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1.  Visualizing Neurotransmitter Secretion at Individual Synapses 
ACS Chemical Neuroscience  2013;4(5):648-651.
To advance understanding of the brain, the ability to measure both nerve cell electrical spiking and chemical neurotransmission with high spatial resolution is required. In comparison to the development of voltage sensors and Ca2+ indicator dyes over the past several decades, high resolution imaging of neurotransmitter (NT) release at single synapses has not been possible. In this Viewpoint, we discuss two recent developments toward this goal, namely, the design of fluorescent false neurotransmitters (FFNs) and optical neurotransmitter sensors.
PMCID: PMC3656740  PMID: 23862751
neurotransmitter release; fluorescent imaging; FFNs; optical tracers; neurotransmitter sensors; brain activity maps
2.  APP+, a Fluorescent Analogue of the Neurotoxin MPP+, Is a Marker of Catecholamine Neurons in Brain Tissue, but Not a Fluorescent False Neurotransmitter 
ACS Chemical Neuroscience  2013;4(5):858-869.
We have previously introduced fluorescent false neurotransmitters (FFNs) as optical reporters that enable visualization of individual dopaminergic presynaptic terminals and their activity in the brain. In this context, we examined the fluorescent pyridinium dye 4-(4-dimethylamino)phenyl-1-methylpyridinium (APP+), a fluorescent analogue of the dopaminergic neurotoxin MPP+, in acute mouse brain tissue. APP+ is a substrate for the dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), and as such represented a candidate for the development of new FFN probes. Here we report that APP+ labels cell bodies of catecholaminergic neurons in the midbrain in a DAT- and NET-dependent manner, as well as fine dopaminergic axonal processes in the dorsal striatum. APP+ destaining from presynaptic terminals in the dorsal striatum was also examined under the conditions inducing depolarization and exocytotic neurotransmitter release. Application of KCl led to a small but significant degree of destaining (approximately 15% compared to control), which stands in contrast to a nearly complete destaining of the new generation FFN agent, FFN102. Electrical stimulation of brain slices at 10 Hz afforded no significant change in the APP+ signal. These results indicate that the majority of the APP+ signal in axonal processes originates from labeled organelles including mitochondria, whereas only a minor component of the APP+ signal represents the releasable synaptic vesicular pool. These results also show that APP+ may serve as a useful probe for identifying catecholaminergic innervations in the brain, although it is a poor candidate for the development of FFNs.
PMCID: PMC3656749  PMID: 23647019
APP+; neuronal imaging agent; fluorescent false neurotransmitters; catecholamine neurons; two-photon microscopy; acute mouse brain slice
3.  The zebrafish reference genome sequence and its relationship to the human genome 
Howe, Kerstin | Clark, Matthew D. | Torroja, Carlos F. | Torrance, James | Berthelot, Camille | Muffato, Matthieu | Collins, John E. | Humphray, Sean | McLaren, Karen | Matthews, Lucy | McLaren, Stuart | Sealy, Ian | Caccamo, Mario | Churcher, Carol | Scott, Carol | Barrett, Jeffrey C. | Koch, Romke | Rauch, Gerd-Jörg | White, Simon | Chow, William | Kilian, Britt | Quintais, Leonor T. | Guerra-Assunção, José A. | Zhou, Yi | Gu, Yong | Yen, Jennifer | Vogel, Jan-Hinnerk | Eyre, Tina | Redmond, Seth | Banerjee, Ruby | Chi, Jianxiang | Fu, Beiyuan | Langley, Elizabeth | Maguire, Sean F. | Laird, Gavin K. | Lloyd, David | Kenyon, Emma | Donaldson, Sarah | Sehra, Harminder | Almeida-King, Jeff | Loveland, Jane | Trevanion, Stephen | Jones, Matt | Quail, Mike | Willey, Dave | Hunt, Adrienne | Burton, John | Sims, Sarah | McLay, Kirsten | Plumb, Bob | Davis, Joy | Clee, Chris | Oliver, Karen | Clark, Richard | Riddle, Clare | Eliott, David | Threadgold, Glen | Harden, Glenn | Ware, Darren | Mortimer, Beverly | Kerry, Giselle | Heath, Paul | Phillimore, Benjamin | Tracey, Alan | Corby, Nicole | Dunn, Matthew | Johnson, Christopher | Wood, Jonathan | Clark, Susan | Pelan, Sarah | Griffiths, Guy | Smith, Michelle | Glithero, Rebecca | Howden, Philip | Barker, Nicholas | Stevens, Christopher | Harley, Joanna | Holt, Karen | Panagiotidis, Georgios | Lovell, Jamieson | Beasley, Helen | Henderson, Carl | Gordon, Daria | Auger, Katherine | Wright, Deborah | Collins, Joanna | Raisen, Claire | Dyer, Lauren | Leung, Kenric | Robertson, Lauren | Ambridge, Kirsty | Leongamornlert, Daniel | McGuire, Sarah | Gilderthorp, Ruth | Griffiths, Coline | Manthravadi, Deepa | Nichol, Sarah | Barker, Gary | Whitehead, Siobhan | Kay, Michael | Brown, Jacqueline | Murnane, Clare | Gray, Emma | Humphries, Matthew | Sycamore, Neil | Barker, Darren | Saunders, David | Wallis, Justene | Babbage, Anne | Hammond, Sian | Mashreghi-Mohammadi, Maryam | Barr, Lucy | Martin, Sancha | Wray, Paul | Ellington, Andrew | Matthews, Nicholas | Ellwood, Matthew | Woodmansey, Rebecca | Clark, Graham | Cooper, James | Tromans, Anthony | Grafham, Darren | Skuce, Carl | Pandian, Richard | Andrews, Robert | Harrison, Elliot | Kimberley, Andrew | Garnett, Jane | Fosker, Nigel | Hall, Rebekah | Garner, Patrick | Kelly, Daniel | Bird, Christine | Palmer, Sophie | Gehring, Ines | Berger, Andrea | Dooley, Christopher M. | Ersan-Ürün, Zübeyde | Eser, Cigdem | Geiger, Horst | Geisler, Maria | Karotki, Lena | Kirn, Anette | Konantz, Judith | Konantz, Martina | Oberländer, Martina | Rudolph-Geiger, Silke | Teucke, Mathias | Osoegawa, Kazutoyo | Zhu, Baoli | Rapp, Amanda | Widaa, Sara | Langford, Cordelia | Yang, Fengtang | Carter, Nigel P. | Harrow, Jennifer | Ning, Zemin | Herrero, Javier | Searle, Steve M. J. | Enright, Anton | Geisler, Robert | Plasterk, Ronald H. A. | Lee, Charles | Westerfield, Monte | de Jong, Pieter J. | Zon, Leonard I. | Postlethwait, John H. | Nüsslein-Volhard, Christiane | Hubbard, Tim J. P. | Crollius, Hugues Roest | Rogers, Jane | Stemple, Derek L.
Nature  2013;496(7446):498-503.
Zebrafish have become a popular organism for the study of vertebrate gene function1,2. The virtually transparent embryos of this species, and the ability to accelerate genetic studies by gene knockdown or overexpression, have led to the widespread use of zebrafish in the detailed investigation of vertebrate gene function and increasingly, the study of human genetic disease3–5. However, for effective modelling of human genetic disease it is important to understand the extent to which zebrafish genes and gene structures are related to orthologous human genes. To examine this, we generated a high-quality sequence assembly of the zebrafish genome, made up of an overlapping set of completely sequenced large-insert clones that were ordered and oriented using a high-resolution high-density meiotic map. Detailed automatic and manual annotation provides evidence of more than 26,000 protein-coding genes6, the largest gene set of any vertebrate so far sequenced. Comparison to the human reference genome shows that approximately 70% of human genes have at least one obvious zebrafish orthologue. In addition, the high quality of this genome assembly provides a clearer understanding of key genomic features such as a unique repeat content, a scarcity of pseudogenes, an enrichment of zebrafish-specific genes on chromosome 4 and chromosomal regions that influence sex determination.
PMCID: PMC3703927  PMID: 23594743
4.  C3d adjuvant activity is reduced by altering residues involved in the electronegative binding of C3d to CR2 
Immunology letters  2010;129(1):32-38.
The final degradation product of the complement protein C3, C3d, has been used as a molecular adjuvant to various antigens. Chimera proteins of the antigen and multiple copies of C3d were developed to test the adjuvant effect of this molecule. The main mechanism by which C3d enhances the immune response is interaction with CR2. In-vitro studies showed that the avidity of C3d for CR2 is affected by residues located at the interacting surface (e.g. 170N) as well as by residues located in other areas. The role of the latter residues has been proposed to depend on the electrostatic nature of the C3d-CR2 interaction, where the charges of the whole molecules are responsible for their binding. C3d is primarily a negatively charged molecule, while CR2 is a positive one. Previous experiments demonstrated that elimination of a positive charge (K162A) in C3d enhanced its avidity for CR2, while elimination of negative charges or addition positives ones (D163A N170R, respectively), impaired the avidity for CR2. Despite the extensive in-vitro research, the role of these residues in the adjuvant effect of C3d is unclear. To study the role of residues at the interacting and non-interacting surface of C3d on the adjuvanticity, single as well as a double residue substitutions were engineered in the murine C3d (R162A, D163A, N170R and D163A-N170R) gene. Two copies of these mutant molecules were fused to HIV-1 Envgp120 and the proteins were tested for their avidity to bind CR2 (sCR2). Later, these DNA constructs were tested in mice to determine their adjuvant capability. Mutation at residue 162 (R162A) neither enhanced nor impaired the avidity of Envgp120-C3d2 for sCR2 in-vitro. Mutations at residues D163A and N170R, on the other hand, reduced the binding affinity of Envgp120- C3d2 for sCR2. Furthermore, these mutations synergized and abolished the interaction of C3d for CR2. The data correlated with the adjuvant capability of these molecules in the mouse model. In summary, residues that alter the electronegative status of C3d (D163A and N170R) impair the binding of chimera proteins to CR2, reducing the adjuvant activity of this molecule.
PMCID: PMC3755894  PMID: 20064559
Molecular adjuvant; C3d; CR2; DNA vaccine
5.  Trophic Interactions and Distribution of Some Squaliforme Sharks, Including New Diet Descriptions for Deania calcea and Squalus acanthias 
PLoS ONE  2013;8(3):e59938.
Squaliforme sharks are a common but relatively vulnerable bycatch in many deep water fisheries. Eleven species of squaliforme shark are commonly caught at depths of 200–1200 m on Chatham Rise, New Zealand, and their diversity suggests they might occupy different niches. The diets of 133 Deania calcea and 295 Squalus acanthias were determined from examination of stomach contents. The diet of D. calcea was characterised by mesopelagic fishes, and S. acanthias by benthic to pelagic fishes, but was more adaptive and included likely scavenging. Multivariate analyses found the most important predictors of diet variability in S. acanthias were year, bottom temperature, longitude, and fish weight. The diet of the nine other commonly caught squaliforme sharks was reviewed, and the spatial and depth distribution of all species on Chatham Rise described from research bottom trawl survey catches. The eleven species had a variety of different diets, and depth and location preferences, consistent with niche separation to reduce interspecific competition. Four trophic groups were identified, characterised by: mesopelagic fishes and invertebrates (Centroselachus crepidater, D. calcea, and Etmopterus lucifer); mesopelagic and benthopelagic fishes and invertebrates (Centroscymnus owstoni, Etmopterus baxteri); demersal and benthic fishes (Centrophorus squamosus, Dalatias licha, Proscymnodon plunketi); and a generalist diet of fishes and invertebrates (S. acanthias). The trophic levels of the species in each of the four groups were estimated as 4.18–4.24, 4.20–4.23, 4.24–4.48, and 3.84 respectively. The diet of Oxynotus bruniensis and Squalus griffini are unknown. The different niches occupied by different species are likely to influence their vulnerability to bottom trawl fisheries. Some species may benefit from fisheries through an increased availability of scavenged prey.
PMCID: PMC3607562  PMID: 23536896
6.  Durability of the Effects of Testosterone and Growth Hormone Supplementation in Older Community Dwelling Men: The HORMA Trial 
Clinical endocrinology  2011;75(1):103-111.
Determine the durability of anabolic effects and adverse events (AEs) after stopping testosterone and growth hormone supplementation in older men.
Secondary analysis of a double-masked, randomized controlled trial of testosterone gel (5g or 10g/daily) plus rhGH (0, 3, or 5ug/kg/day) with follow-up of outcomes 3-months later.
108 community-dwelling 65-90 year-old-men.
Testosterone and IGF-1 levels, body composition (DEXA), 1-repetition maximum (1-RM) strength, stair-climbing power, quality-of-life (QOL) and activity questionnaires, AEs.
Despite improvements in body composition during treatment, residual benefits 3-months later (week-28) were variable. For participants with improvements exceeding their week-17 median changes, benefits were sustained at week 28 for lean body mass (LBM, 1.45±1.63kg, 45% of week-17 values, p<0.0001-vs-baseline), appendicular skeletal muscle mass (ASMM, 0.71±1.01kg, 42%, p<0.0001), total fat (-1.06±2.18kg, 40%, p<0.0001,), and trunk fat (-0.89±1.42kg, 50%, p<0.0001,); retention of ASMM was associated with greater week-16 protein intake (p=0.01). For 1-RM strength, 39%-43% of week-17 improvements (p≤0.05) were retained and associated with better week-17 strength (p<0.0001), change in testosterone from week-17-to-28 (p=0.004) and baseline PASE (p=0.04). Framingham 10-year cardiovascular risks were low (~14%), didn’t worsen, and improved by week-28 (p=0.0002). The hypothalamic-pituitary-gonadal axis recovered completely.
Durable improvements in muscle mass, strength, and fat mass were retained 3-months after discontinuing hormone supplementation in participants with greater than median body composition changes during treatment, but not in others with smaller gains. AEs largely resolved after intervention discontinuation. Additional strategies may be needed to sustain or augment muscle mass and strength gains achieved during short-term hormone therapy.
PMCID: PMC3529980  PMID: 21521283
Lean body mass; fat mass; muscle performance; quality of life; cardiovascular risks
7.  Hypotheses of Spatial Stock Structure in Orange Roughy Hoplostethus atlanticus Inferred from Diet, Feeding, Condition, and Reproductive Activity 
PLoS ONE  2011;6(11):e26704.
We evaluate hypotheses for meso-scale spatial structure in an orange roughy (Hoplostethus atlanticus) stock using samples collected during research trawl surveys off the east coast of New Zealand. Distance-based linear models and generalised additive models were used to identify the most significant biological, environmental, and temporal predictors of variability in diet, proportion of stomachs containing prey, standardised weight of prey, fish somatic weight, fish total weight, and reproductive activity. The diet was similar to that observed elsewhere, and varied with ontogeny, depth, and surface water temperature. Smaller sized and female orange roughy in warmer bottom water were most likely to contain food. Fish condition and reproductive activity were highest at distances more than 20 km from the summit of the hills. Trawl survey catches indicated greater orange roughy densities in hill strata, suggesting hill habitat was favoured. However, analyses of feeding, condition, and reproductive activity indicated hill fish were not superior, despite fish densities on hills being reduced by fishing which, in principle, should have reduced intra-specific competition for food and other resources. Hypotheses for this result include: (1) fish in relatively poor condition visit hills to feed and regain condition and then leave, or (2) commercial fishing has disturbed feeding aggregations and/or caused habitat damage, making fished hills less productive. Mature orange roughy were observed on both flat and hill habitat during periods outside of spawning, and if this spatial structure was persistent then a proportion of the total spawning stock biomass would remain unavailable to fisheries targeting hills. Orange roughy stock assessments informed only by data from hills may well be misleading.
PMCID: PMC3206028  PMID: 22069464
9.  Conservation of Notochord Gene Expression Across Chordates: Insights From the Leprecan Gene Family 
Genesis (New York, N.Y. : 2000)  2008;46(11):683-696.
The notochord is a defining character of the chordates, and the T-box transcription factor Brachyury has been shown to be required for notochord development in all chordates examined. In the ascidian Ciona intestinalis, at least 44 notochord genes have been identified as bona fide transcriptional targets of Brachyury. We examined the embryonic expression of a subset of murine orthologs of Ciona Brachyury target genes in the notochord to assess its conservation throughout chordate evolution. We focused on analyzing the Leprecan gene family, which in mouse is composed of three genes, as opposed to the single-copy Ciona gene. We found that all three mouse Leprecan genes are expressed in the notochord. Additionally, while Leprecan expression in C. intestinalis is confined to the notochord, expression of its mouse orthologs includes dorsal root ganglia, limb buds, branchial arches, and developing kidneys. These results have interesting implications for the evolution and development of chordates.
PMCID: PMC3065379  PMID: 18798549
Ciona; Brachyury; notochord; ascidian; leprecan; chordates; mouse; prolyl 3-hydroxylase
10.  Diet of Two Large Sympatric Teleosts, the Ling (Genypterus blacodes) and Hake (Merluccius australis) 
PLoS ONE  2010;5(10):e13647.
Ling and hake are tertiary consumers, and as a result both may have an important structuring role in marine communities. The diets of 2064 ling and 913 hake from Chatham Rise, New Zealand, were determined from examination of stomach contents. Ling was a benthic generalist, and hake a demersal piscivore. The diet of ling was characterised by benthic crustaceans, mainly Munida gracilis and Metanephrops challengeri, and demersal fishes, mainly Macrourids and scavenged offal from fishing vessels. The diet of hake was characterised by teleost fishes, mainly macrourids and merlucciids. Multivariate analyses using distance-based linear models found the most important predictors of diet variability were depth, fish length, and vessel type (whether the sample was collected from a commercial or research vessel) for ling, and fish length and vessel type for hake. There was no interspecific predation between ling and hake, and resource competition was largely restricted to macrourid prey, although the dominant macrourid species predated by ling and hake were different. Cluster analysis of average diet of intraspecific groups of ling and hake confirmed the persistent diet separation. Although size is a central factor in determining ecological processes, similar sized ling and hake had distinctly different foraging ecology, and therefore could influence the ecosystem in different ways, and be unequally affected by ecosystem fluctuations.
PMCID: PMC2965093  PMID: 21048962
11.  Enhancement of anti-DIII antibodies by the C3d derivative P28 results in lower viral titers and augments protection in mice 
Virology Journal  2010;7:95.
Antibodies generated against West Nile virus (WNV) during infection are essential for controlling dissemination. Recent studies have demonstrated that epitopes in all three domains of the flavivirus envelope protein (E) are targets for neutralizing antibodies, with determinants in domain III (DIII) eliciting antibodies with strong inhibitory properties. In order to increase the magnitude and quality of the antibody response against the WNV E protein, DNA vaccines with derivatives of the WNV E gene (full length E, truncated E, or DIII region, some in the context of the pre-membrane [prM] gene) were conjugated to the molecular adjuvant P28. The P28 region of the complement protein C3d is the minimum CR2-binding domain necessary for the adjuvant activity of C3d. Delivery of DNA-based vaccines by gene gun and intramuscular routes stimulated production of IgG antibodies against the WNV DIII region of the E protein. With the exception of the vaccine expressing prM/E given intramuscularly, only mice that received DNA vaccines by gene gun produced protective neutralizing antibody titers (FRNT80 titer >1/40). Correspondingly, mice vaccinated by the gene gun route were protected to a greater level from lethal WNV challenge. In general, mice vaccinated with P28-adjuvated vaccines produced higher IgG titers than mice vaccinated with non-adjuvanted vaccines.
PMCID: PMC2885341  PMID: 20462412
12.  The evolutionarily conserved leprecan gene: its regulation by Brachyury and its role in the developing Ciona notochord 
Developmental biology  2009;328(2):561-574.
In Ciona intestinalis, leprecan was identified as a target of the notochord-specific transcription factor Ciona Brachyury (Ci-Bra) (Takahashi et al., 1999). By screening ~14 kb of the Ci-leprecan locus for cis-regulatory activity, we have identified a 581-bp minimal notochord-specific cis-regulatory module (CRM) whose activity depends upon T-box binding sites located at the 3’-end of its sequence. These sites are specifically bound in vitro by a GST-Ci-Bra fusion protein, and mutations that abolish binding in vitro result in loss or decrease of regulatory activity in vivo. Serial deletions of the 581-bp notochord CRM revealed that this sequence is also able to direct expression in muscle cells through the same T-box sites that are utilized by Ci-Bra in the notochord, which are also bound in vitro by the muscle-specific T-box activators Ci-Tbx6b and Ci-Tbx6c. Additionally, we created plasmids aimed to interfere with the function of Ci-leprecan and categorized the resulting phenotypes, which consist of variable dislocations of notochord cells along the anterior-posterior axis. Together, these observations provide mechanistic insights generally applicable to T-box transcription factors and their target sequences, as well as a first set of clues on the function of Leprecan in early chordate development.
PMCID: PMC2666983  PMID: 19217895
Ciona; Brachyury; notochord; muscle; ascidian; leprecan; T-box; Tbx6; prolyl 3-hydroxylase; cis-regulation
13.  The DNA sequence of the human X chromosome 
Ross, Mark T. | Grafham, Darren V. | Coffey, Alison J. | Scherer, Steven | McLay, Kirsten | Muzny, Donna | Platzer, Matthias | Howell, Gareth R. | Burrows, Christine | Bird, Christine P. | Frankish, Adam | Lovell, Frances L. | Howe, Kevin L. | Ashurst, Jennifer L. | Fulton, Robert S. | Sudbrak, Ralf | Wen, Gaiping | Jones, Matthew C. | Hurles, Matthew E. | Andrews, T. Daniel | Scott, Carol E. | Searle, Stephen | Ramser, Juliane | Whittaker, Adam | Deadman, Rebecca | Carter, Nigel P. | Hunt, Sarah E. | Chen, Rui | Cree, Andrew | Gunaratne, Preethi | Havlak, Paul | Hodgson, Anne | Metzker, Michael L. | Richards, Stephen | Scott, Graham | Steffen, David | Sodergren, Erica | Wheeler, David A. | Worley, Kim C. | Ainscough, Rachael | Ambrose, Kerrie D. | Ansari-Lari, M. Ali | Aradhya, Swaroop | Ashwell, Robert I. S. | Babbage, Anne K. | Bagguley, Claire L. | Ballabio, Andrea | Banerjee, Ruby | Barker, Gary E. | Barlow, Karen F. | Barrett, Ian P. | Bates, Karen N. | Beare, David M. | Beasley, Helen | Beasley, Oliver | Beck, Alfred | Bethel, Graeme | Blechschmidt, Karin | Brady, Nicola | Bray-Allen, Sarah | Bridgeman, Anne M. | Brown, Andrew J. | Brown, Mary J. | Bonnin, David | Bruford, Elspeth A. | Buhay, Christian | Burch, Paula | Burford, Deborah | Burgess, Joanne | Burrill, Wayne | Burton, John | Bye, Jackie M. | Carder, Carol | Carrel, Laura | Chako, Joseph | Chapman, Joanne C. | Chavez, Dean | Chen, Ellson | Chen, Guan | Chen, Yuan | Chen, Zhijian | Chinault, Craig | Ciccodicola, Alfredo | Clark, Sue Y. | Clarke, Graham | Clee, Chris M. | Clegg, Sheila | Clerc-Blankenburg, Kerstin | Clifford, Karen | Cobley, Vicky | Cole, Charlotte G. | Conquer, Jen S. | Corby, Nicole | Connor, Richard E. | David, Robert | Davies, Joy | Davis, Clay | Davis, John | Delgado, Oliver | DeShazo, Denise | Dhami, Pawandeep | Ding, Yan | Dinh, Huyen | Dodsworth, Steve | Draper, Heather | Dugan-Rocha, Shannon | Dunham, Andrew | Dunn, Matthew | Durbin, K. James | Dutta, Ireena | Eades, Tamsin | Ellwood, Matthew | Emery-Cohen, Alexandra | Errington, Helen | Evans, Kathryn L. | Faulkner, Louisa | Francis, Fiona | Frankland, John | Fraser, Audrey E. | Galgoczy, Petra | Gilbert, James | Gill, Rachel | Glöckner, Gernot | Gregory, Simon G. | Gribble, Susan | Griffiths, Coline | Grocock, Russell | Gu, Yanghong | Gwilliam, Rhian | Hamilton, Cerissa | Hart, Elizabeth A. | Hawes, Alicia | Heath, Paul D. | Heitmann, Katja | Hennig, Steffen | Hernandez, Judith | Hinzmann, Bernd | Ho, Sarah | Hoffs, Michael | Howden, Phillip J. | Huckle, Elizabeth J. | Hume, Jennifer | Hunt, Paul J. | Hunt, Adrienne R. | Isherwood, Judith | Jacob, Leni | Johnson, David | Jones, Sally | de Jong, Pieter J. | Joseph, Shirin S. | Keenan, Stephen | Kelly, Susan | Kershaw, Joanne K. | Khan, Ziad | Kioschis, Petra | Klages, Sven | Knights, Andrew J. | Kosiura, Anna | Kovar-Smith, Christie | Laird, Gavin K. | Langford, Cordelia | Lawlor, Stephanie | Leversha, Margaret | Lewis, Lora | Liu, Wen | Lloyd, Christine | Lloyd, David M. | Loulseged, Hermela | Loveland, Jane E. | Lovell, Jamieson D. | Lozado, Ryan | Lu, Jing | Lyne, Rachael | Ma, Jie | Maheshwari, Manjula | Matthews, Lucy H. | McDowall, Jennifer | McLaren, Stuart | McMurray, Amanda | Meidl, Patrick | Meitinger, Thomas | Milne, Sarah | Miner, George | Mistry, Shailesh L. | Morgan, Margaret | Morris, Sidney | Müller, Ines | Mullikin, James C. | Nguyen, Ngoc | Nordsiek, Gabriele | Nyakatura, Gerald | O’Dell, Christopher N. | Okwuonu, Geoffery | Palmer, Sophie | Pandian, Richard | Parker, David | Parrish, Julia | Pasternak, Shiran | Patel, Dina | Pearce, Alex V. | Pearson, Danita M. | Pelan, Sarah E. | Perez, Lesette | Porter, Keith M. | Ramsey, Yvonne | Reichwald, Kathrin | Rhodes, Susan | Ridler, Kerry A. | Schlessinger, David | Schueler, Mary G. | Sehra, Harminder K. | Shaw-Smith, Charles | Shen, Hua | Sheridan, Elizabeth M. | Shownkeen, Ratna | Skuce, Carl D. | Smith, Michelle L. | Sotheran, Elizabeth C. | Steingruber, Helen E. | Steward, Charles A. | Storey, Roy | Swann, R. 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Nature  2005;434(7031):325-337.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
PMCID: PMC2665286  PMID: 15772651
14.  Local delivery of osteoprotegerin inhibits mechanically mediated bone modeling in orthodontic tooth movement 
Bone  2007;41(3):446-455.
The RANKL-OPG axis is a key regulator of osteoclastogenesis and bone turnover activity. Its contribution to bone resorption under altered mechanical states, however, has not been fully elucidated. Here we examined the role of OPG in regulating mechanically induced bone modeling in a rat model of orthodontic tooth movement.
The maxillary first molars of male Sprague-Dawley rats were moved mesially using a calibrated nickel–titanium spring attached to the maxillary incisor teeth. Two different doses (0.5 mg/kg, 5.0 mg/kg) of a recombinant fusion protein (OPG-Fc), were injected twice weekly mesial to the first molars. Tooth movement was measured using stone casts that were scanned and magnified. Changes in bone quantity were measured using micro-computed tomography and histomorphometric analysis was used to quantify osteoclasts and volumetric parameters. Finally, circulating levels of TRAP-5b (a bone resorption marker) was measured using enzyme-linked immunosorbent assay.
The 5.0 mg/kg OPG-Fc dose showed a potent reduction in mesial molar movement and osteoclast numbers compared to controls (p<0.01). The molar movement was inhibited by 45.7%, 70.6%, and 78.7% compared to controls at days 7, 14, and 21 respectively, with the high dose of OPG. The 0.5 mg dose also significantly (p<0.05) inhibited molar movement at days 7 (43.8%) and 14 (31.8%). While incisor retraction was also decreased by OPG-Fc, the ratio of incisor to molar tooth movement was markedly better in the high-dose OPG group (5.2:1, p<0.001) compared to the control group (2.3:1) and the low-dose OPG group (2.0:1).
Local delivery of OPG-Fc inhibits osteoclastogenesis and tooth movement at targeted dental sites.
PMCID: PMC2581749  PMID: 17588510
RANKL inhibitor; OPG; Osteoclast; Micro-computed tomography; Tooth movement

Results 1-14 (14)