Developing Biomarkers for Methamphetamine Addiction

There are an estimated 11.7 million methamphetamine (MA) abusers in the United States and epidemics of MA addiction are occurring worldwide. In our human laboratory and outpatient clinical trials we use innovative methods to quantify the severity of MA addiction and test biomarkers that may predict response to therapy or risk of relapse. One potential biomarker of addiction is the quantity of abused drug intake. Qualitative urinalysis is used in clinical trials and during treatment but provides only a binary outcome measure of abuse. Using non-pharmacologic doses of deuterium labeled l-MA we have developed a continuous quantitative measure to estimate the bioavailable amount of MA addicts ingest. Brain Derived Neurotrophic Factor is a neurotrophin that encourages growth and differentiation of new neurons and synapses. Low BDNF levels are seen in many addictive disorders and BDNF is elevated in recovering MA addicts, suggesting BDNF may be a marker of MA addiction. We are investigating the effects of controlled doses of MA on BDNF levels and gene regulation and measuring BDNF in our clinical trials. We believe both patients and clinical researches will benefit from the addition of new, objective and quantifiable outcome measures that reflect disease severity and recovery from addiction

The possibilities are endless : making sense of local system modelling

Future visions of local energy systems have been increasingly supported by detailed and sophisticated modelling work, incorporating both spatial and temporal dimensions to a greater and greater degree. This has enabled the creation of ever more complex (and complicated) techno-economic simulation models based on a vast range of scenarios considering technologies, networks and energy consumer behaviour. However, such a variety and wealth of models, often based on a great breadth of (often irreconcilable) assumptions, often leads to a form of ‘analysis paralysis’: too many options and possibilities are presented, often without the underlying modelling having considered the actual decision-making processes towards which it may be expected to contribute. This is particularly the case where Whole Systems modelling is concerned, where the form of optimisation in use may presume the existence of a ‘System Architect’ capable of intervening at any level of the system, as opposed to the actual policy mechanisms which may exist in reality. This presentation considers the gap between the wealth of system modelling data being made available by technical modellers and the near-term development of policy. With a particular focus on the domestic heat sector (based on work conducted within UKERC Phase 3 ), we discuss the development of ‘least regret’ options in an energy context with extremely high technological and economic uncertainties, as well as the determination of top-down carbon abatement values which may feed directly into a policy pipeline. The need for clear energy pathway narratives is discussed, and illustrated with examples from the Great Britain energy system, considering the multiple challenges that apply in particular to decentralised systems. With respect to domestic heating, we propose a framework for the development of local heat strategy, based on techno-economic analysis but distilling the results into clear findings, which moves beyond RD&D funded projects through to the ‘first million’ homes with low carbon heating , incorporating the needs and system actions that may be employed in the near term by home owners, network operators, local authorities and policymakers. This is used as a basis to highlight future modelling work which will be required to assist the development of policy as technical and economic uncertainties around the sector are reduced

Zoning for local heat and energy efficiency strategies

Any plan to decarbonise heat will need plenty of input from those familiar with Scotland’s diverse urban, rural and social geography. The Scottish Government is helping local authorities pilot an ambitious approach to local heat planning which, if done right, could provide the blueprint for low-carbon heat industries to flourish. So how are these plans shaping up, what benefits might they provide and will they really work for the industry

Electrified heat and transport : energy demand futures, their impacts on power networks and what it means for system flexibility

Demand electrification, system flexibility and energy demand reduction (EDR) are three central tenets of most energy system decarbonisation pathways in the UK and other high-income countries. However, their combined impacts on local energy systems remain understudied. Here, we investigate the impact of different UK energy demand future scenarios on the loading of local electricity networks, and the ability of electrified demand to act flexibly in (i) mitigating the need for network reinforcement and (ii) shifting demand around according to variable tariffs reflecting wider system needs. These scenarios are used to drive spatially- and temporally-explicit technology uptake and energy demand modelling for heating and transport in a localised context, for application to a local electricity network. A particular case study energy network in Scotland, representative of many networks in the UK and Northern Europe, is selected to demonstrate the method. On the basis of the presented case study, which considered a typical winter demand day, energy futures based on EDR policies were found on average to reduce evening transformer loading by up to 16%. Further reductions of up to 43% were achieved with flexible smart charging and up to 69% with the use of vehicle-to-grid. Therefore, we find that policies focused on EDR can mitigate the need for reinforcement of electricity networks against the backdrop of demand electrification. However, flexibility in electricity demand contributes a larger difference to a network’s ability to host electrified heat and transport than relying solely on EDR. When used in tandem, policies that simultaneously pursue EDR and electricity system flexibility are shown to have the greatest benefits. Despite these benefits, peak electricity demand is very likely to increase significantly relative to the current baseline. Therefore, widespread reinforcement is required to local electricity networks in the net-zero transition and, accordingly, urgent investment is required to support the realisation of the UK’s legally-binding climate goals

3D spectroscopy with VLT/GIRAFFE - III: Mapping electron densities in distant galaxies

We used the moderately high spectral resolution of FLAMES/GIRAFFE (R=10000) to derive electron densities from [OII] line ratios in 6 galaxies at z~0.55. These measurements have been done through the GIRAFFE multiple integral field units and are the very first mapping of electron densities in such distant objects. This allows us to confirm an outflow and identify the role of giant HII regions in galactic disks. Such measurements could be used in the future to investigate the nature of the physical processes responsible for the high star formations rates observed in galaxies between z~0.4 and z~1.Comment: (1) GEPI, Obs. Meudon, France ;(2) MPE, Germany. See also ESO press release http://www.eso.org/outreach/press-rel/pr-2006/pr-10-06.html. To appear in A&

Functional Group and Substructure Searching as a Tool in Metabolomics

BACKGROUND: A direct link between the names and structures of compounds and the functional groups contained within them is important, not only because biochemists frequently rely on literature that uses a free-text format to describe functional groups, but also because metabolic models depend upon the connections between enzymes and substrates being known and appropriately stored in databases. METHODOLOGY: We have developed a database named "Biochemical Substructure Search Catalogue" (BiSSCat), which contains 489 functional groups, >200,000 compounds and >1,000,000 different computationally constructed substructures, to allow identification of chemical compounds of biological interest. CONCLUSIONS: This database and its associated web-based search program (http://bisscat.org/) can be used to find compounds containing selected combinations of substructures and functional groups. It can be used to determine possible additional substrates for known enzymes and for putative enzymes found in genome projects. Its applications to enzyme inhibitor design are also discussed

Homeotic Evolution in the Mammalia: Diversification of Therian Axial Seriation and the Morphogenetic Basis of Human Origins

Despite the rising interest in homeotic genes, little has been known about the course and pattern of evolution of homeotic traits across the mammalian radiation. An array of emerging and diversifying homeotic gradients revealed by this study appear to generate new body plans and drive evolution at a large scale.This study identifies and evaluates a set of homeotic gradients across 250 extant and fossil mammalian species and their antecedents over a period of 220 million years. These traits are generally expressed as co-linear gradients along the body axis rather than as distinct segmental identities. Relative position or occurrence sequence vary independently and are subject to polarity reversal and mirroring. Five major gradient modification sets are identified: (1)--quantitative changes of primary segmental identity pattern that appeared at the origin of the tetrapods ; (2)--frame shift relation of costal and vertebral identity which diversifies from the time of amniote origins; (3)--duplication, mirroring, splitting and diversification of the neomorphic laminar process first commencing at the dawn of mammals; (4)--emergence of homologically variable lumbar lateral processes upon commencement of the radiation of therian mammals and ; (5)--inflexions and transpositions of the relative position of the horizontal septum of the body and the neuraxis at the emergence of various orders of therian mammals. Convergent functional changes under homeotic control include laminar articular engagement with septo-neural transposition and ventrally arrayed lumbar transverse process support systems.Clusters of homeotic transformations mark the emergence point of mammals in the Triassic and the radiation of therians in the Cretaceous. A cluster of homeotic changes in the Miocene hominoid Morotopithecus that are still seen in humans supports establishment of a new "hominiform" clade and suggests a homeotic origin for the human upright body plan

APBSmem: A Graphical Interface for Electrostatic Calculations at the Membrane

Electrostatic forces are one of the primary determinants of molecular interactions. They help guide the folding of proteins, increase the binding of one protein to another and facilitate protein-DNA and protein-ligand binding. A popular method for computing the electrostatic properties of biological systems is to numerically solve the Poisson-Boltzmann (PB) equation, and there are several easy-to-use software packages available that solve the PB equation for soluble proteins. Here we present a freely available program, called APBSmem, for carrying out these calculations in the presence of a membrane. The Adaptive Poisson-Boltzmann Solver (APBS) is used as a back-end for solving the PB equation, and a Java-based graphical user interface (GUI) coordinates a set of routines that introduce the influence of the membrane, determine its placement relative to the protein, and set the membrane potential. The software Jmol is embedded in the GUI to visualize the protein inserted in the membrane before the calculation and the electrostatic potential after completing the computation. We expect that the ease with which the GUI allows one to carry out these calculations will make this software a useful resource for experimenters and computational researchers alike. Three examples of membrane protein electrostatic calculations are carried out to illustrate how to use APBSmem and to highlight the different quantities of interest that can be calculated

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference