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Reds' first-round pick gets No. 5 starter job
GOODYEAR, ARIZ.(AP) —The Cincinnati Reds made Mike Leake(notes) their fifth starter on Friday, clearing the way for the right-hander to make his major league debut less than a year after he was drafted.
The 22-year-old Leake beat out Travis Wood(notes), a second-round pick in 2005, and Cuban defector Aroldis Chapman(notes), who was hampered by lower back spasms late in spring training.
"There's no words to describe it, right now," said Leake, the former Arizona State star who was selected eighth overall in last June's draft. "Maybe in a couple days."
Chapman, who agreed to a $30.25 million, six-year deal in January, was optioned to Triple-A Louisville.
"We just felt that competition-wise that's where he should be," general manager Walt Jocketty said.
The Reds also told infielder Aaron Miles(notes) and outfielder Wladimir Balentien(notes) that they did not make the team. Both players are still on the roster while the club tries to trade them.
"There were some tough decisions to make," Jocketty said. "The two players know what their situation is but they are still on the roster, which is at 28. We will break camp with 11 pitchers and finalize everything on Monday."
Leake also will be reassigned to the minors but will be called up when Cincinnati needs a fifth starter.
Infielders Miguel Cairo(notes) and Juan Francisco(notes), outfielder Laynce Nix(notes) and reliever Logan Ondrusek grabbed the last couple of spots on the team. Cairo and Nix were non-roster players.
"Ondrusek rose through the organization last year and dominated at every level," Jocketty said. "He was that way this spring. He handled himself like a pro without having a lot of experience. He was very impressive."
Ondrusek did not allow a run in 9 1-3 innings this spring.
Right-handers Wood, Jared Burton(notes) and Justin Lehr(notes), and lefty Matt Maloney(notes) also were sent to Louisville, along with infielders Chris Burke(notes) and Drew Sutton(notes), and utilityman Wilkin Castillo(notes). Right-hander Kip Wells(notes) was released.
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subset: commoncrawl


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If you have troubles since the update to WordPress 4.5 please read this post before opening a new thread.
Any reason why the Logo Image doesn't show up on the Iphone Browser??? I get a ? in a blue box..everything else works great.
Fixed..the initial logo was a .Png…so I took a snapshot with the Png logo on the background image and uploaded as a Jpeg…works!!
The topic 'Angular Logo On Mobile Phone' is closed to new replies.


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From its first production at the end of Theatre in the Square's 1990-1991 season, Smoke has been a smash. Palmer Wells says the runs of both Smoke and the 4-year-old Sanders Family Christmas routinely sell out and require extensions. The theater has produced the show at Southern Polytechnic State University and Kennesaw State University, but, Wells says, "We have such a devoted following, I think they'd even come to see it in a cow pasture. We call the regulars 'the Smokies.'"
The most seasoned veteran in Theatre in the Square's long-term relationship with Smoke is Karen Howell, who as Vera Sanders comes across like Minnie Pearl getting ready to discipline you with a hickory switch. She attributes part of the show's appeal to the fact that they take the Sanders family seriously. "When we started, Smoke's first director, Dex Edwards, said, 'We have to walk a thin line here,'" Howell recalls. "We want to have fun and entertain, but not go so far overboard that we offend the audience. A lot of us have grown up not that differently from the Sanderses, and we don't want to make the people look ridiculous.'"
Beecham shares that view. "When you exaggerate the Southernness, you're not being real to the character. Even in a musical revue, you have to be true. 'How country is the character? How naive or uneducated?' The easy choice for actors is that, because someone's from the country or the South, they're not smart, and that's not necessarily true. It's more like buffoonery than acting."
Nevertheless, the corn is as high as the proverbial elephant's eye in many popular Southern plays. Sometimes the caricatures are built into the works themselves: Pump Boys & Dinettes includes songs with titles like "Farmer Tan," "Catfish" and "Drinkin' Shoes." Other times, it's a matter of interpretation. When thinking of Steel Magnolias, it's hard not to flash back to the phony, vowel-elongating accents of Olympia Dukakis, Darryl Hannah and even Julia Roberts in the chick-flick adaptation.
"There's a lot that's easy to make fun of in the South," says playwright Philip DePoy, whose play Easy, a mystery set in present-day Atlanta, is in rotating repertory with Negro Dance Lesson at the New South festival. "Southern Crap theater takes things in the South and makes fun of them just to make fun of them, like the way Longhorn Steakhouse has the big-haired lady who's the spokesman. Any play that treats any group with a shallow eye and a heavy hand does the rest of the work a great disservice."
Atlanta audiences tend to have a high tolerance for Southern stereotypes, proving more likely to be tickled than insulted by them. In fact, they tend to revisit them time and again just as the "Smokies" see Smoke on the Mountain year in and year out.
"Audiences in general buy Southern caricatures before they see past them," says DePoy, whose work ranges from the gentle downhome musical revue Appalachian Christmas Homecoming to the religious satire Preacher from the Black Lagoon. "The South still has, to some extent, the vanquished mentality of surrender and burned cities. A way out is humor that is primarily self-deprecating. I believe in, and try to engender, a kind of honor and dignity for the South, especially the rural South, because I love it."
Wells says there isn't a lot of crossover between Smoke and the rest of the theater's shows, and the same could be said about its die-hard fans and the theater's other patrons. You might not expect a "Smokie" to line up for something as edgy as Neil LaBute's Bash, which the theater recently produced in its Alley Stage, but Wells says they seldom even check out similar-themed shows like Fair and Tender Ladies.
"Many of them are church groups, and I wouldn't call them our average subscribers -- there's just this one little show that appeals to them," he says.
Attending with the singles group from First United Methodist Church, Bobbie Therrassee has seen Smoke on the Mountain twice and Sanders Family Christmas once, and she looks forward to seeing both of them again. "Some people ask me, 'How can you see a play more than once?' And I say, 'I've seen The Passion Play every year of my life and still get something out of it."
But Therrassee says her group is less interested in Theatre in the Square's more serious fare. "We went to see The Night of the Iguana there, and I'm sure it was a fine show, but the heavy, tragedy stuff just doesn't go over as well."
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The Drosophila Ten-m (also called Tenascin-major, or odd Oz (odz)) gene has been associated with a pair-rule phenotype. We identified and characterized new alleles of Drosophila Ten-m to establish that this gene is not responsible for segmentation defects but rather causes defects in motor neuron axon routing. In Ten-m mutants the inter-segmental nerve (ISN) often crosses segment boundaries and fasciculates with the ISN in the adjacent segment. Ten-m is expressed in the central nervous system and epidermal stripes during the stages when the growth cones of the neurons that form the ISN navigate to their targets. Over-expression of Ten-m in epidermal cells also leads to ISN misrouting. We also found that Filamin, an actin binding protein, physically interacts with the Ten-m protein. Mutations in cheerio, which encodes Filamin, cause defects in motor neuron axon routing like those of Ten-m. During embryonic development, the expression of Filamin and Ten-m partially overlap in ectodermal cells. These results suggest that Ten-m and Filamin in epidermal cells might together influence growth cone progression.
Citation: Zheng L, Michelson Y, Freger V, Avraham Z, Venken KJT, Bellen HJ, et al. (2011) Drosophila Ten-m and Filamin Affect Motor Neuron Growth Cone Guidance. PLoS ONE 6(8): e22956. doi:10.1371/journal.pone.0022956
Editor: Franck Pichaud, MRC, University College of London, United Kingdom
Received: March 16, 2011; Accepted: July 3, 2011; Published: August 8, 2011
Copyright: © 2011 Zheng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by NIH grants U01 HD39372 and P01 ES11253 to MJJ. www.nih.gov/. This work was supported by Israel Science Foundation Grant 749_04 to RW. www.isf.org.il/english/. HJB is an investigator of the HHMI. www.hhmi.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
During the development of vertebrate and invertebrate nervous systems, motor neurons project axons from the central nervous system (CNS) to reach their targets [1]. This complex, yet stereotyped, process is essential for numerous processes, including coordinated motor activity. The growth cones help motor axons to navigate and find their appropriate targets. As they migrate they sense and respond to guidance cues and make multiple path-finding decisions [2]. The guidance cues include attractive and repulsive factors [3], [4], which bind receptors on the growth cones, impact intracellular signaling pathways and intracellular states [5], and induce cytoskeletal rearrangements.
The fruitfly Drosophila melanogaster has been an excellent model to study motor axon guidance since the mechanisms underlying this process are highly conserved between invertebrates and vertebrates [6]. The Drosophila neuromuscular system is composed of ∼40 motor neurons and 30 muscles in each abdominal hemisegment. The 40 motor neurons have been individually characterized in terms of neuroblast lineage, axon trajectory and muscle target [7], [8], [9]. The motor neurons project axons from the CNS in two bundles, the intersegmental nerve (ISN) and the segmental nerve (SN), before defasciculating into five major branches [10]. Each branch innervates a subset of the 30 stereotypically-arranged muscles at distinct distances from the body wall and in specific dorso-ventral regions [7], [10]. Apart from the ISN and SN nerves, the smaller transverse nerve (TN) is a mixed motor and sensory projection with efferent axons that innervate at least two muscle fibers in the mid-body wall regions [11], [12].
Numerous genes have been shown to affect growth cone guidance. Genetic screens [10], [13] identified homozygous mutant embryos by using monoclonal antibodies against neural specific antigens and histological examination of their axonal projections [14], [15], [16]. Based on similar screens in Drosophila and C. elegans, as well as biochemical experiments, many key players in growth cone guidance have been identified. These include genes with roles only in axon guidance, and those encoding classic morphogens that also function as guidance molecules.
The Tenm/Odz gene family encodes transmembrane proteins that are highly conserved across all metazoan species. Two members (here called Ten-m and Ten-a) have been identified in Drosophila and four members, called Teneurins (Tenm-1 through Tenm-4) in chicken, mouse, rat and human. The proteins contain eight EGF-like domains and seven NHL repeats. The NHL repeats resemble WD repeats and may be involved in protein-protein interactions [17]. Although two mutually exclusive models for the topology of the Ten-m protein have been proposed [18], [19], one documented form of the Drosophila Ten-m is a type I, multiply cleaved heterodimeric transmembrane protein with extracellular EGF domains and a large C-terminal intracellular domain [20]. Comparison of the protein sequences in this family indicates that three domains show higher conservation than the remainder of the protein: the EGF-like domain, the NHL repeats, and the cysteine rich segment between the EGF and NHL repeat stretches.
Drosophila Ten-m was first identified as a pair-rule gene involved in segmentation during embryonic development [19], [21]. Its expression is dynamic during development, first as seven stripes in the cellular blastoderm, then as fourteen stripes from stage 12 onward [19], [21]. It is prominently expressed in the ventral nerve cord, the cardiac mesoderm and epidermis at late embryonic stages [19], [21] and it also expressed in all imaginal discs [22]. Functional information on the vertebrate homologues is accumulating. Chicken Tenm-2 is expressed in the developing limb, somites and craniofacial mesenchyme [23]. Interestingly, its expression in a neuroblastoma cell line leads to excessive filopodia formation and enlarged growth cones [24]. Mouse Tenm4/Odz4 is required for gastrulation, and is likely involved in a number of later developmental processes [25]. The Tenm-4 homologue in rat (called Neurestin) is expressed in various types of neurons [26]. RNAi experiments in C. elegans have implicated Tenm-1 in axon guidance and cell migration [27]. The loss of Tenm3 in mice affects guidance of retinal axons and generation of visual topography [28], and a number of allied processes [29].
To define the function of Ten-m in fruit flies we identified and characterized new mutant alleles and found no evidence for a pair-rule phenotype, in contrast to previous reports [19], [21]. Instead, both disruption, and epidermal over-expression, of Ten-m result in aberrant motor axonal path-finding. We also found that Filamin, an actin-binding protein, whose homologues are associated with various congenital malformations, in the brain cortex in humans, as well as in craniofacial, skeletal and visceral and urogenital tracts in vertebrates [30], interacts with Ten-m. Ten-m and Filamin partially co-localize in Drosophila embryos, and overlap in epidermal co-expression stripes. Disruption of the gene encoding Filamin, cheerio, results in similar aberrant motor axonal path-finding defects as those observed in Ten-m mutants. These results suggest that Ten-m and Filamin influence motor neuron migration either through their activites in the motor neurons, in the epidermis, or through both.
Materials and Methods
Fly strains, genetic and molecular methods
The following strains from the Bloomington stock center are used in this study: y w, Canton S, P{PZ}Ten-m05309 ry506/TM3, ry Sb1, here called "5309" [19], [21], [31], y1w67c23; P{y+mDint2 wBR.E.BR = SUPor-P}Ten-mKG00101 ry506/TM3, Sb1 Ser1, here called "N1" [32]. N1 is a SUPor-P (for suppressor-P element) gypsy-hybrid insertion [32], [33]. The insertion coordinate for N1 was determined through HpaII genomic DNA restriction, then inverse-PCR (http://flypush.imgen.bcm.tmc.edu/pscreen/). The PZ insertion of 5309 is at genome position 3L:22400915, and the P[SUPorP] insertion of N1 is at genome position 3L: 22400924 (Flybase release 5.26). Imprecise excision and revertants of N1 were generated by P-element excision according to established protocols [34]. Also used were: Ten-mCB04632, a GFP expressing insert driven by Ten-m control elements [35], Ten-m628 [36], Df(3L)Ten-mAL1/TM3, ry Sb1, here called "AL1" [22], Df(3L)Ten-mAL29/TM3, ry Sb1, here called "AL29" [22], w1118; Df(3L)Exel6138, P{w+mC = XP-U}Exel6138/TM6B, Tb1, here called "Df (3L) Exel6138" [37], ru1 h1 th1 st1 opa1 cu1 sr1 es ca1/TM3, Sb1, an odd paired allele, and ru1 h1 th1 st1 opa1 cu1 sr1 es ca1/TM3, Sb1 Ser1 [38], [39], cherjoy [40]; cher273/TM6 Tb, with an insertion from the Exelixis collection, and cher1/TM3 Sb [41]. cherio embryos were generated by crossing homozygous males with heterozygous cher females for alleles 273 and 1, or homozygous cherjoy females, to yield 50% or 100% expected homozygotes, respectively. The following Gal4 drivers are used: P{GawB}69B [42]; and paired-Gal4. The 133 kb Ten-m+t133 genomic fragment, gap-repaired in attB-P[acman]-ApR, and integrated into the VK1 docking site is described in [43]. This fragment was additionally integrated into VK37 with a germline phiC31 source [44]. The frequency of rescue to viability was determined by scoring adults lacking balancer markers among total offspring derived from Ten-m balanced heterozygotes carrying the rescue element. The rescue of axon guidance defects (see below) in Ten-m mutant embryos was determined in offspring of Ten-m balanced heterozygotes carrying the rescue element, by assessing FasII staining in embryos lacking balancer markers, yet expressing transgene encoded Ten-m levels. The frequency of rescue reflected the extent of alleviation of the mutant phenotype in the homozygous Ten-m mutants carrying a rescue element.
Two directed deletions of virtually the entire Ten-m gene were generated utilizing FRT bearing P-elements inserted at the three prime end and five prime end of Ten-m [37]. The entire gene was deleted in Ten-mΔ525, which was generated through flippase mediated recombination between a third chromosome bearing PBac{WH}Ten-mf01130, and its homologous chromosome bearing P{XP}Ten-md00619, by an established targeted deletion method [37]. Ten-mΔ510, which has all of Ten-m deleted except for the first exon, was generated in the same manner using a third chromosome bearing PBac{WH}Ten-mf01130, together with one bearing P{XP}Ten-md06452. Lethal Ten-m alleles were either themselves marked with lacZ or GFP, or carried embryonic marked balancers or balancers that contribute no embryonic neuronal phenotypic effects. All Ten-m lethal heterozygous lines, alone or in inter-allelic combinations, give rise to an expected 25% Ten-m mutant embryos. For a comparison across all alleles, frequencies are presented uniformly in one table as the mutant phenotype rates within each entire offspring population. Lethal phase analysis was modified from that described [45] using a Kr-GFP balancer as in [46]. Cuticle preparation was slightly modified from the protocol described elsewhere [47].
Ten-m transgenic fly generation
The Ten-m cDNA containing the whole open reading frame was cloned into the pUAST vector and transgenic lines were obtained according to established methods for P element transposition.
Yeast two hybrid screening
The MATCHMAKER Two-hybrid System 3 (Clontech) was used for screening a Drosophila embryonic cDNA library (cloned into the pACTII vector, Steve Elledge, Harvard University). The bait was the cytoplasmic region of the Drosophila Ten-m gene (nucleotides 3423 to 8891 in X73154), which was cloned into the pGBKT7 vector (Clontech). Positive colonies were identified as those being able to grow on the quadruple dropout media (-trp/-leu/-his/-ade). The positive interactions were then confirmed in beta-galactosidase overlay assays. The candidate plasmids were rescued by electroporation into E. coli cells and then sequenced.
Deletion mapping in yeast
The cytoplasmic region of Ten-m was truncated into several segments and cloned into the pGBKT7 vector. Based on X73154, these are the truncated segments: Seg1, Nt. (nucleotide) 3423–4213; Seg2, Nt. 4213–5193; Seg3, Nt. 5193–8891; Seg4, Nt. 3423–5193; Seg5, Nt. 4213–8891 and Seg6, Nt. 3423–8891. Deletion mapping was carried out by co-transforming two plasmids (Ten-m fragment in pGBKT7, Filamin fragment in pACTII) into the AH109 yeast strain (Clontech). Equal amounts of transformed cells were plated on selective media. The ratio (as a percentage) of the number of colonies that grow on quadruple dropout media (-trp/-leu/-his/-ade + 2.5 mM 3-amino-1,2,4-triazole) over the number of colonies that grow on double dropout media (-trp/-leu) was calculated.
GST pull down assay
GST fusion protein constructs were made with the pGEX4T2 vector (Stratagene). The GST-Filamin fusion proteins, or GST alone, were expressed in BL21 (Stratagene) upon induction by isopropyl thiogalactoside (IPTG) and purified by incubating the resulting bacterial cell lysate with equilibrated Glutathione-sepharose beads (Pharmacia). The beads were washed five times with binding buffer (0.5% NP40 in PBS supplemented with EDTA free protease inhibitor cocktail from Roche). Truncated Ten-m segments 1, 2, and 4 were in vitro translated and 35S labeled with TNT T7 coupled reticulocyte lysate system (Promega). The fusion protein-bound beads and the 35S labeled proteins were mixed, rotated for 2 hours at 4 degrees, washed five times with the binding buffer, then resolved on an SDS PAGE gel that was subsequently fixed, dried and exposed to X-ray film.
Whole mount immunohistochemistry
Drosophila embryos were collected, aged, fixed in 3.7% or 4% formaldehyde and blocked in 5% normal goat serum in PBT (0.1% Tween20 in PBS) according to standard procedures. The following primary antibodies were used in this study: monoclonal anti-Ten-m antibody (Mab113) 1∶300 [21]; monoclonal anti-Ten-m antibody (Mab20) 1∶3000 [19], rat anti-Filamin polyclonal antibody 1∶3000 [48](Lynn Cooley, Yale University); anti-fasciclin II (1D4) 1∶5 [13](obtained from the Developmental Studies Hybridoma Bank (DSHB)); BP102 1∶20, [13](DSHB), 22C10 1∶20 [15](DSHB), and rabbit anti-beta galactosidase 1∶5000 (MP Biomedicals). The embryos were washed in PBST four times for 15 minutes each, then stained with secondary antibodies: biotinylated anti-mouse antibody 1∶400 and biotinylated anti-rat antibody 1∶400 (Vector Laboratory); Alexa488-anti-mouse 1∶400 (Molecular Probes); and Cy3-anti-rat 1∶500 (Jackson ImmunoResearch Laboratories). The embryos were washed again for four times, 15 minutes each and treated in the following way: for the biotinylated staining, a and b solutions (Vector Laboratory) were added and color reactions were performed according to the manufacture's protocol; for fluorescent staining, as above or the embryos were filleted and mounted in 70% glycerol.
New Ten-m mutations, and phenotypic rescues with a genomic construct, show that Ten-m is not a segmentation gene
We found that a homozygous lethal P-element insertion, named PKG0010, abbreviated N1, was inserted in the Ten-m locus [32]. The P-element is inserted in the first exon of Ten-m [19], [21], one of the largest fly genes (Figure 1A). This insertion site is 34 nucleotides downstream of the transcription start site in the 5′ UTR, very close to the P-element insertion site of the most studied Ten-m allele, Ten-ml(3)05309, abbreviated Ten-m5309, or 5309 (Figure 1A). N1 failed to complement the lethality associated with 5309 (Figure 1B), and as had been shown for 5309, is a Ten-m protein null (Supporting Information S1). To demonstrate that the lethality is associated with the N1 insertion, we excised the P-element and reverted the lethality (lines N1-R11 and N1-R60). We also generated deletions of Ten-m (Ten-mΔ510 and Ten-mΔ525, see Figure 1A) using the flippase-mediated directed deletion approach [37], with P-element pairs shown in Figure 1A. The N1 line also fails to complement the lethality of these two Ten-m deletions, or a larger previously generated deletion covering the region, Df (3L) Exel6138 (Figure 1B). The revertants N1-R11 and N1-R60 complement Df (3L) Exel6138, further supporting that the lethality of N1 is caused by the insertion (Figure 1B).
(A) A schematic displaying the introns and exons of Ten-m appears just below the coordinates of the D. melanogaster 3L chromosome arm, (Release 5.26, in kilobases), below which the positions of the P-element insertions of Ten-m alleles 5309 and N1 appear in an expanded view of exon 1. Above the 3L coordinates is a representation of the extent of the genomic rescue element contained in Ten-m+t133. Above that, the positions of the three FRT bearing P-elements used to produce Ten-m deletions Ten-mΔ510 and Ten-mΔ525, and the extent of those deletions as dashed lines, are represented. (B) Complementation tests for viability were conducted among available alleles, deletions, and P-element excisions. L, lethal; V, viable or rescued by Ten-m transgene, N.D., not determined.
The homozygous lethality associated with the Ten-m5309 and Ten-mN1 P-element insertion mutations, as well as the Ten-mΔ510 and Ten-mΔ525 deletions, was rescued using a P[acman] vector containing a 133 kb genomic rescue construct, Ten-m+t133 (Figure 1A, B) [43]. These data demonstrate that N1 is a Ten-m allele, that the lethality associated with the above Ten-m alleles is solely due to mutations in Ten-m, and that these alleles correspond to severe loss of function or null alleles.
Interestingly, no patterning defects were observed in N1 embryos (Figure 2G), contrary to previous data indicating that Ten-m is a pair-rule gene [19], [21]. We rebalanced the Ten-mN1 mutation with a GFP marked balancer chromosome (Kr-GFP) [46], and examined the lethal phase. A majority of homozygous Ten-mN1 mutants hatched and survived to the first larval stage, and some survived to the second larval stage. Ten-m5309 showed the same lethal phase when a different balancer was used than the one in the original stock. These data are not in agreement with the lethal phase of Ten-m mutations, previously reported to be embryonic lethal [21]. We therefore prepared cuticle preparations of embryos of the 5309 allele in the original balanced stock (Ten-m5309/TM3, Sb ry), as well as two X-ray induced deletion alleles, named AL1 and AL29, which are propagated with the same balancer (e.g. Df(3L)Ten-mAL1/TM3, Sb ry) [22]. All three stocks produced embryos with obvious patterning defects as reported previously [22]. To determine if the segmentation defects were associated with the Ten-m mutations or with mutations on the balancer chromosome, we rebalanced the 5309, AL1 and AL29 mutations with another balancer (TM3, Sb). Surprisingly, none of the rebalanced stocks produced embryos with cuticle phenotypes (Figure 2D, E and F). Moreover, the balancers from the original three stocks produced severe cuticle defects when outcrossed and homozygosed (Figure 2A, B and C). These results demonstrate that the cuticle fusion phenotype in the original 5309, AL1 and AL29 stocks are caused by a mutation present on this TM3, Sb ry balancer, and that mutations in Ten-m do not lead to a pair-rule like defect.
(A–I) Cuticles of dechorionated and devitellinized embryos were prepared to visualize exoskeletons and segmentation phenotypes. The cuticle phenotypes in the original Ten-m mutant stock and odd paired alleles are shown. The new Ten-m N1 allele and rebalanced reference alleles fail to reproduce a pair-rule phenotype. Embryos shown are derived from the original: 5309 (A and D) ; Df(3L)Ten-mAL1 (B and E); and Df(3L)Ten-mAL29 (C and F) stocks. (G) N1, (H) odd paired1, and (I) odd paired2. Embryos are oriented: anterior-left.
Since the cuticle defects in these balancers are very similar to those associated with odd-paired (opa), a third chromosome pair-rule gene [39] (Figure 2H and I), we carried out complementation tests between the TM3, Sb ry balancer and odd-paired mutations. The balancer chromosome fails to complement odd-paired mutations (data not shown). We conclude that the odd-paired gene on the balancer chromosomes is mutated, and that it caused the segmentation defects observed in the original 5309, AL1 and AL29 lines.
Drosophila Ten-m mutants show peripheral motor neuron axon guidance defects
As Ten-m is prominently expressed in the nervous system, we stained mutant embryos with neuronally directed antibodies (BP102, 22C10, 1D4), and discovered specific axon guidance defects. The commissural axons (visualized with BP102) do not exhibit defects in Ten-m mutants (data not shown). Sensory neuron placement, their overall morphology, and their axons also display no significant aberrations (visualized with 22C10, data not shown). However, staining with Mab 1D4, which recognizes the neural cell adhesion molecule Fasciclin II and labels motor axons [10], revealed severe motor axon routing defects in Ten-m mutants.
The Drosophila peripheral motor axon projections have a stereotypical pattern [49]. The ISN navigates away from the CNS at embryonic stage 14 and reaches its terminus (near muscle 1) at stage 16 [10]. The ISN has three characteristic side branches: the first branch (FB) at the junction of muscles 3 and 11, the second branch (SB) at the junction of muscles 2 and 10 and a terminal branch at the junction of muscles 1 and 9 (Figure 3A, G) [10], [49]. In Ten-m mutant embryos, the ISN projections exit the CNS normally but aberrant patterns are observed at different extension points when they reach the dorsal or dorsal-lateral region of the body wall (Figure 3B–F, H). These aberrant patterns can be subdivided into at least four different groups. First, some ISNs cross the segmental boundary and fasciculate with adjacent ISNs (Figure 3B). Second, there are ISNs that defasciculate below the FB and the terminus. In some cases, the defasciculated branch crosses the segmental boundary and fasciculates with an adjacent ISN (Figure 3C and D). In others, the defasciculated branch crosses the segmental boundary and remains defasciculated (Figure 3E). Third, some ISNs fail to reach the terminal domain in the dorsal muscle domain (Figure 3B and D). Fourth, the transverse nerve will occasionally fasciculate with an ISN (Figure 3F).
The mutant embryos show severe defects in motor neuron axon navigation as shown by motor axon specific marker anti-fasII staining. (A–G) The embryos examined are all at stage 16, anterior - left, dorsal - up. TN: transverse nerve. m: a characteristic cell lying along transverse nerve. The arrows refer to the defasciculation of ISN and the arrowheads to the premature termination of ISN. FB, first branch; SB, second branch. (A) Wild type. ISN axons have been fully developed with three characteristic branches (FB, SB and Terminal growth cone). (B–F) Ten-m mutants. The adjacent ISNs are fused at different positions along the axon with excessive branching. The fusion point could be below FB (B) or around SB (C). The adjacent ISNs could be connected with a bridge (D). Some ISNs have the "Y" shape (E). In other cases, the transverse nerve travels along the ISN (F). (G) Overview of wild type whole embryo. (H) Overview of mutant whole embryo. Occasionally there are two fusions in one embryo. (I) Penetrance of the mutant phenotype. The percentage (in parentheses) is the number of mutant embryos that show axon fusion out of the total number of embryo offspring derived from balanced stocks. For the lethal Ten-m lines, approximately 25% of offspring are expected to be Ten-m homozygotes. For the viable Ten-mN1-R, wild type, and y w lines, all offspring are of the same genotype.
These defects do not occur in all embryos nor do they occur in all segments. As an example, 68% of Ten-mΔ510 homozygotes, distinguishable from their siblings by their lack of lacZ marked balancers, display defects in axons of at least one segment. Almost half of these have defects in three or more segments, (cases with two and four segments are shown in Figure 3G and H). The defects documented in a series of Ten-m alleles are shown in Figure 3I. The different alleles display phenotypes in 8.5 to 25% of all offspring of lethal Ten-m balanced lines (Figure 3I) (where 25% among all of the offspring are expected to be Ten-m homozygotes). Viable P-element revertants (Ten-mN1-R) do not exhibit motor axon defects (Figure 3I) (where 100% of the offspring are Ten-m homozygotes), demonstrating that the Ten-m lesions are responsible for the observed motor axon phenotypes. Ten-m mutant embryos for two transallelic combinations (Ten-m510/Ten-mCB04632 and Ten-ml(3)5309/Ten-mCB04632) displayed the axon guidance defects at a 60% frequency, close to the frequency of each homozygosed allele. The axon guidance defects are also rescued by the P[acman] genomic Ten-m+t133 transgene (not shown). Approximately 25% of Ten-m homozygotes are rescued to adult viability by a single transgene element, and the extent of alleviation of the FasII scored axon defect phenotypes is similar. We did not observe defects in the Ten-m embryos of the various alleles when they were stained with Mab 22C10 and BP102, suggesting that the motor neurons are specifically affected. In addition, we did not observe segmentation, tracheal, or muscle defects (data not shown).
Ectopic expression of Ten-m results in motor neuron axon guidance defects
The crossover or early termination phenotypes of ISN occur laterally and dorsally, with initial motor axon outgrowth from the CNS unaffected. This is reminiscent of phenotypes for mutations of genes providing distal cues for motor axons with migration defects [1], [6], [50], [51]. These include genes whose expanded peripheral or pan-muscle over-expression produce phenotypes similar to their loss of function phenotypes, suggesting they encode instructive cue molecules with localization essential for proper motor axon migration [50]. Beyond its abundant CNS presence, Ten-m is also expressed in stripes from stage 12 [19], [21], as shown in embryos at late stage 14 (below, Figure 4A and 7B, Supporting Information S1). To determine if ectopic Ten-m expression impacts ISN axon migration, we used the GAL4/UAS system [42] to ectopically express Ten-m throughout the epidermis starting from embryonic stage 9 (see Materials and Methods). Driving expression of Ten-m throughout the epidermis using a single copy of the ubiquitous 69B driver [42], causes no obvious phenotype (Figure 4A–C, J). However, ∼55% of embryos that carry two copies of the 69B GAL4 driver exhibit ISN migration defects, including abnormal defasciculation, segmental boundary crossovers, as well as bifurcations at the termini (Figure 4D–F, J). To test whether Ten-m overexpression in epidermal stripes can cause these defects, we overexpressed Ten-m in every other segment, using the paired-GAL4 driver. In ∼50% of these embryos, we observed abnormal axon guidance defects (Figure 4J). As shown in Figure 4G–I, ectodermal stripes in which Ten-m is overexpressed exhibit a defect in the ISN, often crossing segmental boundaries and fasciculating with the ISN in the adjacent segment. In some cases, the ISN does not cross segmental boundaries but defasciculates and migrates abnormally in the same segment (Figure 4G–I). Hence, ectopic expression of Ten-m in ectodermal cells perturbs axonal guidance, suggesting a possible role for ectodermal Ten-m in axon-guidance.
Stage 16 embryos are stained with Ten-m and FasII antibodies, anterior - left, dorsal -up. Arrows refer to the ISN segmental crossings. (A–C) Control embryos with low-level Ten-m expression driven by one copy of 69B GAL4. The ISN axon routing is normal. (D–F) Embryos with high-level Ten-m overexpression driven by two copies of 69B GAL4. The ISN de-fasciculates in one segment, crosses the segmental boundary and fasciculates with the ISN in the nearby segment. (G–I) Embryos with high-level Ten-m expression in every other segment driven by paired GAL4. Excessive defasciculation occurs in these embryos. ISN axons cross segmental boundaries and fasciculate together. Embryos are stained with Ten-m and FasII antibodies. Paired-Gal4/UAS-Ten-m embryos also display a high frequency of defects. (J) The percentage is the number of stage 16 embryos that exhibit axonal defects versus the total number of embryos that over-express Ten-m.
Drosophila Ten-m interacts with Filamin
Ten-m has been proposed to have several topologies [18], [20]. One of these topologies places the amino-terminal end of Ten-m extracellularly and the carboxy-terminal end in the cytoplasm (Type I topology). To identify intracellular proteins which bind to Ten-m, we carried out a yeast two-hybrid screen using the presumptive intracellular part of Ten-m (amino acid 910–1822) as bait and identified Filamin as an interaction partner from a Drosophila embryonic cDNA library (Supporting Information S1). We obtained seven positive colonies corresponding to five different clones for Filamin. Among the five clones, the 180 amino acids at the C-terminus of the Filamin protein were sufficient for the interaction. The interaction between Ten-m and Filamin was also represented in a Drosophila whole proteome matrix ([52]; http://portal.curagen.com/cgi-bin/interaction/flyHome.pl.).
To narrow down the part of Ten-m that is sufficient for the interaction with Filamin, the Ten-m encoding region was divided into six segments (Figure 5A). The predicted NHL repeats, which were previously reported to be putative protein-protein interaction domains [25] are present in segment 2 (seg 2). The protein sequences upstream and downstream of seg 2 were designated seg 1 and seg 3, respectively. As shown in Figure 5B (and Supporting Information S1), seg1 showed the strongest interaction whereas seg4 showed weaker interactions, suggesting that seg1 may be sufficient for Ten-m to bind Filamin. To provide additional evidence for this interaction, we carried out a GST pull down assay using a GST-Filamin fusion protein, and 35S labeled Ten-m seg1, seg2 and seg4. Under these conditions, seg1 and seg4 bound the GST-Filamin fusion protein much more efficiently than seg2 (Figure 5C), indicating that seg1 is sufficient for the interaction. Thus, Drosophila Ten-m interacts with Filamin and a region in seg1 is mostly responsible for this interaction. Seg1 corresponds to the cysteine rich region between the EGF-like repeat domain and the NHL repeat domain, from amino acids 910 to 1173. Together with the EGF and NHL repeat domains, this previously undefined region is the most highly conserved between Ten-m/Odz family members. We named seg1 the Filamin interacting domain (FID).
(A) The domain structure of Ten-m. For deletion mapping of the filamin binding domain, the C-terminus was further truncated into six segments. SP: signal peptide. EGF: epidermal growth factor repeats. TM: transmembrane domain. NHL: domain shared by Ncl1, Hta2 and Lin41. Y: putative tyrosine phosphorylation site. (B) Deletion mapping of the filamin interaction domain of Ten-m by yeast co-transformation. The leftmost column shows the individual Ten-m segment being co-transformed with Filamin into the AH109 yeast. Seg1, showing the highest percentage, is sufficient for interacting with Filamin. (C) GST pull down assay. In vitro translated Ten-m seg1, seg2 and seg4 were labeled with 35S. The GST-Filamin fusion protein efficiently pulls down seg1 and seg4 (which includes seg1). Lanes 1–3: seg 1; 2 and 4 input. Lanes 4–6: GST-Filamin plus seg 1; 2 and 4. Lanes 7–9: GST plus seg 1; 2 and 4.
Filamin is necessary for proper peripheral motor axon guidance
Filamin is encoded by the cheerio locus [41], for which several mutations have been isolated. We examined embryos homozygous for cherjoy, and for the female sterile alleles cher1, and cher273. Embryos homozygous for these cheerio alleles have ISN projections that exit the CNS normally, but display peripheral neuron motor axon defects (Figure 6A–G) of the types observed for Ten-m mutant alleles. The aberrant patterns include ISNs that cross the segmental boundary and fasciculate with adjacent ISNs (Figure 6A–B, G), including those that defasciculate before crossing the segment boundary to fasciculate with an adjacent ISN (Figure 6D–E). Also included are ISNs that do not reach the terminal domain (Figure 6C, F). The frequency of defects is significant for all three alleles (Figure 6H). From crosses between homozygous cherjoy females and cher273 males, 18% of the resulting transallelic cher273/cherjoy embryos bore axon guidance defects. The nature and frequency of the phenotypes were like those of the 20% observed for cherjoy homozygous embryos. These data provide in vivo evidence that Filamin and Ten-m affect growth cone guidance of motor neurons.
Fasciclin II expression in homozygous mutant embryos for cheerio (Filamin). (A–C) cher273; (D–F) cherjoy; (G) cher1. The aberrant axon morphologies seen in peripheral axons are much like those seen for Ten-m mutant embryos. All embryos are: head, left; dorsal, top. (H) Percentage of embryos showing at least one aberrant axon phenotype. cher1 and cher273 are viable, female sterile alleles propagated with balancer chromosomes. cherjoy is viable and fertile for which all offspring are homozygotes.
Epidermal Ten-m and Filamin expression overlap, and might influence motor axon guidance
Expression patterns for Ten-m and for Filamin suggest that the two interacting proteins might be expressed in the same ectodermal cells in restricted patterns during embryonic development. At stage 8, Ten-m and Filamin are expressed in all furrows and the posterior midgut, although Filamin is expressed more widely than Ten-m. Like Ten-m, Filamin is expressed in a repetitive pattern, at stage11. By stage 13, Ten-m is abundant in the ventral nerve cord while the repetitive expression pattern of Filamin mostly disappears, to then be expressed in the epidermis. At stage 15, Ten-m is expressed in the axons of the CNS as well as in epidermal stripes. Filamin is also expressed in epidermal stripes at stage 15. At high resolution, the overlap of the stripes includes distinct domains of cellular co-expression of these two proteins (Figure 7).
(A) The Ten-mCB04362 enhancer trap expresses Ten-m driven GFP in double rows of epidermal cell nuclei at segment boundaries, and in the CNS at stage 16. (B–D) Ten-m and Filamin are co-localized in the epidermal stripes in stage 15 and early stage 16 embryos. The embryos are shown as lateral views: anterior - left, dorsal - up. (B-B′′′) Ten-m protein (red) and Ten-mCB04362 enhancer trap expression (green) appear in the same cells, in the cytoplasm and nucleus, respectively. Double rows of epidermal cells express Ten-m, as do a number of scattered hemocytes. (B′′′) is an enlargement of the area marked in the merged image of (B′′). (C-C′′′) Filamin (red) and Ten-mCB04362 enhancer trap expression (green) appear in the same cells, in the cytoplasm and nucleus, respectively. Double rows of epidermal cells express the highest levels of Filamin. (C′′′) is an enlargement from (C′′). (D-D′′′) Filamin protein (red) and Ten-m protein (green) appear in the same epidermal cells in a cytoplasmic and cell surface distribution. (D′′′) is an enlargement from (D′′). Scale bars are: 40 µm in A, 10 µm in B, and 2 µm in B′′′.
Double staining of the two proteins establishes the cell-by-cell stripewise epidermal co-expression of these proteins (Figure 7D). A high resolution assessment of the proteins' co-expression is best demonstrated with a nuclear GFP exon trap of an insertion into the 5-prime UTR of Ten-m, Ten-mCB04632 (Figure 7A) [35]. In Ten-mCB04632 embryos, cytoplasmic Ten-m protein imaged by immunofluorescence, and endogenous nuclear GFP Ten-m reporter expression occur in the same cells (Figure 7B). This indicates that the nuclear GFP faithfully represents the expression of Ten-m. When anti-Filamin immunofluorescence of these embryos is imaged, the cytoplasmic cheerio encoded protein product co-localizes to cells expressing the nuclear GFP in distinct rows of epidermal cells (Figure 7C). This co-localization data indicate that during Drosophila embryonic development, Ten-m and Filamin are co-expressed in belts of epidermal cells at segmental boundaries at embryonic stage 15. ISN motor axon projections migrate out of the CNS at embryonic stage 14 and reach the dorsal muscle terminus at stage 16 [10]. Ten-m and Filamin epidermal expression, including co-expression of Ten-m and Filamin in epidermal stripes (Figure 7C, D) at stage 15, may impact motor axon navigation. These data, in light of the Ten-m ectopic expression data, suggest that spatially restricted expression of these genes in epidermal cells may play a role in helping to ensure accurate axonal guidance.
In this study, we characterized new alleles of Ten-m that were generated in a large scale P element mutagenesis project [32] to find that mutant Ten-m does not cause segmentation defects, but leads to abnormal motor axon navigation. We also identified Filamin as an interacting partner of Ten-m, and showed that mutations in the gene encoding Filamin lead to the same motor axon phenotypes those of Ten-m. The data suggest that Filamin and Ten-m may function together to influence motor axon migration.
Ten-m in body pattern formation
Ten-m was thought to be the first non-transcription factor pair-rule gene [19], [21]. Three P-element insertion alleles were reported to lie in the same complementation group and be embryonic lethal. One allele, 5309, showed a severe pair-rule phenotype, one allele showed a moderate version of the same phenotype, whereas other lethal alleles did not have a significant cuticle phenotype [19], [21]. Here we show that the cuticle phenotype associated with the original 5309 stock segregates with the balancer chromosome. Indeed, the Df(3L)Ten-mAL1 and Df(3L)Ten-mAL29 deletion alleles exhibit fusions similar to the 5309 allele when balanced with the same balancer chromosome as the one used in 5309 (Figure 2). Our data show that the "Ten-m" cuticle phenotype analyzed previously is an odd-paired mutation on the balancer chromosome and is not due to the Ten-m mutation itself. It should be noted that the embryonic CNS longitudinal connective discontinuity phenotype documented [19] for Ten-m5309 is also due to a mutation on that original balancer.
Ten-m in motor axon migration
When Ten-m is not expressed, or is ectopically expressed in the ectoderm, aberrant motor axon growth cone guidance occurs. Growth cones use various kinds of substrates and guidance cues to navigate through a specific path to find their targets [4]. In Drosophila and C. elegans, genetic screens have identified many secreted or transmembrane guidance cues including Netrins, Semaphorins, Slits, Nephrins, and classic morphogens that also act as guidance molecules [10], [53], [54], [55]. Most of these cues are expressed either by axonal tracts themselves or along the axonal trajectory by peripheral tissues, such as muscles. We have identified a transmembrane protein affecting migration, Ten-m, which is expressed in epidermal stripes and in neurons. In both vertebrate and invertebrate embryos, axons must first exit the CNS, and then migrate along stereotyped pathways to reach their specific targets in the periphery. Since motor axons in both Ten-m loss of function mutants, and Ten-m ectopic expression embryos, exit the CNS normally but do not migrate along their specific paths (Figure 3 and Figure 4), Ten-m appears to be dispensable for axonal extension but necessary for pathfinding decisions in the periphery.
Ten-m is often required for correct choice point determination. During embryonic development, axons preferably extend along the surface of other axons to form axon bundles or fascicles (selective fasciculation), and exit those fascicles to navigate into their targets (selective defasciculation). These processes are regulated by both attractive and repulsive cues [49]. These attractive and repulsive molecules can originate from the axonal tracts themselves or from the surrounding peripheral tissues [6]. A guidance cue disruption of a repulsive molecule should cause abnormal defasciculation. In the case of Ten-m loss of function mutations, or gain of function, the ISN branches fail to maintain their segmental boundaries and invade the adjoining segments, occasionally to fuse with the adjacent segmental nerve (Figure 3 C, D and E). In mutants, loss of Ten-m activity in the motor axons could lead to failing to respond properly to cues, among other possible failings of the neurons. However, epidermal ectopic, or Paired-driven Ten-m expression leading to the same phenotypes suggest that Ten-m impacts peripheral cues, assuming that the overexpression effects were specific.
Axon guidance disruptions observed when Ten-m is ectopically expressed suggests that Ten-m either: maintains peripheral cells to allow them to reach a stage to express a cue for motor axons; or more directly regulates the expression of cues to which motor axons respond. We speculate that Ten-m might itself act as a peripheral cue for migration. We suggest that epidermal Ten-m, and perhaps specifically its expression spatially restricted to stripes, could help position a repulsive guidance cue for the ISN axons and prevent them from crossing into the adjacent segments. Given the collection of defects observed in motor neuron axons, Ten-m might induce a gene product that is, or might itself be, both a repulsive and an attractive guidance molecule, a situation that is not uncommon. For example, Netrins were first found as a chemoattractant for vertebrate commissural axons [56] and circumferential axons in C. elegans [54], [57]. However, Netrins can also repel some axons, as demonstrated in unc-6/netrin mutant C. elegans and Drosophila [54], [58]. DCC/frazzled (deleted in colorectal carcinoma), a netrin receptor, mediates both attraction and repulsion [59] while UNC-5, another netrin receptor, functions exclusively in repulsion [59], [60], [61].
Filamin and axon guidance
Filamins are very large proteins with an actin binding domain and more than 20 Ig-like repeats, that self associate as dimers. They act as Actin crosslinking proteins that are also scaffolds for a very large number and variety of binding partners. As such, they are involved in many functions, but especially relevant are cell adhesion and migration. This includes interactions with different cytoskeletal complexes. In flies, Filamin affects peripheral motor axon navigation in a manner similar to that of Ten-m (Figure 6). This function echoes vertebrate filamin activities. In contrast to Drosophila, mammals have three filamin proteins, A, B and C. Loss of function mutations in Filamin A are found in the human disease periventricular heterotopia, which is a defect in axonal migration that has been associated with the dynamic regulation of actin [62], [63], [64], [65]. However, detailed studies of patients carrying mutations shows evidence for a more complex regulation of axonal navigation than can be explained by simply an effect on growth cone motility [66], [67], [68]. Our studies in flies suggest that in addition to growth cone motility, the context and restricted expression pattern of Filamin might influence axon guidance. In Drosophila, Filamin associates with the seg1 domain of Ten-m, a highly conserved domain within the Ten-m/Odz family that we have named the FID (Figure 5). These two proteins are expressed in the epidermis, including co-expression in a series of 'belts' of epidermal cells, strongest laterally (Figure 7).
How might Ten-m, together with Filamin, regulate axonal guidance? We hypothesize that anchored epidermal Ten-m and Filamin might influence lateral motor axon navigation. These two proteins might set the stage for proper development leading to the expression of spatially restricted epidermal axon guidance cues, or directly impact the regulation of such cues, as ISN motor axon projections start to migrate out of the CNS and begin to reach their lateral and dorsal muscle targets. One speculation is that Ten-m linked to Filamin could itself be a candidate cue for motor axons.
Supporting Information
Supporting Information S1.
Supporting figures.
We thank the following for invaluable technical support and help: Karen L. Schuzle, June Cao, Yuchun He, Hongling Pan, Amir Fayyazuddin, Rong Grace Zhai, Yael Kinel-Tahan, and Anna Levine. We thank Stefan Baumgartner, Allan Spradling, Lynn Cooley, Juan Pablo Labrador, Josh Dubnau, Tim Tully and the Bloomington Drosophila Stock Center for kindly providing reagents. Antibodies obtained from the Developmental Studies Hybridoma Bank (DSHB) were developed under the auspices of the NICHD and maintained by the University of Iowa, Department of Biological Sciences.
Author Contributions
Conceived and designed the experiments: LZ YM VF ZA KJTV HJB MJJ RW. Performed the experiments: LZ YM VF ZA KJTV RW. Analyzed the data: LZ YM VF ZA KJTV HJB MJJ RW. Contributed reagents/materials/analysis tools: LZ YM VF ZA KJTV HJB MJJ RW. Wrote the paper: LZ HJB MJJ RW.
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- 51. Kolodziej PA, Timpe LC, Mitchell KJ, Fried SR, Goodman CS, et al. (1996) frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87: 197–204.
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- 55. Killeen MT, Sybingco SS (2008) Netrin, Slit and Wnt receptors allow axons to choose the axis of migration. Dev Biol 323: 143–151.
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Fashion makes turnover - PSI, as well as half of the trade visitors who are interested in promotional textiles, know that. For this reason textiles are a focus at PSI 2017: Hall 10 will become a textiles hall featuring a fantastic CATWALK and many printing- and finishing machines for the textile industry.
Be there when Europe's promotional products industry meets in Düsseldorf and take advantage of this comprehensive, multifaceted platform. You'll get deep insights into the market, create added value for your customers and generate new business. Get in touch with us right now to secure your stand for 2017.
Don't miss any PSI 2017 news, for example about the Industry Day, the new show days or the "textiles hall", Hall 10.
MORE EXHIBITORS, MORE VISITORS, MORE INTERNATIONALITY: with 932 exhibitors from 31 countries and 16,810 visitors from 74 countries, the event grew at a healthy clip again. From 13 to 15 January 2016, promotional products professionals received an overview of the trends and innovations of the industry.
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PSI - My first choice.Become an exhibitor, now!
Order your tickets for the leading european trade show of the promotional product industry now.
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Fashion makes money, the textile hall in hall 10 shows everything about fashion.
IPSA is the only specialised promotional and merchandising industry exhibition in Russia and CIS.
Optimising processes, services and products, protecting the environment and creating fair working conditions: the PSI Sustainability Awards 2016 show how the promotional...
"Wednesday to Friday" is turning into "Tuesday to Thursday": PSI, Europe's most important promotional products industry trade show, will take place on new days of the week from...
Walter Medien, Kahla Thüringen Porzellan, Brand Addition, Halfar System, uma Schreibgeräte, Fair Squared and Michael Schiffer Promotion – these were the big winners at the first...


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Welcome to Craig Hickey Photography, we're a Leicestershire-based wedding photography service covering the whole of the UK and we capture joy. It's what we do. We pride ourselves on capturing personality too, because we think the little quirks make up the big picture. At the end of your wedding day we'll deliver outstanding imagery that you and your family will cherish for a lifetime.
Engagement Shoots
Your wedding is a once-in-a-lifetime event, so what better way to get prepared and create even more lasting memories than with an engagement shoot. It's an excellent way to experience being in front of the camera; helping you to relax before your wedding photography. Click here for the detail.
Wedding Photography
On your wedding day, you can count on us to provide a relaxed, unobtrusive service that still hits the spot when it comes to delivering outstanding images. Because your day deserves exactly that.
We know wedding photography like the back of our hand. We staunchly believe in capturing the emotion that comes with the day, and we'll work diligently to provide you with images that stand the test of time. Click to learn more about the magic we capture.
Aerial Videography
Aerial filming and photography add a whole new dimension to your wedding day.
Using the latest cutting edge UAV technology, we're now able to take photos and videos of you, your guests and your venue from unique aerial viewpoints. Click here for a rundown.
Family Shoots
Family portrait shoots are an excellent way to get together and capture some awesome images of the whole gang. Let us put some extra sparkle into your family album. Find out more here.
Corporate Photography
Yes, we do this too. From staff head-shots to events coverage; building unveilings to Christmas parties. We'll even capture natural images of the workplace in full-flow. We're here to put your company in the best light possible. Discover the finer details here.
owner, professional lead photographer
Photography is what gets Craig out of bed in the morning. He loves his job so much you could say he's married to it (fitting, right?) When Craig's not taking photos he's thinking about taking photos. If you pinned him down Craig would describe his style as alternative, vibrant and emotive. Above all, Craig wants to capture the story of your day and the essence of your personalities through images. He thinks this is a must, quite rightly too.
professional photographer
Steve likes to think he's not there, although he really is. Steve's self-proclaimed "natural reportage" style will document your day from a different angle than Craig. This is good, because variety is the spice of life. Steve really loves capturing spontaneity, so when your guests are enjoying themselves dancing the night away you can bet your bottom dollar he'll be nearby.
creative director
Kelly is our resident innovator. She's the creative mind behind all the concepts that support the company brand, marketing and product goals. Kelly's creativity stretches even further as she balances her duties here with running her own full-time business as a freelance wedding hair stylist. We let Kelly carry her scissors when she wants to. She's vowed not to run with them.
assistant photographer
Georgia holds the team together. Her main role is to provide assistance to Craig, but whenever she gets the chance she'll be straight behind the camera snapping away. She enjoys capturing the candid moments throughout the day that often end up making the best photographs. Georgia lives by the phrase 'timing is everything'; you'll see why when you see your photographs.
Thank you Craig for such stunning photographs we had a great day and you captured all of those moments for us to treasure forever. Your relaxed, friendly and non intrusive approach shone through as all of our photos are amazing everyone looks so happy! A day we'll never forget thank you so much! Have recommended you several times already!Michelle & Lea
First and for most I would like to thank Craig and Steve for their high level of professionalism and creatively. I had called Craig with very short-notice as I had been let down by another photographer last minute, Craig instantly put my mind at ease and explained what information he required regarding my engagement ceremony and had taken note and actions of details I required like individuals of who to photograph and as well as open rain on photography. His timing is impeccable as well as communication to match; I was very impressed by his ability to capture such small intimate moments at a very crowded event. Even post-event Craig informed me how long it would take to receive the pictures (quicker than I had expected!) and use of the Client Area on his website so my friends and family could see and enjoy the photographs even down to the detail of the lovely presentation box it was truly faultless. I could not recommend Craig anymore highly for any event and we will sure be using his talent and skills in the future, Truly a pleasure!Kiran and Chandni
All our friends and family commented on how friendly and professional you were and also how relaxed you made everyone feel! Many thanks for making our day so memorable and giving us such amazing photos!James and Claire
Thank you so much for being such a huge part of our wedding, we had such an incredible time! The amount of time and effort you put into the photography blew us away.Sara and Stuart
Thanks for helping the day run so smoothly and taking the most beautiful photos! You really do have a special talent in wedding photography. You made us feel totally relaxed and at ease on the day, just as you said you would! Thank you again for an excellent service.David and Sarah
Thank you Craig and Georgia for photographing our special day. We loved your relaxed, friendly and fun approach to taking photos. You were so enthusiastic and passionate which made us feel we were in good hands! Our guests also commented on how great you were! We will highly recommend you!Charlie and Simon


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AnswerThe correct entries in the dmconfig.txt file are:
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1719 Torrey Pines Court
Reston, Virginia, 20190
Commute to Downtown Reston
Most errands require a car.
About your score
1719 Torrey Pines Court has a Walk Score of 46 out of 100. This location is a Car-Dependent neighborhood so most errands require a car.
This location is in Reston. Nearby parks include Presidents Park, Reston Town Square Park and Lake Fairfax County Park.
Explore how far you can travel by car, bus, bike and foot from 1719 Torrey Pines Court.
Rail lines:
Silver Metrorail Silver Line
0.8 mi
Bus lines:
574 Reston Town Center - Tysons
0.2 mi
RIBS 2 South Lakes
0.2 mi
552 North Shore - Lake Fairfax
0.2 mi
554 Wiehle Ave - Center Harbor
0.4 mi
558 Center Harbor - Lake Fairfax
0.4 mi
RIBS 3 Hunters Woods - Lake Anne
0.4 mi
981 Wiehle - Dulles Airport
0.4 mi
556 Bennington Woods
0.4 mi
983 Wiehle - Dulles Airport
0.4 mi
952 Sunset Hills
0.4 mi
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Popular apartment searches include pool, fireplace and fitness.
Search for homes in Reston or find a Reston real estate agent who knows walkable neighborhoods. Links will open on our partner site Redfin.com.
This location is in the city of Reston, VA. Reston has an average Walk Score of 37 and has 58,404 residents.


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James E. Causey offers his perspectives on a variety of issues on urban affairs, crime, city hall, education and sports.
Blacks kill more blacks than the KKK ever did
King students celebrate top high school honor
The streets around King International High School were blocked off by Milwaukee Police Tuesday morning and many neighbors stood out on their porches and stood in their yards to see what was going on.
King students were treated to an outdoor prep rally to celebrate being ranked as one of the nation's best high schools, according to the U.S. News and World Report. King and Ronald Wilson Reagan Preparatory High School were ranked among the top 200 in the country.
Superintendent Gregory Thornton told the students that he appreciates their hard work, their parents, teachers and everyone that touched them. He told them that they did not get there by themselves and he encouraged them to help others.
What made the celebration special is that King's senior class has been offered more than $6.5 million in scholarships ranging from renewable $1,000 awards to a $240.000 prize. One school official said about 1/3 of all seniors have at least one scholarship. That's great news, and it shows that MPS can do great things.
Rufus King was ranked 130th nationally and Reagan was ranked 197th, according to the report.
King and Reagan have been one of Thornton's bright marks on the year. My Sunday column in Crossroads will look at the year Thornton had and the challenges he faces moving ahead from the problems with violence in the schools to doing more with less.
Dealing with suspensions
Superintendent Gregory Thornton said Milwaukee Public School suspends too many kids.
MPS, an urban district with 85,000 students, suspended more students than Los Angeles Unified, which has more than 694,000 students. »Read Full Blog Post(26)
Thornton was dealt a bad hand
The rumors are out: MPS Superintendent Gregory Thornton may be leaving. If he is on the way out, who could blame him?
When he became the leader of MPS less than a year ago, he never bargained for the hand he was dealt. »Read Full Blog Post(24)


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Bring the beach home with nautical decor.
Your coupon will be applied to the highest regular-price, eligible item in your cart.
Offer good for one item at regular price only. Limit one coupon per customer per day. Must present coupon at time of purchase. Offer is not valid with any other coupon, discount or previous purchase. One cut or one bolt of fabric or trim "by the yard" equals one item. Online fabric & trim discount is limited to 10 yards, single cut. Excludes Heidi Swapp™ Minc.™ Foil Applicator, CRICUT® products, Tim Holtz® Vagabond™ Machine, Silhouette CAMEO® Machine, candy & snack products, gum & mints, helium tanks, gift cards, custom orders, special orders, labor, rentals or class fees. Cash Value 1/10¢.
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Look here for exciting designs.
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Art starts with creativity & inspiring supplies.
Crafty days call for crochet projects.
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Jewelry making is bolder in colorful shades.
Totes, hats and scarves for vacation time.
Express yourself in whimsical and artistic strokes with White Pastel Sticks. Popular among artists from the Renaissance period and modern times alike, these white pastel sticks feature a smooth, buttery feel and a creamy vibrancy when applied to your desired surfaces. Draw and blend them on canvas and watercolor paper!
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Located in Saratoga, Saint Andrew's Episcopal School is a premier private coeducational, Pre-Kindergarten through Grade Eight day school. Saint Andrew's offers an advanced, comprehensive academic program plus enrichment in the areas of the studio and performing arts, physical education, Spanish, technology, character development, religion and community service.
Founded by Saint Andrew's Episcopal Church in September 1961, the school opened with single sections of Kindergarten and First Grade, then subsequent grades were added each year to Grade 8. Today the school has 379 students from over 15 communities in the San Jose / South Bay and Peninsula Area.


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Violent crimes in the 109th Precinct declined over the first half of 2002, but burglaries and car thefts rose, police statistics show.
Rape declined by 41.6 percent compared to the same period last year, while robberies dropped 10.8 percent and felony assaults dropped 11.9 percent. The murder rate remained unchanged at two.
Burglaries increased by 13 percent, however, jumping from 468 to 529 cases in the 109th Precinct, which covers Flushing, Whitestone, College Point and Bay Terrace.
Car thefts increased by 14.1 percent, with 566 vehicles stolen in the first half of 2002 compared to 496 during the first half of 2001.
The increase in burglaries and car thefts pushed the overall crime rate up by 2.6 percent in the precinct.
Grand larcenies, the seventh major crime category, fell by 7.1 percent.
Deputy Inspector Owen Monaghan and Capt. Michael Lau have targeted burglaries and car thefts since their arrival at the precinct in February.
At a meeting in late June, Lau described burglaries and car thefts as the two thorns in our side.
I am not happy with the increase at this point, said Monaghan of the two crimes.
Monaghan credited targeting quality-of-life crimes as leading to the reduction in violent crime.
Its the back-to-basics approach, he said. We are engaging those who are committing low-level, quality-of-life crimes.
Were constantly doing everything we can to combat grand larceny autos and burglaries, said Community Affairs Police Officer Ki-Soo Kim. We have crime prevention programs and we have burglary prevention tips.
Kim said the precinct often answers calls for its free burglary prevention surveys of homes and its vehicle identification number etching program, where the VIN number of the automobile is placed on the windshield.
The precinct recently added officers to its burglary and grand larceny auto units.
Despite the precincts targeting of the crimes, burglaries increased by 47.6 percent and car thefts by 11.8 percent during the month of June.
The precinct is a very affluent area, Monaghan said. There are a lot of targets here. The population has increased tremendously as far as apartments and private houses. The targets available have increased.
For the most part, the crime rates match the patterns of the other seven precincts which make up Patrol Borough Queens North.
In Patrol Borough Queens North, murders, rapes, robberies and felonious assaults all dropped, while burglaries rose by 14.2 percent.
The 109th differed from the overall Queens North rates in that car thefts in Queens North dropped by 8.6 percent, while grand larcenies increased in Queens North by 6.6 percent.
Kim described the typical burglar and car thief as someone who would do anything to avoid being seen. With the precinct cut through by several highways, it is susceptible to criminals looking to make a quick getaway, Kim said.
Many of the car thieves are residents of South Jamaica, the Bronx and Jackson Heights, while many others live within the confines of the precinct, Kim said.
Despite the recent spike in the two crimes, the burglary and car theft rates remain significantly lower compared to the early 1990s.
Burglaries have dropped by 55.2 percent compared to the first half of 1993, while car thefts have decreased by 71.1 percent.
Car thefts compared to several years ago have been going down, Kim said.
Reach reporter Alexander Dworkowitz by e-mail at email@example.com or call 229-0300, Ext. 141.
©2002 Community News Group
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The biggest font size requirement is that the user is able to adjust their font size and the application inherits their preference. In Web, this means we use a relational… Continue Reading Accessible Font Sizing
ARIA Label Bookmarklet
I love simple bookmarklets that visualize coding patterns. I was working on a project today and wanted to verify that aria-labels were sufficiently descriptive. So I put together this quick… Continue Reading ARIA Label Bookmarklet
Students: build your brand and get your dream job
An online "brand" is critical for students. Especially for students with a disability, as it can open doors & provide opportunities. Continue Reading Students: build your brand and get your dream job
Android Accessibility – The Missing Manual
This presentation was created for the Bangalore Accessibility Week at Intuit, October 2015. It's a collection of hard to discover information on making an Android application accessible. Android Accessibility –… Continue Reading Android Accessibility – The Missing Manual
Create Accessible Word Documents
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The way people 'vote with their feet' for a new path through a park has something in common with the way they establish new grammatical usages by using them.
Activists are reframing the terms of public debate by refusing to call road deaths 'accidents' – and they've gotten the attention of The Associated Press.
Simplification of European place names continues as Prague government adopts a one-word name for the country.
While others sort out the legal and political implications, the Monitor's language columnist has her eye on what the megaleak means for adjectives.
A psychologist seeks to enrich the emotional landscape of English speakers by introducing them to 216 "untranslatable" foreign words
A return visit to a familiar beach house prompts some thoughts on time and the ebb and flow of the ocean.
Why 'female president' isn't the best term, however this year's election turns out.
The US presidential race affords an opportunity to consider the difference between 'heir apparent' and 'heir presumptive.'
A look at a go-to metaphor for headline writers: Who are yeomen, anyway?
Child jockeys take part in the Shetland Pony Grand National during The Game Fair 2016 at Ragley Hall in Alcester, Warwickshire, England, on Saturday. The Shetland Pony Grand National raises money each year for a nominated charity and The Game Fair celebrates British field sports and country life.
A look at oil metaphors in the lexicon of political put-downs – and food.
A look at the College Board's new approach to testing vocabulary.
Engineering is all around us, but let's not forget its warlike roots.
In language as in law, Antonin Scalia showed a welcome capacity for collaboration and friendship across ideological divides.
A look at the metaphors behind the names of parliaments
When British scientists get approval to 'edit' human genes, it's clear the verb has slipped its moorings in the world of publishing.
Remember the old days, when political parties had 'wings'?
When Benjamin Franklin needed a name for his device for storing electricity, he borrowed a military term.
New research helps explain how infants acquire language skills – by losing their ability to discriminate sounds they don't need.
A friend's question about possible connections between a couple of sound-alike words serves as a reminder that with words, just as with people, some that appear closely related, aren't, and others that don't, are.
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ARLINGTON, Texas -- At the break and the Cowboys lead 10-6 at Cowboys Stadium. We have some highlights for you.
1. The Cowboys pass rush is getting to Matt Moore. DeMarcus Ware is going one-on-one against Jake Long. Anthony Spencer is challenging Marc Colombo, who is clearly not the same player he once was. But it was a Ware pressure, forcing Moore to move up in the pocket, that gave Victor Butler a sack with 9:40 to play in the first half. Kenyon Coleman picked up his first sack of the season with a rush inside; after a weak block by guard Vernon Carey, he got to Moore. The Cowboys have three sacks.
2. Here's why DeMarco Murray is so good. On an 18-yard run, Murray juked past Sean Smith at the line of scrimmage and knocked over safety Reshad Jones. You can say Smith is a corner and Jones a free safety, but a running back is supposed to win these battles on a consistent basis, and that's what Murray is doing when faced with these situations.
3. Dan Bailey's 32-yard field goal with 4:38 to play was his 25th consecutive made kick.
4. Cameron Wake is having a busy first half. He's making life miserable for the Cowboys' blockers. The weakside linebacker shook off a block of Jason Witten to tackle Murray for a 5-yard loss.
5. Tony Romo has two picks today. The first on an underthrown ball to Martellus Bennett and the second toward Laurent Robinson, which was snagged by Sean Smith.
6. It was not a good first half for Moore. He fumbled three snaps, the last with 61 seconds to play in the half gave the Cowboys the ball at the Miami 5. Ware was quick enough to land on the ball for the Cowboys. It was Romo finding Robinson with the 5-yard touchdown pass that gave the Cowboys a 10-3 lead. What made the play work was the play-action pass that froze the defense. It was also the first touchdown allowed by the Dolphins' defense in its last 231 snaps. Miami hadn't allowed a touchdown in its last three victories.
7. It was a sloppy first half. The teams combined for seven penalties for 55 yards. We had penalties on offense, defense and special teams. The biggest penalty of the half was 20 yards when Alan Ball failed to find the ball on a deep pass to Brian Hartline down the sideline. That play pushed the ball from the Cowboys' 33 to the Cowboys' 13 with 17 seconds left. It set up the 28-yard field goal by Shayne Graham that cut the deficit to 10-6.
8. Romo's first half line: 9-of-16 for 82 yards with one touchdown, two interceptions and a 51.6 quarterback rating. Romo threw one deep ball away toward Dez Bryant in the end zone and was hurt by a drop by Robinson, who got two hands on the ball. His touchdown pass to Robinson was on a good ball that he caught low.
9. Former Cowboys linebacker Kevin Burnett leads the Dolphins with four tackles. He's been pretty active in this first half.
10. Spencer is having another strong game. He's got four tackles in the first half a a tackle-for-loss.


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The presence of multiple national authorities in the EU poses substantial coordination problems for the supervision of multinational banks. The Single Supervisory Mechanism aims to solve the resulting coordination failures. This column explores how banks could strategically react to the introduction of a supranational supervisor. The banking system is likely to endogenously react by reverting to an organisational form for which supranational supervision is actually less essential.
EU policies
New EU trade agreements could adversely affect Turkey as a non-EU member. This column presents new findings of an economic analysis in which different trade policy scenarios are considered. The results point to a clear policy recommendation – Turkey and the EU should mutually deepen their customs union by including the agriculture and service sectors as soon as possible.
To make the no-bailout clause credible and to enhance the effectiveness of crisis assistance, private creditors should contribute to crisis resolution in the Eurozone. This column proposes a mechanism to allow for orderly restructuring of sovereign debt as part of ESM programmes. If debt exceeds certain thresholds, the mechanism triggers an immediate maturity extension. In a second stage, a deeper debt restructuring could follow, depending on the solvency of a country. The mechanism could be easily implemented by amending ESM guidelines.
Whatever happens as a result of the UK's referendum on EU membership, those in British politics, and in the British Civil Service, now face an enormous task. This column suggests how their hard work might actually lead to an outcome in which the UK remains a member of the EU. It describes a four-part action plan for those who would like to see this possibility kept open.
Eurozone countries are facing a stalemate in the completion of the Banking Union, at the heart of which is the regulation of banks' sovereign exposures. This column introduces the latest issue of European Economy, which examines the interactions between banks and sovereign risk, the build up of sovereign risk during the crisis, and the policy proposals on the table to severe the loop and, more broadly, to finally complete the Banking Union.
Other Recent Articles:
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Use the tools below to refine your search by only displaying reviews with a certain number of star ratings or to only show reviews from a certain time period. Eg click on '1 star' to just display the reviews we have which received a 1 star rating click or 'Within the last month' to display just reviews posted over the last month.
Written on: 04/08/2010 by Bekki31 (1 review written)
I ordered my ninja suit on Monday and sent them a message saying that I needed it by Thursday.
They replied straight away reassuring me that I will recieve my order in time. I was hopefull, but since I was a new customer I was a bit sceptical. (I'd had trouble with late deliveries with other online shops in the past).
Suprisingly I recieved my order the next day! (Tuesday). Brilliant customer service, good prices and fast delivery. I would definately recommend this shop… Read Full Review
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text:
Is there any side effects after stop taking avodart?
- Posted:
- 21 Jan 2011 by bing67
- Topics:
- avodart, side effect
Answers (1)
Further Information
- Avodart Information for Consumers
- Avodart Information for Healthcare Professionals (includes dosage details)
- Side Effects of Avodart (detailed)
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