Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats [post-print]

Ketogenic diets (KDs) are high-fat, low-carbohydrate formulations effective in treating medically refractory epilepsy, and recently we demonstrated lowered sensitivity to thermal pain in rats fed a KD for 3 to 4 weeks. Regarding anticonvulsant and hypoalgesic mechanisms, theories are divided as to direct effects of increased ketones and/or decreased glucose, metabolic hallmarks of these diets. To address this point, we characterized the time course of KD-induced thermal hypoalgesia, ketosis, and lowered glucose in young male rats fed ad libitum on normal chow or KDs. A strict 6.6:1 (fat:[carbohydrates + protein], by weight) KD increased blood ketones and reduced blood glucose by 2 days of feeding, but thermal hypoalgesia did not appear until 10 days. Thus, ketosis and decreased glucose are not sufficient for hypoalgesia. After feeding a 6.6:1 KD for 19 days, decreased thermal pain sensitivity and changes in blood chemistry reversed 1 day after return to normal chow. Effects were consistent between 2 different diet formulations: a more moderate and clinically relevant KD formula (3.0:1) produced hypoalgesia and similar changes in blood chemistry as the 6.6:1 diet, thus increasing translational potential. Furthermore, feeding the 3.0:1 diet throughout an extended protocol (10–11 weeks) revealed that significant hypoalgesia and increased ketones persisted whereas low glucose did not, demonstrating that KD-induced hypoalgesia does not depend on reduced glucose. In separate experiments we determined that effects on thermal pain responses were not secondary to motor or cognitive changes. Together, these findings dissociate diet-related changes in nociception from direct actions of elevated ketones or decreased glucose, and suggest mechanisms with a slower onset in this paradigm. Overall, our data indicate that metabolic approaches can relieve pain

Weed suppression greatly increased by plant diversity in intensively managed grasslands:A continental-scale experiment

1. Grassland diversity can support sustainable intensification of grassland production through increased yields, reduced inputs and limited weed invasion. We report the effects of diversity on weed suppression from three years of a 31-site continental-scale field experiment. 2. At each site, fifteen grassland communities comprising four monocultures and eleven 4-species mixtures based on a wide range of species? proportions were sown at two densities and managed by cutting. Forage species were selected according to two crossed functional traits, ?method of nitrogen acquisition? and ?pattern of temporal development?. 3. Averaged across sites, years, and sown densities, annual weed biomass in mixtures and monocultures was 0.5 and 2.0 t DM ha-1 (7% and 33% of total biomass respectively). In over 95% of mixtures (across sites and years) weed biomass was lower than the average of monocultures, and, in about two thirds of cases, lower than in the most suppressive monoculture (transgressive suppression). Suppression was significantly transgressive for 58% of site-years. Transgressive suppression by mixtures was maintained across years and was independent of site productivity. 4. Based on models, predicted average weed biomass in mixture over the whole experiment was 52% less (95% confidence interval 30% to 75%) than in the most suppressive monoculture, and was significantly lower than the most suppressive monoculture across all mixtures and along functional trait axes. Transgressive suppression of weed biomass was significant at each year across all mixtures and for each mixture. 5. Weed biomass was consistently low across all mixtures and years and although, in some years, it increased with increasing sown legume proportion and decreased with increasing sown proportion of persistent species, the level of weed biomass was not largely different from that in the equiproportional mixture. 6. The average variability (standard deviation in t DM ha-1) of annual weed biomass within a site was much lower for mixtures (0.42) than for monocultures (1.77). 7. Synthesis and applications. Weed invasion can be diminished through combining forage species selected for complementarity and persistence traits in systems designed to reduce reliance on fertilizer nitrogen. The effects of mixtures on weed suppression were consistently strong across mixtures varying widely in species proportions and over time. The level of weed biomass did not vary greatly across mixtures varying widely in proportions of sown species. The benefits of plant diversity in intensively managed grasslands are highly relevant for the sustainable intensification of agriculture; importantly, this can be achieved through practical farm-scale actions.publishersversionPeer reviewe

Ablation of Dicer from murine Schwann cells increases their proliferation while blocking myelination

The myelin sheaths that surround the thick axons of the peripheral nervous system are produced by the highly specialized Schwann cells. Differentiation of Schwann cells and myelination occur in discrete steps. Each of these requires coordinated expression of specific proteins in a precise sequence, yet the regulatory mechanisms controlling protein expression during these events are incompletely understood. Here we report that Schwann cell-specific ablation of the enzyme Dicer1, which is required for the production of small non-coding regulatory microRNAs, fully arrests Schwann cell differentiation, resulting in early postnatal lethality. Dicer(-/-) Schwann cells had lost their ability to myelinate, yet were still capable of sorting axons. Both cell death and, paradoxically, proliferation of immature Schwann cells was markedly enhanced, suggesting that their terminal differentiation is triggered by growth-arresting regulatory microRNAs. Using microRNA microarrays, we identified 16 microRNAs that are upregulated upon myelination and whose expression is controlled by Dicer in Schwann cells. This set of microRNAs appears to drive Schwann cell differentiation and myelination of peripheral nerves, thereby fulfilling a crucial function for survival of the organism

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

An ecological future for weed science to sustain crop production and the environment. A review

Sustainable strategies for managing weeds are critical to meeting agriculture's potential to feed the world's population while conserving the ecosystems and biodiversity on which we depend. The dominant paradigm of weed management in developed countries is currently founded on the two principal tools of herbicides and tillage to remove weeds. However, evidence of negative environmental impacts from both tools is growing, and herbicide resistance is increasingly prevalent. These challenges emerge from a lack of attention to how weeds interact with and are regulated by the agroecosystem as a whole. Novel technological tools proposed for weed control, such as new herbicides, gene editing, and seed destructors, do not address these systemic challenges and thus are unlikely to provide truly sustainable solutions. Combining multiple tools and techniques in an Integrated Weed Management strategy is a step forward, but many integrated strategies still remain overly reliant on too few tools. In contrast, advances in weed ecology are revealing a wealth of options to manage weedsat the agroecosystem levelthat, rather than aiming to eradicate weeds, act to regulate populations to limit their negative impacts while conserving diversity. Here, we review the current state of knowledge in weed ecology and identify how this can be translated into practical weed management. The major points are the following: (1) the diversity and type of crops, management actions and limiting resources can be manipulated to limit weed competitiveness while promoting weed diversity; (2) in contrast to technological tools, ecological approaches to weed management tend to be synergistic with other agroecosystem functions; and (3) there are many existing practices compatible with this approach that could be integrated into current systems, alongside new options to explore. Overall, this review demonstrates that integrating systems-level ecological thinking into agronomic decision-making offers the best route to achieving sustainable weed management

Developments in Copyright Policy and Network Technologies: The First Generation

There has been tremendous attention devoted to the medium of the Internet. However, the technologies that constitute the Web have created a legal environment that has and will continue to compel changes in traditional approaches to several issues, including copyright. The objective of this article is to review and discuss case and statutory law in copyright policy recently developed in the context of network technologies

Consumer Attribute and Profile Preferences for Affinity Credit Cards

Banks and financial institutions are interested in lasting relationships with profitable, reliable customers. Many financial services firms have found some success by developing affinity or cobranded credit cards. This two part study was undertaken to gain insight into consumer attribute preferences of university-sponsored affinity cards

Trademark Strategies Online: Implications for Intellectual Property Protection

The growth and increasingly mainstream appeal of various aspects of the Internet could have a lasting effect on a firm\u27s marketing mix. The authors address one of the external environmental factors that marketing and brand managers, as well as public policymakers, should continually monitor as the online community further develops: trademark law. As managers attempt to leverage the value of the trademarked brand, the authors examine the impact of the current state of technology and the law to understand the reach of current legal interpretations and the implications for present and future trademark strategy online