximately reflected the atmospheric levels present during the first 17 yr of life, indicating that the tendon core is formed during height growth and is essentially not renewed thereafter. In contrast, (14)C levels in muscle indicated continuous turnover. Our observation provides a fundamental premise for understanding tendon function and pathology, and likely explains the poor regenerative capacity of tendon tissue.-Heinemeier, K. M., Schjerling, P., Heinemeier, J., Magnusson, S. P., Kjaer, M. Lack of tissue renewal in human adult Achilles tendon is revealed by nuclear bomb (14)C.

Concepts: Mass spectrometry, Biology, Tendon, Achilles tendon, Nuclear weapon, Tendons, Carbon-14, Accelerator mass spectrometry


Serotonin and vitamin D have been proposed to play a role in autism; however, no causal mechanism has been established. Here, we present evidence that vitamin D hormone (calcitriol) activates the transcription of the serotonin-synthesizing gene tryptophan hydroxylase 2 (TPH2) in the brain at a vitamin D response element (VDRE) and represses the transcription of TPH1 in tissues outside the blood-brain barrier at a distinct VDRE. The proposed mechanism explains 4 major characteristics associated with autism: the low concentrations of serotonin in the brain and its elevated concentrations in tissues outside the blood-brain barrier; the low concentrations of the vitamin D hormone precursor 25-hydroxyvitamin D [25(OH)D3]; the high male prevalence of autism; and the presence of maternal antibodies against fetal brain tissue. Two peptide hormones, oxytocin and vasopressin, are also associated with autism and genes encoding the oxytocin-neurophysin I preproprotein, the oxytocin receptor, and the arginine vasopressin receptor contain VDREs for activation. Supplementation with vitamin D and tryptophan is a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.-Patrick, R. P., Ames, B. N. Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.

Concepts: Protein, Vitamin D, Hormone, Receptor, Oxytocin, Vasopressin, Serotonin, Tryptophan hydroxylase


The global decline in the abundance and diversity of insect pollinators could result from habitat loss, disease, and pesticide exposure. The contribution of the neonicotinoid insecticides (e.g., clothianidin and imidacloprid) to this decline is controversial, and key to understanding their risk is whether the astonishingly low levels found in the nectar and pollen of plants is sufficient to deliver neuroactive levels to their site of action: the bee brain. Here we show that bumblebees (Bombus terrestris audax) fed field levels [10 nM, 2.1 ppb (w/w)] of neonicotinoid accumulate between 4 and 10 nM in their brains within 3 days. Acute (minutes) exposure of cultured neurons to 10 nM clothianidin, but not imidacloprid, causes a nicotinic acetylcholine receptor-dependent rapid mitochondrial depolarization. However, a chronic (2 days) exposure to 1 nM imidacloprid leads to a receptor-dependent increased sensitivity to a normally innocuous level of acetylcholine, which now also causes rapid mitochondrial depolarization in neurons. Finally, colonies exposed to this level of imidacloprid show deficits in colony growth and nest condition compared with untreated colonies. These findings provide a mechanistic explanation for the poor navigation and foraging observed in neonicotinoid treated bumblebee colonies.-Moffat, C., Pacheco, J. G., Sharp, S., Samson, A. J., Bollan, K. A., Huang, J., Buckland, S. T., Connolly, C. N. Chronic exposure to neonicotinoids increases neuronal vulnerability to mitochondrial dysfunction in the bumblebee (Bombus terrestris).

Concepts: Acetylcholine, Pollination, Pollinator decline, Bee, Bumblebee, Pollinator, Insecticide, Neonicotinoid


The purpose of this work was to determine the effects of varying levels of dietary protein on body composition and muscle protein synthesis during energy deficit (ED). A randomized controlled trial of 39 adults assigned the subjects diets providing protein at 0.8 (recommended dietary allowance; RDA), 1.6 (2×-RDA), and 2.4 (3×-RDA) g kg(-1) d(-1) for 31 d. A 10-d weight-maintenance (WM) period was followed by a 21 d, 40% ED. Body composition and postabsorptive and postprandial muscle protein synthesis were assessed during WM (d 9-10) and ED (d 30-31). Volunteers lost (P<0.05) 3.2 ± 0.2 kg body weight during ED regardless of dietary protein. The proportion of weight loss due to reductions in fat-free mass was lower (P<0.05) and the loss of fat mass was higher (P<0.05) in those receiving 2×-RDA and 3×-RDA compared to RDA. The anabolic muscle response to a protein-rich meal during ED was not different (P>0.05) from WM for 2×-RDA and 3×-RDA, but was lower during ED than WM for those consuming RDA levels of protein (energy × protein interaction, P<0.05). To assess muscle protein metabolic responses to varied protein intakes during ED, RDA served as the study control. In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat-free mass during short-term weight loss.-Pasiakos, S. M., Cao, J. J., Margolis, L. M., Sauter, E. R., Whigham, L. D., McClung, J. P., Rood, J. C., Carbone, J. W., Combs, G. F., Jr., Young, A. J. Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: a randomized controlled trial.

Concepts: Protein, Metabolism, Nutrition, Energy, Randomized controlled trial, Mass, Adipose tissue, Kilogram


We evaluated the therapeutic potential of a sustained nitric oxide (NO)-releasing compound to correct the molecular hallmarks and pathophysiology of priapism, an important but poorly characterized erectile disorder. 1,5-Bis-(dihexyl-N-nitrosoamino)-2,4-dinitrobenzene (C6') and an inactive form of the compound [1,5-bis-(dihexylamino)-2,4-dinitrobenzene (C6)] were tested in neuronal cell cultures and penile lysates for NO release (Griess assay) and biological activity (cGMP production). The effect of local depot C6' or C6 was evaluated in mice with a priapic phenotype due to double neuronal and endothelial NO synthase deletion (dNOS(-/-)) or human sickle hemoglobin transgenic expression (Sickle). Changes in NO signaling molecules and reactive oxygen species (ROS) surrogates were assessed by Western blot. The physiological response after C6' treatment was assessed using an established model of electrically stimulated penile erection. C6' generated NO, increased cGMP, and dose dependently increased NO metabolites. C6' treatment reversed abnormalities in key penile erection signaling molecules, including phosphodiesterase type 5, phosphorylated endothelial nitric oxide synthase, and phosphorylated vasodilator-stimulated phosphoprotein. In Sickle mice, C6' also attenuated the increased ROS markers gp91(phox), 4-hydroxynonenal, and 3-nitrotyrosine. Finally, C6' corrected the excessive priapic erection response of dNOS(-/-) mice. Exogenous sustained NO release from C6' corrects pathological erectile signaling in mouse models of priapism and suggests novel approaches to human therapy.-Lagoda, G., Sezen, S. F., Hurt, K. J., Cabrini, M. R., Mohanty, D. K., Burnett, A. L. Sustained nitric oxide (NO)-releasing compound reverses dysregulated NO signal transduction in priapism.

Concepts: Oxygen, Molecular biology, Nitric oxide, Erectile dysfunction, Nitric oxide synthase, Penis, Erection, Priapism


Does PubMed Central-a government-run digital archive of biomedical articles-compete with scientific society journals? A longitudinal, retrospective cohort analysis of 13,223 articles (5999 treatment, 7224 control) published in 14 society-run biomedical research journals in nutrition, experimental biology, physiology, and radiology between February 2008 and January 2011 reveals a 21.4% reduction in full-text hypertext markup language (HTML) article downloads and a 13.8% reduction in portable document format (PDF) article downloads from the journals' websites when U.S. National Institutes of Health-sponsored articles (treatment) become freely available from the PubMed Central repository. In addition, the effect of PubMed Central on reducing PDF article downloads is increasing over time, growing at a rate of 1.6% per year. There was no longitudinal effect for full-text HTML downloads. While PubMed Central may be providing complementary access to readers traditionally underserved by scientific journals, the loss of article readership from the journal website may weaken the ability of the journal to build communities of interest around research papers, impede the communication of news and events to scientific society members and journal readers, and reduce the perceived value of the journal to institutional subscribers.-Davis, P. M. Public accessibility of biomedical articles from PubMed Central reduces journal readership-retrospective cohort analysis.

Concepts: Cohort study, Open access, XML, Markup language, Wiki, HTML, XHTML, DocBook


Thylakoid membranes, the universal structure where photosynthesis takes place in all oxygenic photosynthetic organisms from cyanobacteria to higher plants, have a unique lipid composition. They contain a high fraction of 2 uncharged glycolipids, the galactoglycerolipids mono- and digalactosyldiacylglycerol (MGDG and DGDG, respectively), and an anionic sulfolipid, sulfoquinovosediacylglycerol (SQDG). A remarkable feature of the evolution from cyanobacteria to higher plants is the conservation of MGDG, DGDG, SQDG, and phosphatidylglycerol (PG), the major phospholipid of thylakoids. Using neutron diffraction on reconstituted thylakoid lipid extracts, we observed that the thylakoid lipid mixture self-organizes as a regular stack of bilayers. This natural lipid mixture was shown to switch from hexagonal II toward lamellar phase on hydration. This transition and the observed phase coexistence are modulated by the fine-tuning of the lipid profile, in particular the MGDG/DGDG ratio, and by the hydration. Our analysis highlights the critical role of DGDG as a contributing component to the membrane stacking via hydrogen bonds between polar heads of adjacent bilayers. DGDG interactions balance the repulsive electrostatic contribution of the charged lipids PG and SQDG and allow the persistence of regularly stacked membranes at high hydration. In developmental contexts or in response to environmental variations, these properties can contribute to the highly dynamic flexibility of plastid structure.-Demé, B., Cataye, C., Block, M. A., Maréchal, E., Jouhet, J. Contribution of galactoglycerolipids to the 3-dimensional architecture of thylakoids.

Concepts: Cyanobacteria, Photosynthesis, Chloroplast, Plant, Lipids, Thylakoid, Light-dependent reactions, ATP synthase