text:
Think of the music business as a puzzle with 10,000 pieces. You'll have to work through trial and error to put everything together, but if you are organized and focused it's only a matter of time before you solve the puzzle.
Don't get overly excited just because you've got the bottom left corner done. That doesn't mean you've completed the picture. In other words, if you're beginning to get paid bookings or if club djs are playing your single heavy the picture isn't complete yet. These are accomplishments, but they're not completion of your task to be successful with your music.
Sitting around staring at the box and daydreaming won't help you….but studying the whole picture AND the pieces can help you begin to place things in their proper place.
Don't try to force pieces where they don't belong in an attempt to make them fit the way that YOU want them to fit.
Study the big picture and master the process of connecting and linking the pieces until the picture begins to form. As portions of the picture begin to form, remain focused at trying different pieces in different locations. Keep an open mind and don't be distracted by anyone saying that this puzzle is too complicated.
In the music industry you'll see super talented artists not get their proper recognition. Don't allow yourself to say "the industry doesn't like talented artists". Look at Kendrick Lamar, Schoolboy Q, AB Soul — look at J. Cole — look at Big Sean — none of these guys are "gangster rappers" and all of them are lyrical. Dig deeper than their latest video to understand their rise to fame. Decipher the puzzle. Did all Big Sean need was a Kanye co-sign? Or did he make great music that was marketed to perfection by Def Jam (which distributes GOOD Music)?
Also in the industry you'll see artists rise to prominence that aren't exactly stellar talents. I won't name names. I'll just say that as an indie artist you can be discouraged by the next person's success. They may have made a simple song with a catchy hook and on point production that they pushed and pushed and pushed until breaking through. When you're working on your puzzle don't compare your talent to others as a way of complaining for your lack of success. Don't ever ever blame. Study the bigger picture. Break it down into pieces that plainly show the process that can lead a mediocre skilled artist to prominence.
It is your responsibility to separate and sort the pieces. It is your responsibility to put all the pieces in place exactly how they fit & precisely where they go. If you work on this puzzle consistently and are dedicated to solving it, the process will take time.
The amount of time you need to put everything in it's place and create the completed picture of your music industry destiny depends solely on you. It's not an overnight process or a one month process. The completion of this puzzle takes years (yes YEARSSSS)!!!
Be dedicated. Remain focused. Stay consistent. For those few who are able to decipher the placement of all the pieces; success in the music industry is a beautiful picture.
I wish you the best in pursuit of your dreams.
Tony Guidry is Senior Marketing Manager for A Scratchy Throat. A Scratchy Throat – the brainchild of music industry mainstay Wendy Day – provides professional social media marketing specifically designed for today's aspiring artists. Tony is also owner of Authentic Artists Alliance and exclusive booking contact for Trouble (Duct Tape Ent/2 Tru Ent), O.Z. Mr. 28 Grams (Fratt Boi Muzic Group) and Racked Up Ready (Bow Ent). For digital marketing services or booking inquiries email: firstname.lastname@example.com or firstname.lastname@example.com


text:
It's time to pay your 2017 SPCA dues! SPCA's membership year is based on a calendar year, so if you haven't paid your dues since January 1, then it's time to renew. Dues are just $25/household and members get discounts on garden tour tickets, yard sale registration, and t-shirts.
SPCA dues are paid on an annual basis. The membership year is from January 1 to December 31.
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text:
... for some time now, and it is just not helping at all.I was wondering which of the following drugs were from the strongest to less strong. I can not take Tylenol or aspirin. The drugs are, codeine, Demerol, morphine, Oxycontin, hydrocodone, or any other pain medicine you can think of. I now have a fracture in the arch of my foot, and the pain is 100 times worse. I know this is a big question, but please help if you can.
thank you


text:
The bj-league's promotional campaign for the upcoming playoffs includes a slick slogan — "nobody knows what will happen" — and that surely applies to the Niigata Albirex BB as well.
Sunday's series finale against the host Toyama Grouses was a bold reminder of that.
The Albirex defeated the Grouses 89-81 in double overtime to complete the weekend sweep.
Niigata overcame a 15-point deficit in the final 7:58 of the fourth quarter to force overtime. Coach Masaya Hirose's helter-skelter squad trailed 60-45, but went on a 19-4 run to close out the fourth quarter.
Nigerian native Uche Echefu's 3-pointer with 1 second left on the clock tied it at 64-64 and sent the game into overtime.
In the first overtime, Calvin Chitwood, known primarily for his tenacious defense, scored the Albirex's second jaw-dropping basket of the game, a shot with 29 seconds to play that tied it at 72-72 and forced a second overtime.
From that point on, Niigata dominated.
The Albirex (24-26) used a 15-0 spurt to open the second OT and lock up the hard-earned victory.
Echefu, a power forward out of Florida State, paced Niigata with a season-high 32 points (his previous high was 20) and nine rebounds. Yuichi Ikeda had 13 points, Paul Butorac added 12 points and eight boards and Antonio Burks scored 11, while Tyrone Levett's muscle-and-hustle effort (nine points, 18 rebounds) helped secure the win. Chitwood contributed seven points and six boards and Takato Sato scored zero points, but chipped in with seven rebounds and five assists.
Brian Harper finished with 20 points and 13 rebounds for Toyama (16-34), which is now tied with the Saitama Broncos for the worst record in the Eastern Conference. Johan Collins had 19 points, seven rebounds and five assists in defeat, while Bilal Abdullah scored 12 and Brandon Thomas had 10.
Also Sunday, Mike Bell scored 29 points and grabbed 17 rebounds in the Oita HeatDevils' 80-68 home win over the Shiga Lakestars.
Ricky Woods added 18 points, Matt Lottich scored 13 and handed out five assists and Hiroki Sato scored eight for the HeatDevils (25-25), who earned a series split.
The Lakestars, guided capably by second-year coach Bob Pierce, ended the regular season portion of their schedule with a 29-23 record and a first-ever playoff berth. Shiga was 19-33 as an expansion team in 2008-09.
The Lakestars' Mikey Marshall scored a team-best 19 points and collected 10 rebounds. Takamichi Fujiwara added 15 points, Ray Schafer scored 13 and Gary Hamilton chalked up his 30th double-double of the season (10 points, 15 boards).
Hamilton ended the season as Shiga's leader in assists, steals, blocks and rebounds. He's also the league's top rebounder (14.3 per game).
Elsewhere, the Sendai 89ers beat the visiting Tokyo Apache 81-77.
Josh Peppers led the 89ers with 29 points, frontcourt mate Chris Holm had a 24-point, 22-rebound, five-assist performance and Gyno Pomare poured in 11 points, Hikaru Kusaka added nine points for Sendai (35-15), the Eastern Conference's No. 2 seed for the playoffs.
The 89ers outscored the Apache 27-15 in the decisive fourth quarter.
For Tokyo (21-29), Julius Ashby scored 20 points and pulled down 11 rebounds and Michael Chappell added 14 points and nine boards. Cohey Aoki added 13 points, while Rasheed Sparks chipped in with nine points, seven rebound and seven assists.
Jumpei Nakama, Takanori Goya and Jerrell Smith each scored seven points for the Apache.
Golden Week basketball continues on Monday as the Kyoto Hannaryz play host to the Osaka Evessa in the series opener.


text: I just want to make it known that I regularly follow NASCAR racing and I find it to be the most exciting racing circuit that you can regularly watch on TV. I know those guys are very talented. Plus they need to have a talented pit crew to win. Makes it even more interesting. Paul 91 200q ************************************************************** Paul Waterloo TEL: (860) 267-7714 HydroAire Incorporated FAX: (860) 267-7387 875 Old Hartford Rd Colchester, CT 06415 EMAIL: firstname.lastname@example.com **************************************************************


text: Gospel Music Roundup Lets Freedom Ring! Posted on July 4, 2008 by admin A blessed and honorable Fourth of July celebration to you all! I hope you are able to incorporate this episode into your weekend, and in a small way, minister to those around you with the music! The political air of the day may seem unstable, and looking to the future makes you feel a tad unsure, but the only way to see where you are going is to take a clear look at where we have been! The Word of God is our roadmap, and to follow it's direction, we need to pay close attention to the signposts God has placed there for us along the way. A few of those responsible for the FIREWORKS in this episode: Dave Berland, with 2 songs! Roy Harris Martin Adams The Burneys Dan Adkins David James Firesong Rick Brady Kathy Wedvick The Crownsmen Still Waters 70 x 7 Canaan's Road A Circle of Friends "Legs" Lawrenzi Also, thanks to these fine gentlemen for their great quotes: – George Washington –Thomas Jefferson – Benjamin Franklin – Patrick Henry – Abraham Lincoln – Andrew Johnson – Franklin Roosevelt – Ronald Reagan And above all else, Thanks Be To God, for the opportunity he has granted me to be in the shelter of his wings and the forgiveness he gives me through the blood of Jesus Christ! To Him be the Glory, Forever!!! For an extra blessing, Visit THIS SITE AND VIEW THE VIDEO!


text:
Nazis, Nazis everywhere.
The days of McCarthyism are long gone – but liberals have managed to bring it back. Instead of seeing communists everywhere, they're seeing Nazis everywhere.
Ann Coulter became a target the other day when she allegedly revealed her Nazi ties over Twitter. What did she tweet? The number fourteen. Seriously.
So how do you infer that Ann is publicly revealing she's been in bed with Hitler this whole time? Here's why the geniuses in the liberal media came to that conclusion, and yes, it's a huge stretch:
In reality, what did the number fourteen mean? She was counting down the number of days until Obama is out of office…. like she does everyday.
Not long-after this embarrassing spectacle of mental gymnastics, the modern McCarthyists found the latest Nazi in hiding: Paul Ryan. Where did he subtly declare his alliance to the Third Reich? In a new logo bearing his name.
So was Ryan's symbol inspired by Nazi imagery?
Despite countless articles from liberal websites on the supposed Nazi imagery, all they really had to do to understand the inspiration for the symbol was type "Speaker of the House symbol" into Google. Here's what they would've found:
A version of that logo has been in existence since, um…1789. Who knew Ryan could've copied a symbol from the Nazis that predates their existence? One can only wonder where today's McCarthyists see Nazis next.
[Note: This post was authored by Matt Palumbo. Follow him on Twitter @MattPalumbo12]


text:
I have some friends and acquaintances whose initials of their first and last names are CC. Some even have the middle initial C, making their name CCC. A few of my friends are speech and language pathologists whose credentials are CCC. (Certified….something or other…I"ll google it later!). But, today's brief topic is a different type of three C's.
I read it on a 12-step list of concepts, relating to my struggle with overeating…and my powerlessness over food. Rabbi Dr. Abraham J. Twersky, expert in relationships, self esteem and addictive personalities, talks about it in all his Torah-oriented books. It has become one of my mantras for living and self-growth: I didn't Cause it. I cannot Cure it. I cannot Control it.
There, you have it. The next time someone in my life's comments or behaviors are particularly irksome, annoying, or inappropriate to me, I can simply accept the reality that I cannot fix others. I can only change myself.
All very simple sounding, and quite obvious. Yet this quotable quote is a reminder to me to focus on myself in growth, and "fuhgettabout" the others' annoying stuff —- because I can't do a thing about it anyway!
Okay – off to do my day now! Have a great and productive day!
Remember the CCC's! They can really help out in a pinch!


text:
Drum and bass pioneer Goldie is much more than a music producer and DJ. He's a pioneer in sonic architecture, an actor, successful graffiti artist and entrepreneur. Many who listen to electronic music know Goldie is a legend, but few truly know why. In this BBC interview Goldie reveals that Yoga is a big reason for his success.
You may also like: How Yoga Helped Me Heal My Broken Heart


text:
The thymic medulla represents a key site for the induction of T cell tolerance. In particular, autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) provide a spectrum of tissue-restricted Ags that, through both direct presentation and cross-presentation by dendritic cells, purge the developing T cell repertoire of autoimmune specificities. Despite this role, the mechanisms of Aire+ mTEC development remain unclear, particularly those stages that occur post-Aire expression and represent mTEC terminal differentiation. In this study, in mouse thymus, we analyze late-stage mTEC development in relation to the timing and requirements for Aire and involucrin expression, the latter a marker of terminally differentiated epithelium including Hassall's corpuscles. We show that Aire expression and terminal differentiation within the mTEC lineage are temporally separable events that are controlled by distinct mechanisms. We find that whereas mature thymocytes are not essential for Aire+ mTEC development, use of an inducible ZAP70 transgenic mouse line—in which positive selection can be temporally controlled—demonstrates that the emergence of involucrin+ mTECs critically depends upon the presence of mature single positive thymocytes. Finally, although initial formation of Aire+ mTECs depends upon RANK signaling, continued mTEC development to the involucrin+ stage maps to activation of the LTα–LTβR axis by mature thymocytes. Collectively, our results reveal further complexity in the mechanisms regulating thymus medulla development and highlight the role of distinct TNFRs in initial and terminal differentiation stages in mTECs.
After their recruitment to the thymus, T cell precursors proliferate and differentiate to produce a large pool of immature CD4+8+ thymocytes that resides within the thymic cortex. As a result of the random recombination of gene segments at TCR-α and TCR-β loci, CD4+8+ thymocytes express a diverse repertoire of αβTCRs (αβTCR), and so are required to undergo selection events based on αβTCR specificity. Positive selection rescues thymocytes capable of self-MHC recognition from cell death, with the lineage commitment mechanism ensuring that changes in coreceptor expression result in the generation of CD4+ and CD8+ cells recognizing MHC class II and MHC class I, respectively (1, 2). Newly selected thymocytes are then screened further for their ability to recognize self-peptide/MHC complexes, with negative selection purging the αβTCR repertoire of potentially autoreactive specificities (3). Such combined selection events ensure that T cell production in the thymus leads to the generation of a naive T cell pool that recognizes self-MHC molecules but is able to discriminate between self and nonself Ags.
Positive and negative selection events occur within specialized intrathymic environments defined by distinct stromal components (4). Positive selection signals are provided by cortical thymic epithelial cells (cTECs), a function that is at least in part due to their expression of a unique MHC-bound self-peptide repertoire generated by cTEC-specific expression of Prss16 (the gene encoding thymus-specific serine protease) and the β5t thymoproteosomal subunit (5–7). In contrast, the medulla provides a microenvironment where self-tolerance is imposed, through both negative selection and FoxP3+ regulatory T cell (Treg) production. Moreover, autoimmune regulator (Aire) expressing medullary thymic epithelial cells (mTECs) have been shown to play a role in both processes (8–10), highlighting their importance in the avoidance of autoimmunity. Several advances have recently been made in understanding the regulation of Aire+ mTEC development. For example, the TNFRs RANK and CD40 are key to the generation of Aire+ mTECs (11–15), a process involving lymphostromal cross-talk with RANKL+ lymphoid tissue inducer cells and RANKL+/CD40L+CD4+ thymocytes. An additional TNFR family member, LTβR, also plays a pivotal yet poorly understood role in mTEC development (16–20). Interestingly, the medulla is also recognized as a dynamic thymic compartment, with mature mTECs displaying a turnover time of 2–3 wk (21, 22). Collectively, such findings suggest that Aire+ mTEC production is a continuous process stemming from a TEC progenitor pool that is under hemopoietic cell control. Despite these advances, critical to our understanding of mTEC development and homeostasis are events that occur in mTEC post-Aire expression. Whereas initial studies suggested that Aire may induce apoptosis as a means to regulate mTEC homeostasis (23), others suggest that it plays a role in further mTEC differentiation (24, 25), with recent cell fate mapping approaches directly demonstrating that mTEC differentiation continues beyond the Aire+ stage (26). Moreover, late-stage mTEC differentiation has been shown to involve expression of involucrin (25, 26), a component of the cross-linked cornified envelope and a marker of terminal differentiation in keratinocytes (27). However, whether progression to this stage is a cell-autonomous process post-Aire expression or also requires cross-talk and regulation by hemopoietic elements is unknown. This is a key issue in understanding the regulation of mTEC homeostasis and hence the efficiency of self-Ag presentation for central tolerance.
In this study, we have analyzed cellular and molecular regulation of the mTEC lineage, including the requirements for developmental stages post-Aire expression. We show an ordered ontogenetic appearance of distinct Aire+ and involucrin+ mTEC subsets in the thymus medulla, the latter appearing postnatally at a time point correlating with the initial accumulation of positively selected thymocytes. By analyzing mTEC development in mouse models where positive selection is either absent or can selectively be restored by an inducible Zap70 transgene, we provide direct evidence that whereas the absence of positive selection does not preclude generation of Aire+ mTECs, development of terminally differentiated involucrin+ mTECs strictly depends upon the presence of mature thymocytes. Finally, we show that the requirement for positive selection in mTEC terminal differentiation cannot be met by provision of RANKL and instead maps to activation of LTβR signaling. Collectively, our data define cross-talk mechanisms in mTEC terminal differentiation, help explain the poorly understood role of LTβR in thymus medulla development, and highlight the temporal requirement for distinct TNFR signaling during initial and late-stage mTEC differentiation.
Materials and Methods
Wild-type (WT) C57BL/6 (B6) mice at 4–6 wk of age were used as indicated. Zap70−/− (28), Ltbr−/− (29), Lta−/− (30), Cd40lg−/− (31) mice have been described previously. Tetracycline-inducible Zap70 transgenic mice (Zap70Tre rtTAhuCD2 Zap70−/−; TetZap70 hereon) have been described in detail elsewhere (32). Zap70 expression in adult mice was induced by administration of tetracycline derivative doxycycline (dox) in food (3 mg/g). Mice were bred and maintained in the Biomedical Services Unit, University of Birmingham, with the exception of TetZap70 mice, which were bred and maintained at the National Institute for Medical Research (Mill Hill, London, U.K.). All experiments were carried out with institution and U.K. Home Office approval.
Human thymus samples
Fresh thymic tissue was provided by Birmingham Children's Hospital (Birmingham, U.K.) from pediatric patients undergoing routine cardiac surgery. Tissues were obtained after informed consent and with the ethical approval of National Health Service North Staffordshire Local Research Committee.
Immunofluorescent confocal analysis and mTEC quantitation
Freshly isolated mouse and human thymus tissue was embedded in OCT compound (Sakura Fintek UK, Thatcham, U.K.) and frozen on dry ice. Sections were cut at 5-μm thickness, fixed in acetone, and stained with Abs as described previously (12b + and involucrin+ mTECs, medullary areas were initially identified on the basis of CD4, CD8 staining to identify regions containing CD4+8− and CD4−8+ cells but not CD4+8+ cortical thymocytes. For each mouse, a minimum of three separate thymus sections at least 10 sections apart were analyzed. From each section, medullary areas of up to 200,000 μm2 were imaged, and the number of involucrin+ and Aire+ cells was determined to give the number of involucrin+ and Aire+ cells per square millimeter.
Statistical analysis
Analysis was performed using a two-tailed unpaired Student t test with Prism software (GraphPad, San Diego, CA). Significance is denoted with asterisks (i.e., *p < 0.05; **p < 0.01; ***p < 0.001).
Retroviral transduction and bone marrow chimeras
To generate RANKL-expressing retrovirus, PCR-cloned cDNA fragments of murine RANKL, using the primers 5′-CTCGAGGAAGGGAGAGAACGATC-3′ and 5′-CTCGAGTCAGTCTATGTCCTGAACTTTG-3′, were cloned into XhoI site of MIGR1 (a gift from Dr. W.S. Pear, University of Pennsylvania, Philadelphia, PA). Retroviral supernatants were prepared as described (33) using the packaging cell line Plat-E (34). To generate bone marrow (BM) chimeras, adult WT B6 or Zap70−/− mice were treated with 150 mg/kg 5-fluorouracil, and 4 d later, Sca1+ progenitors were isolated from femurs and tibias by magnetic sorting (Miltenyi Biotec, Auburn, CA). Retrovirus infection of sorted Sca1+ cells was performed as described (13). Briefly, freshly sorted BM cells were cultured in IMDM supplemented with 20% FCS, l-glutamine, sodium pyruvate, nonessential amino acids, penicillin, streptomycin, 50 ng/ml stem cell factor, 50 ng/ml IL-6, and 10 ng/ml IL-3. After 48, 72, and 96 h, cells were spin-infected with retrovirus by centrifuging the culture plates in the presence of 10 μg/ml polybrene for 90 min. Following infection, total cells were intravenously injected into irradiated recipients (900 rad for WT B6 and 700/800 rad for Zap70−/− hosts), and mice were analyzed 4–5 wk after injection.
Flow cytometry
Freshly prepared WT neonatal and adult thymocyte samples were centrifuged and then analyzed by flow cytometry as described (12). Cells were acquired using CellQuest software on a Becton Dickinson LSR flow cytometer. For analysis of TetZap70 mice, thymocyte suspensions were analyzed on a FACSCanto II (Becton Dickinson) using FACS diva software v6.1.2. All samples were then analyzed postacquisition with Flo-Jo software (Tree Star, Ashland, OR).
Analysis of Aire and involucrin expression identifies temporal regulation in the development of distinct mTEC compartments
The keratinocyte terminal differentiation marker involucrin, a component of the cornified envelope in skin, has recently been reported to identify a subset of mTEC in adult mouse thymus (25, 26). Importantly, cell fate mapping studies show that mTEC maturation extends beyond the Aire+ stage and further suggest that involucrin expression may follow Aire expression, a relationship that is suggestive of a terminal differentiation program in mTECs (26). To investigate further these poorly defined stages in thymus medulla development, we initially analyzed the phenotype and ontogenetic timing of the appearance of Aire+ and involucrin+ mTECs in both adult murine and human pediatric thymus. In human thymus (Fig. 1B, 1D, 1F), involucrin identifies Hassall's corpuscles (HCs), representing swirled epithelial structures formed from terminally differentiated epithelial cells (25, 35). In agreement with a recent study (25), analysis of adult mouse thymus (Fig. 1A, 1C, 1E) shows a similar staining pattern, with small, medullary-located involucrin+ cells displaying an organization reminiscent of HC-like structures in human thymus. Interestingly, in both mouse (Fig. 1E) and human (Fig. 1F) thymus, Aire and involucrin expression were consistently found to be nonoverlapping. However, although we failed to detect mTECs that coexpressed involucrin and Aire, Aire+involucrin− mTECs and Aire−involucrin+ mTECs were often found in close proximity to one another (Fig. 1E, 1F). Further phenotypic analysis (Fig. 2) with a panel of epithelial markers demonstrated that in contrast with Aire+ mTECs, which are enriched for CD80+MHCII+keratin10− cells, involucrin+ mTECs are uniformly CD80−MHCII− and express keratin10+, an additional marker of epithelial differentiation in skin (36). Thus, our data suggest that Aire+ mTECs and terminally differentiated involucrin+ mTECs represent distinct subsets of epithelial cells within the thymic medulla.
We next investigated the timing of appearance of Aire+ and involucrin+ mTECs in mouse thymus development. By quantitative confocal microscopy, we found that Aire+ mTECs, which were more abundant than involucrin+ mTECs at all stages analyzed, were readily detectable at postnatal day 0 (Fig. 3A, 3B), a finding that is in agreement with the initial emergence of Aire+ cells at E16 of gestation (12). In contrast, involucrin+ mTECs were found to be absent in embryonic thymus (data not shown) and immediately after birth, being first detected at postnatal day 5 (Fig. 3A, 3C), a time point coinciding with the appearance of positively selected CD4+αβTCRhigh and CD8+αβTCRhigh thymocytes (Fig. 3D). Collectively, these findings identify an ordered appearance of distinct Aire+involucrin− and Aire−involucrin+ mTEC subsets during thymus development, with the emergence of the latter correlating with the accumulation of mature thymocytes within thymic medullary areas.
Positive selection is essential for mTEC terminal differentiation
To determine whether the emergence of involucrin+ mTECs is functionally linked to the presence of positively selected thymocytes, we next analyzed Aire and involucrin expression by mTECs in Zap70−/− mice, where thymocyte development is blocked at the immature CD4+8+ stage due to an absence of αβTCR-mediated positive selection signals (28). In Zap70−/− mice, medullary thymus areas were still readily detectable, identified as regions surrounded by cortical areas containing CD4+8+ thymocytes (Fig. 4A). Whereas Aire+ mTECs were clearly detectable in both adult WT and Zap70−/− thymic medullary areas, albeit at reduced frequency in the latter (Fig. 4A, 4B), the absence of mature CD4+ and CD8+ cells correlated with the absence of involucrin+ mTECs in Zap70−/− mice (Fig. 4A, 4C), suggesting that signals from CD4+ and/or CD8+ thymocytes are important for late stages of mTEC development. To test this possibility directly, we analyzed mTEC development in TetZap70 mice, in which thymocyte positive selection in Zap70-deficient animals can be restored by controlled expression of a tetracycline-inducible Zap70 transgene within the T cell lineage (32). Fig. 5A shows that, as reported previously, compared with untreated controls (−dox), treatment of adult TetZap70 mice with dox (+dox) for 14 d resulted in the restoration of positive selection and the appearance of mature CD4+8− and CD4−8+ thymocytes. Subsequent confocal analysis of medullary microenvironments showed that the restoration of positive selection by dox treatment was accompanied by an increase in Aire+ mTEC frequency (Fig. 5B, 5C) and the emergence of involucrin+ mTECs (Fig. 5B, 5D) at a frequency similar to that seen in unmanipulated adult WT mice (Fig. 4C). Collectively, these findings suggest that whereas mature thymocytes are not essential for the generation of Aire+ mTECs, they are an essential requirement to provide signals that drive later stages of mTEC differentiation, including generation of Aire-involucrin+ mTECs.
Terminal differentiation of mTEC is regulated by LTα–LTβR signaling
Several studies have identified a role for various TNFRs in thymus medulla development, including RANK, CD40, and LTβR. Of these, the requirement for RANK signaling during Aire+ mTEC development in adult thymus has shown to map to the presence of positively selected thymocytes (13). However, whether RANK signaling explains the requirement for single positive thymocytes in post-Aire involucrin+ mTEC development has not been addressed. Due to the dramatic reduction in Aire+ mTECs in Rank−/− thymus (11, 14), such mice cannot be readily used to determine the role of RANK in mTEC development post-Aire expression. Thus, we next determined whether RANKL could replace the requirement for single positive thymocytes in the development of involucrin+ mTECs. To this end, we established chimeras in which BM progenitors from Zap70−/− mice were transduced with retroviral constructs, resulting in constitutive expression of RANKL by thymocytes that are blocked at the CD4+8+ stage. Sca1+ BM progenitors from adult Zap70−/− mice were subjected to multiple rounds of retroviral transduction in vitro with either mouse stem cell virus (MSCV)–internal ribosomal entry site (IRES)–GFP or MSCV–RANKL–IRES–GFP biscistronic retroviral constructs. Retrovirally infected cells were then injected i.v. into sublethally irradiated Zap70−/− hosts, and thymus tissue was collected and analyzed 4 to 5 wk later. In agreement with Hikosaka et al. (13), RANKL expression by thymocytes in the absence of single positive cells (data not shown) resulted in an increase in the sizes of thymic medullary areas (data not shown) and an increase in the numbers of Aire+ mTECs (Fig. 6A), indicating that retroviral RANKL in Zap70−/− BM is expressed at a functional level. In marked contrast, however, despite these effects on the thymus medulla, RANKL expression in MSCV–RANKL–IRES–GFP Zap70−/− chimeras failed to induce the appearance of involucrin+ mTECs (Fig. 6B). Thus, despite the increased availability of RANKL, the absence of single positive thymocytes still resulted in a block in later stages of mTEC differentiation. We next made chimeras using WT BM precursors and WT hosts, in which positive selection and generation of CD4+ and CD8+ thymocytes occurred (data not shown). Flow cytometric analysis shows comparable levels of RANKL expression on CD4+8+ thymocytes in WT and Zap70−/− chimeras and CD4+ and CD8+ thymocytes in WT chimeras (data not shown). As expected, when RANKL was overexpressed, there was an increase in the frequency of Aire+ mTECs (Fig. 6C), again showing that retroviral RANKL expression in WT BM is expressed at a functional level. Importantly, in contrast with chimeras generated using Zap70−/− BM (Fig. 6B), involucrin+ mTECs were detected when WT BM was transduced with either MSCV–IRES–GFP or MSCV–RANKL–IRES–GFP constructs (Fig. 6D). Moreover, no difference was observed in the frequency of involucrin+ mTECs in both types of WT BM chimeras (Fig. 6D). Overall, these experiments suggest that the requirement for single positive thymocytes is a rate-limiting step in mTEC terminal differentiation and cannot be simply explained by provision of RANKL alone. Instead, these data indicate that positively selected thymocytes provide additional signals that regulate the appearance of involucrin+ mTECs. To investigate the nature of these signals, we next analyzed mTEC development in mice genetically deficient in additional TNFR ligands that are provided by mature thymocytes, namely CD40L (12, 15) and LTα (16). Although comparison of thymus medullary areas in WT and Cd40lg−/− adult mice showed no differences in the frequency of involucrin+ mTECs (Fig. 7), we found striking differences in mTEC development in mice with disrupted LTα–LTβR signaling. Thus, despite a relatively normal frequency of Aire+ mTECs, Lta−/− mice showed a marked and specific decrease in the frequency of involucrin+ mTECs, a phenotype that was also evident in Ltbr−/− adult thymus (Fig. 7). Collectively, these findings suggest that activation of the LTα–LTβR axis by LT-expressing mature thymocytes drives post-Aire mTEC development and the appearance of involucrin+ mTECs.
The importance of intrathymic medullary microenvironments in the establishment of T cell tolerance is well established. In particular, mTECs expressing Aire have been linked to both negative selection and the induction of Treg development (3). Recent studies have begun to uncover the developmental program of mTEC maturation, which begins with bipotent cTEC/mTEC progenitors (37, 38) and leads to the generation of postmitotic Aire+ mature mTECs via a RANK-dependent mTEC progenitor stage (11). In addition, several studies have now addressed the mechanisms regulating the generation of Aire+ mTECs (reviewed in Ref. 39). Several models of mTEC development have been proposed, including those that are postulated to involve either a "terminal differentiation" or a "progressive restriction" model (reviewed in Ref. 40). While the former model involves a linear differentiation program in which Aire+ mTECs expressing the most tissue-restricted Ags represent the most mature cells, the progressive restriction model suggests that expression of Aire and Aire-dependent tissue-restricted Ags occurs within immature mTECs, which under the influence of Aire become progressively restricted to stages that mimic gene expression patterns seen in other epithelia. Whereas evidence for both scenarios exists, little is known about the program of mTEC differentiation post-Aire expression. Relevant to this, the role of Aire itself in mTEC differentiation is not clear, and several models have been proposed in which Aire is involved in either the initial (41) or later stages (23, 25, 26) of terminal differentiation. In our study, we provide evidence that the generation of Aire+ mTECs is followed by a program of terminal differentiation that is associated with the loss of Aire expression and the acquisition of the terminal differentiation marker involucrin. Thus, the data presented in this study support a linear terminal differentiation program of Aire+ mTEC development and provide clues about the regulation of mTEC development post-Aire expression. First, the ontogenetic appearance initially of Aire+ mTECs and then involucrin+ mTECs is strongly suggestive of a precursor-product relationship between these cells, as was shown previously for CD80− and CD80+ mTEC subsets (11). Second, that the development of Aire+ and involucrin+ mTEC subsets appears to be controlled by cross-talk mechanisms involving distinct TNFR argues for a series of distinct steps in a program of differentiation. Importantly, this scenario is supported by data from recent cell-fate mapping studies demonstrating continued differentiation of Aire-lineage cells (26) and also by studies reporting the direct involvement of Aire expression in mTEC differentiation, as indicated by altered p63 and cytokeratin expression in mTECs from Aire-deficient mice (24, 41). That involucrin-expressing epithelial cells in murine thymus are reminiscent of involucrin+ HCs in the human thymic medulla is further suggestive of a terminal differentiation mTEC program that continues post-Aire expression. Interestingly, it is currently not clear whether involucrin represents a universal marker of mTEC terminal differentiation or is specifically indicative of terminal differentiation of the Aire+ mTEC lineage. Indeed, the relative paucity of involucrin+ cells in the adult mouse thymus is of interest, as it may suggest that its expression represents terminal differentiation of a distinct mTEC subset, rather than the total mTEC lineage. Moreover, this low frequency of involucrin+ clusters may indicate that they do not represent long-lived structures but are efficiently cleared as progressively apoptotic cells by the thymic phagocyte system. The functional significance of involucrin+ mTEC clusters is also currently unclear, and study of this is currently hampered by the lack of methods for their isolation. While in human thymus the generation of Tregs has been linked to HCs (42), which resemble involucrin+ mTEC clusters in the mouse, FoxP3+ Tregs develop normally in Ltbr−/− mice (17), which we show in this study to lack involucrin+ mTECs. The finding that mTECs have a turnover time of 2–3 wk may suggest an alternative functional significance of involucrin+ mTEC differentiation that is perhaps linked to epithelial homeostasis in the thymic medulla. For example, as tissue-restricted Ags can be divided into at least three distinct "gene pools," the expression of which is linked to progressive mTEC differentiation (43), a normal program of terminal differentiation and mTEC homeostasis may help to ensure an adequate representation of "early" and "late" self-Ags within the thymic medulla.
Our data also show that Aire+ mTEC development and the appearance of involucrin+ terminally differentiated mTECs are separable depending upon the availability of signals provided by positively selected thymocytes. Interestingly, Aire-deficient mice have reduced numbers of involucrin+ mTECs (25), an observation that further suggests that Aire plays a role in mTEC development. However, our findings indicate that Aire expression per se is not sufficient to drive mTEC terminal differentiation and that additional signals are required. Indeed, in analysis of Lta−/− and Ltbr−/− mice, we find that activation of the LTα–LTβR axis is required for the generation of involucrin+ mTECs. In addition, our data show that Ltbr−/− mice have a slight and nonsignificant decrease in Aire+ mTECs (Fig. 7). Our experiments were performed on both male and female mice of 4–6 wk of age using the Ltbr−/− line on a C57BL/6 background (29). As reviewed recently by Fu and colleagues (44), the role of LTβR signaling in mTEC development is unclear. For example, disruption of LTβR signaling clearly impacts on thymus medulla organization (16), and one study reports a decrease in MHC class IIhigh Aire+ cells within the mTEC pool of Ltbr−/− mice (19). However, this study also showed significant differences in multiple mTEC subsets, including MHC class IIlow and Aire−MHC class IIlow subsets. While initial studies analyzing whole thymus samples reported decreases in Aire mRNA expression in the absence of LTβR signaling (20, 45), two more recent studies using purified mTEC preparations showed that Aire mRNA expression levels are normal in Ltbr−/− mice (16, 17). Finally, another study shows that in vitro stimulation of TECs via LTβR results in only a very modest induction of Aire mRNA expression (14). Thus, although the role of LTβR signaling in Aire+ mTEC development remains controversial, our observation that Ltbr−/− thymus lacks Aire−involucrin+ mTECs extends our understanding of the role of LTβR in thymus medulla development and fits well with previous studies suggesting that medullary abnormalities in the absence of LTβR signaling cannot be fully explained by a block in the generation of Aire+ mTECs (16–19). Instead, the requirement for LTβR signaling in late-stage mTEC development described in this study suggests that alterations in the thymus medulla of Ltbr−/− mice may occur at least in part as a result of disrupted mTEC homeostasis following a block in mTEC terminal differentiation post-Aire expression. Finally, we also find that thymic positive selection is an essential requirement for terminal differentiation and the appearance of involucrin+ mTECs. This link between positively selected thymocytes and mTEC homeostasis may then help to ensure that medullary environments expressing the appropriate spectrum of self-Ags are available to screen each newly generated cohort of mature thymocytes for potential autoreactivity. Interestingly, however, our data demonstrate that, unlike earlier stages in mTEC development, late-stage mTEC development is driven by LTα-LTβR, but not RANKL–RANK, signaling. Thus, we propose that following their involvement in the induction of Aire+ mTEC differentiation by provision of RANKL, mature thymocytes continue to influence late-stage mTEC terminal differentiation by their expression of LTα and stimulation of LTβR. Such a model further underscores the importance of lymphostromal cross-talk between mature CD4+ and CD8+ thymocytes and epithelial cells in the thymus medulla and identifies a stage-specific requirement for distinct thymocyte-expressed TNFR ligands at different stages of mTEC development.
We thank Dr. Art Weiss for Zap70 knockout mice. We thank Dr. Valerie Horsley for valuable discussion and critical review of the manuscript. We also acknowledge the help of Dr. David Barron, pediatric cardiac surgeon at the Birmingham Children's Hospital.
Disclosures The authors have no financial conflicts of interest.
This work was supported by a Medical Research Council Programme grant (to G.A. and E.J.J.) and by core facilities of the Medical Research Council Centre for Immune Regulation.
Abbreviations used in this paper:
- Aire
- autoimmune regulator
- bone marrow
- cTEC
- cortical thymic epithelial cell
- dox
- doxycycline
- Hassall's corpuscle
- internal ribosomal entry site
- murine stem cell virus
- mTEC
- medullary thymic epithelial cell
- Treg
- regulatory T cell
- wild type.
- Received June 29, 2010.
- Accepted August 18, 2010.
- Copyright © 2010 by The American Association of Immunologists, Inc.


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Frequently Asked Questions About Celiac Disease 09/30/2015This Celiac.com FAQ on celiac disease will guide you to all of the basic information you will need to know about the disease, its diagnosis, testing methods, a gluten-free diet, etc. Subscribe to Celiac.com's FREE weekly eNewsletter What are the major symptoms of celiac disease? Celiac Disease Symptoms What testing is available for celiac disease? Celiac Disease Screening Interpretation of Celiac Disease Blood Test Results Can I be tested even though I am eating gluten free? How long must gluten be taken for the serological tests to be meaningful? The Gluten-Free Diet 101 - A Beginner's Guide to Going Gluten-Free Is celiac inherited? Should my children be tested? Ten Facts About Celiac Disease Genetic Testing Is there a link between celiac and other autoimmune diseases? Celiac Disease Research: Associated Diseases and Disorders Is there a list of gluten foods to avoid? Unsafe Gluten-Free Food List (Unsafe Ingredients) Is there a list of gluten free foods? Safe Gluten-Free Food List (Safe Ingredients) Gluten-Free Alcoholic Beverages Distilled Spirits (Grain Alcohols) and Vinegar: Are they Gluten-Free? Where does gluten hide? Additional Things to Beware of to Maintain a 100% Gluten-Free Diet What if my doctor won't listen to me? An Open Letter to Skeptical Health Care Practitioners Gluten-Free recipes: Gluten-Free Recipes
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The conference will highlight the fundamental opportunities and challenges faced by all in conducting Clinical Research in India, through solution driven sessions presented by experts from the industry and academia with practical global experience. Fostering free discussion, the programme will concentrate on the real-world issues and look to develop a consensus on how India should move forward practically to ensure accurate, auditable and above all ethical pre and post marketing Clinical Research data.
Current Clinical Research Scenerio In India
As the demand for reducing drug development costs and achieving higher patient recruitment rate increases globally, India is being projected to become a dominant clinical trial location. By 2011, it is expected that India will conduct more than 15% of the total number of global clinical trials. Several factors are responsible for this predicted growth which includes India's large, genetically diverse, treatment – native patient population (over one billion), thereby greatly facilitating patient recruitment and significantly reducing the cost of conducting clinical research (60% less than in the West), have all turned up as the major contributing factors. The emergence of common Western diseases in the Indian population is another factor as is the high rate of English proficiency among clinical investigators.
Despite the presence of many leading biopharmaceutical companies in India, however, there are several challenges that Global companies continue to face. These include language and cultural barriers, socioeconomic factors and the effects of genetic diversity on drug testing. In addition to it, because of the continued surge of clinical trial activity in the country and the lack of professionals adequately trained in ICH-GCP practices, issues regarding ethical practices have raised concern. Finally, despite an improved regulatory environment, sponsors must overcome hurdles in the regulatory approval process. The recent regulatory initiatives like Registry of Clinical Trials, Review of Ethical Committees, Registration of CRO's, transparency in the regulatory system & pharmacovigilance activity and FDA's presence in India are the clear indicators of India turning up as an emerging destination for clinical trials.


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I had a puppy once. When I was 10. I will get into all of the things I did wrong with that one in another post, but suffice it to say I knew when I got my next puppy, things would be different.
13 years and a B.S. in Animal Sciences later, that day finally came.
I am a research junkie and before I make any decisions I typically browse the web to see what other people have done, how it worked out, and what I could do for best success. Having my puppy was no different, especially since I was also working a full-time job which involved me being away from home for about 12 hours a day.
My research uncovered that basically, if you get a puppy with a full-time job, you are Satan and should be shot. People were all super passionate that if you had a full-time job, you should not get a dog, let alone a puppy.
I read all the arguments: potty training nightmares, hiring help, separation anxiety, general destruction and mayhem, the puppy's well-being, etc. I found almost no success stories without people shelling out huge sums for daycare and drop in walkers or taking weeks off from work. Anyone who asked about getting a puppy with a job on forums was quickly roasted to a little charcoal crisp. I realized that I probably shouldn't get one at this point in my life.
Nevertheless, when I happened to stumble across a sweet little Golden Retriever/Labrador pup, the logic part of my brain went out the window.
Forget "probably shouldn't", we NEED him.
I was determined to prove everyone wrong and even more determined to prove to myself that I could raise a well-mannered wonderful dog. I re-read (for at least the fifth time) Dr. Ian Dunbar's book Before and After Getting Your Puppy. I got a good sturdy crate (or three, is that excessive?) and a plethora of Kong and stuffable toys. I scheduled four days off from work. Then we brought little Jackson home.
After work on a Thursday, I drove down to pick up Jackson as an 8-week-old pup. I had put a deposit down when he was about 3 weeks old, and we had already met him when he was 5 weeks. He was the cutest damn thing.
But cute or not, we couldn't cuddle him all day. We knew that in a couple short days he would be left home alone for over 8 hours, and we had to start preparing him for that, stat.
Determined to crate-train, and on a tight timeline, we did not have the luxury of clicker training him to the crate or easing him into it. He had to know this was how it was and that the crate was the best place in the world!
As soon as I got home with him on the first day, he got a potty break, 30 minutes of play, then he went into the crate with a food-stuffed Kong. He did not go in quite willingly, but didn't put up much of a fight once he saw the food in there. He didn't cry much, but any noises he did make fell on deaf ears.
After about an hour we went out for potty and lo-and-behold he went! He got lots of praise and treats immediately for eliminating. That was our routine for the rest of the night, 30 minutes supervised (like a hawk supervises) play then in the crate for an hour. By bed time we had one last potty then we brought the crate to our bedroom next to the bed and he went in for the night. He cried for about 15 minutes, then went into a dead sleep.
At about 12:00 I heard some whining and got my slippers on for a potty trip. Without a word, I took him out of his crate, carried him to the door, grabbed some treats and went straight outside. "Jackson, go potty" was met with elimination. He received treats and quiet praise, then was carried back to the crate. He cried again for about 10 minutes, then heavenly silence. Again at about 4:00, at his soft whimpering, we repeated.
The next day, we repeated the schedule of 30 minutes of play, 1 hour of crate time with and without food in the crate. When there wasn't food, he cried for a while before falling asleep. If he was asleep after an hour went by, I woke him up to take him to potty. He went nearly every time. If there was no potty, it was back to the crate for 10 minutes before another try.
At night, we repeated the same thing as before with roughly the same wake up times. He didn't cry when we put him in his crate anymore. I think the reason for his quick transition was the fact that he was the last puppy to go home, so when we finally got him he had already been sleeping alone but now he got to sleep in a crate next to us so it was actually better.
The next day, Saturday, we started getting him used to his playpen, or what Dr. Dunbar calls his "long-term confinement area". He quickly shredded the puppy pad and hated seeing us leave the room, a reaction he never had while in the crate, but he eventually settled down. We made an effort to consciously look away from him when he started making a fuss and would only take him out when he was quiet and sitting. In retrospect we probably should have played with him and fed him more in the pen to make it less scary, but he got it eventually.
He would stay in the play pen when we went out to do yard work or farm chores, but no matter what, we took him outside on the hour to potty. Then he got his treat and well-deserved play session.
We also interspersed a few crated time-outs for food and our own sanity.
That night we gave no more food or water after 8:00. We only got up once to potty.
The next day was more of the same, but the intervals were closer to 1.5 hours in his play pen. He received lots of stuffed toys before we left the room, which he did not mind in the least. When we sat down to eat dinner, he was making a fuss, trying to climb over the wire playpen. Then we heard shrieking that made my husband and I both jump up, he had gotten his paw stuck in the gate of the pen and could not free it.
Our plan had been to keep him in the playpen the whole day we were at work, however if he could injure himself in it or get stuck, it was a plan that had to be rethought.
We decided to keep the playpen for day-use when we were home, and use our bathroom for a puppy room when we were gone at work. We knew in either case, he was not going to be able to hold his bladder until we got home, we knew there would be a mess. We also hated our bathroom and knew a remodel was not so far down the road.
The first day back at work was terrifying for me. I stuffed all of the Kongs we had and picked up everything in the bathroom that he could get into, including the shower curtain! Then we shut him in and left.
While we were gone, I constantly wondered what he was doing and if he was okay. When we finally got home, the house was dead silent. I was certain he was dead.
He wasn't. Opening the bathroom door I found a happy wiggly puppy thrilled that we were back. There was somewhat of a mess in the bathroom, but he kept it all to one corner. We went out immediately to go potty and then played the night away.
And that was our routine for months. On weekends when we were home, we didn't play with him non-stop. He had a lot of time in his crate and in his playpen. We had to have him know that we weren't everything in the world, that he'd be perfectly okay while we were gone, and that we'd always come back.
As far as chewing went, Kongs and nylabones were our go-tos as they were the least destructible. I would measure out his kibble each day and stuff about 3/4 of it into his Kongs for while we were gone. He would get the last bit as training treats or in Kongs when we got home.
As he was able to start mastering a tightly stuffed kibble Kong, we added in wet food, trickier treats, and started freezing them. I don't know exactly how long it took him to get through all of the Kongs we gave him each day, but he seemed content. He started with a medium puppy Kong, a large puppy Kong, and a Kong activity ball. I would also give him a piece of carrot or apple to chew on and a frozen cube of yogurt, oatmeal, or wet food. After about a month I added in a Kong tire and a dense hollow rubber bone, and then around five months he got two more large adult Kongs. He did chew a little on the trim in the bathroom, but considering how much time he had every day to be destructive, I'm okay with it!
Jackson was officially potty-trained at about 3 months old. He had a total of maybe four accidents in the house (all our fault for not following the crating schedule). The magic happened suddenly when we had friends over one day and one of them said, "hey, your dog's scratching at the door, does he need to go out?" Jackson must have thought he was king of the world with all of the praise he got for telling us he had to go outside. And to us, he was. It was like a switch was flipped. He never had another accident.
Now at nearly 6 months old, Jackson seems quite comfortable with his schedule and has excellent house manners. In the morning he knows that the bathroom is a wonderful place full of yummy stuffed toys and he runs straight there after his morning potty break.
I know we still have a long way to go, but I think we're on the right track and things are going great!
Want more? Read our post on how we socialized and trained Jackson here or see our update on his 1st birthday here.
Comment with other tips on raising a dog you'd like to see!


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My prefatory comment, as noted in our earlier posting, is that my wife and I are senior citizens; that fact of life limits our energy and appetites, not our enthusiasm. That said, here are our observations (and factoids):
Re Barcelona: 1) We had lunch at Carballiera. I had the specialty of the house, Pulpo Gallego; my wife had Almejas Marinera. We split an ensalada fresca, split a half bottle of white wine, and had two coffees. All straight-forward and done to perfection. Cost: E65. An elegant restaurant which displays an elegant assortment of the seafood available inside the front door. Our reaction: go.
2) We had lunch at Fonda Gaig. We started with two crocqettas. Divine .Next we had a wonderful insalata fresca. For mains, I had their famous canelones; my wife had absolutrly perfect scallops a la plancha with artichokes. We also had a bottle of wine, split a crema catalunya, and had two coffees. Having seen on-line photos of the canelones, I was a little apprehensive that the dish would be too rich and too heavy. Wrong! Cost: E83. Our reaction: run, don't walk.
3) We had "breakfast" at Pinotxo at the Bocqeria. We both had "scrambled eggs" with shrimp and greens, and two glasses of wine. Cost: E 28. Our reaction: Have the buffet at your hotel or go to Kiosco Universal (Quim was not open). Our eyes were betrayed by the apparent "charm" of Pinotxo. Food was only so-so.
4) We had dinner at Cal Pep. Our appetite was diminished by a previous stop for elegant pinxtos at Euskal Extea, where we had five "items" (one free) and two cavas each. Our reaction: don't miss. Cost E16. At Cal Pep we had gambas a la plancha, garbanzos with cuttlefish (chipperones not available). peppers, and artichokes. Also two glasses each of white wine. Cost: E50. Our reaction: Cal Pep is a master at frying. The peppers and artichokes were very good, as was the frito mixto (which our "neighbors" shared in exchange for some of our peppers and artichokes). The gambas were a touch over-cooked and the garbanzos and cuttlefish was bland. Our reaction: Cal Pep is a "happeniing" that draws tourists like a magnet. Better food is available and easier to access in Barcelona; but, they do know how to fry.
Re Madrid, we had two objectives: paella and suckling lamb. The first objective led us to El Ventorilllo Murciano. There we had the most expensive paella mariscara they offer, shared a wonderful, and unique, ensalada murciano, and a bottle of wine. The house provided a perfect amuse bouche of lightly-fried zucchine and a post-meal of dessert wine, compliments of the house. Cost: E85. A lovely restaurant in a very local setting, not far from the Prado and Reina Sofia. Our reaction: run, don't walk. Reservations should be made.
As for the lamb, our intention was to go to Asador Tierra Aranda in Salamanca, much recommended on this site, but the ravages of age, exacerbated by a taxing day of museum crawling, led us to Asador del Aranda, also noted on this site, which was less than 10 meters from our excellent hotel, the Preciados. There we had a plate of lovely jamon, compliments of the house, shared a very fresh salad, shared a quarto of lamb, two coffees, and after dinner drinks on the house. Cost: E68. If you have ever enjoyed more mature lamb roasted on a spit, by all means try the suckling lamb. Wonderful! We leave the choice of asadors to your judgment, but cast a vote for Asador del Aranda.
Finally, a couple of side comments re Barcelona: Some time ago, a commenter mentioned Jabal, a spice vendor at Calle Princessa,38, around the corner from the Museo Picasso. Don't miss it! Even if you don't want to buy some saffron, at 1/5 the price charged in the U.S,, stop by anyway. The smell of spices is worth the visit. Spanish paprikas in bins! Wow! Shops like this take you back in time. How soon will they disappear? Second, I believe it was PBSF who noted sandwiches at Can Conesa at the Jaume 1 subway stop. It appeared to us to have been replaced by a bakery/confectionary named La Colmena. If so, it is a worthy successor. Great little sandwiches for E2.
Thanks again to those who recommended the restaurants and shops we enjoyed. Viva Espana!


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Quest Says It's Not Infringing Myriad's Gene Patents
Quest says Myriad has threatened a patent infringement suit against any company that makes, uses, sells or offers to sell genetic tests and related services that use sequencing and analysis of BRCA1 and BRCA2 genes, which encode specific proteins responsible for repairing...
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The various genetic diseases
Severe skeletal disorders resulting in intrauterine death or death up to the age of a few weeks – lethal types of skeletal disease
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Severe skeletal disorders resulting in intrauterine death or death up to the age of a few weeks - lethal types of skeletal disease
Types and clinical signs
These are severe diseases that result in intrauterine death or death up to the age of a few weeks. There are a number of types:
One is
osteogenesis imperfecta
type 2 (see:
Osteogenesis imperfecta (defective mineralization of bone)
) in which a defect in the collagen 1 molecule can be demonstrated in skin cells.
The second is thanatophoric dysplasia, a lethal form of skeletal disease featuring changes mainly in the structure of the long bones. The defect here is in the gene causing
, which is FGFR3. This condition can be identified by its characteristic intrauterine X-ray and ultrasound signs.
The third is achondrogenesis, a lethal type of skeletal disease that manifests as a major disorder in the formation of the vertebrae with characteristic signs in the long bones. The gene is the one for the collagen 2 molecule, the same as in
spondylo-epiphyseal dysplasia
Other disorders - there are a number of other rare diseases in which the chest does not develop normally and there are marked breathing difficulties - the signs depend on the specific type and distribution of cases in the family.
Concerning all the sections below, the following must be remembered:
A precise diagnosis is important, and a diagnosis made in the past may not always have been made according to today-s standards and methods and is not always accurate by today-s standards. Because of this, the diagnosis must always be confirmed in a genetic institute by examining the patient, or at least by looking at the clinical picture, photographs, X-rays and other data.
Even though we know a lot about the inheritance patterns, the risk of recurrence, the mechanism of the manifestations of the disease, etc., most of these diseases have exceptions, and each case/family must be examined individually in a genetic institute.
Inheritance pattern
Thanatophoric dysplasia -
autosomal dominant
. All cases are born to healthy parents and usually represent a new mutation.
Achondrogenesis -
autosomal dominant
. There are also cases with
autosomal recessive inheritance
Other disorders - the inheritance pattern depends on the specific type and the distribution of cases in the family.
Always full.
Associated features that can be demonstrated in tests performed during pregnancy
Thanatophoric dysplasia - the changes in the skeleton are prominent on
ultrasound examination
Achondrogenesis - the changes in the skeleton are prominent on ultrasound examination.
Other disorders - depends on the type.
In all these cases it is important to refer the couple for
genetic counseling
, to which they should bring all data, including the results of other tests performed during the pregnancy such as
nuchal translucency
, etc.
What is the risk of recurrence in a subsequent pregnancy?
Thanatophoric dysplasia - a couple who has had an affected child in a previous pregnancy has a low risk of recurrence, as long as the diagnosis was correct. For more distant relatives or siblings of an affected individual, the risk of having a child with the same condition is less than 1%.
Achondrogenesis - a couple who has had an affected child in a previous pregnancy usually has a low risk of recurrence, but this risk can be up to 25% in some families. For more distant relatives or siblings of an affected individual, the risk of having a child with the same condition is less than 1%.
Other disorders - the risk of recurrence depends on the specific type of disease, the inheritance pattern, and the relationship to the patient, in accordance with the laws of inheritance.
The risk for more distant relatives depends on the number of affected individuals in the family, the degree of relationship between the relatives and the affected individuals,
between the parents, if present, etc. This risk is established within genetic counseling.
Molecular genetic information
The gene for the disease
Thanatophoric dysplasia - this is caused by a mutation in the same gene that causes
. This gene is called FGFR3, and it is situated on the short arm of chromosome 4 (4p16.3). The mutation in thanatophoric dysplasia is different from the one responsible for
- it is in a different base and it apparently causes more severe damage to the gene.
Achondrogenesis - genes for proteins forming type 2 collagen.
Other disorders - depends on the exact type.
Genetic testing
Thanatophoric dysplasia - the common mutations in the gene can be tested for directly. This test is practical but usually unnecessary. See:
Testing the disease-causing gene for mutations that are common in a specific ethnic group - autosomal dominant diseases
Achondrogenesis - this is a complex test that requires the testing of a number of genes. As noted, collagen 2 can be examined in skin cells (or
chorionic villus
or amniotic fluid cells) directly using biochemical methods. See: Indirect testing for genetic markers in a family with a number of patients in the family - when there are a number of different genes that can each cause the disease - all of the genes having been located / identified / mapped - autosomal dominant disease. See also:
Screening test for identifying defects (mutations) using various methods such as SSCP - autosomal dominant diseases
Other disorders - depends on the specific type.
Carrier testing
Thanatophoric dysplasia - there is no carrier status. Carriers are affected.
Achondrogenesis - in families in whom the mutation in the gene responsible for the disease has been found, other relatives may be tested both for signs of the disease itself and for carrier status. There are no carrier tests for the healthy population.
Fetal testing
As for diagnostic testing.
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Target Clothing Infringed Fabric Maker's Design: Judge
Star Fabrics brought the lawsuit against Target, clothing manufacturer Kandy Kiss of California Inc. and fellow fabric designer Morex Enterprises Inc., in October 2010, after it discovered Target was selling kimono-style dresses made of material allegedly bearing one of its copyrighted designs.
Star Fabrics alleges Kandy...
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Web site design projects of the yore were not very complex and carried the sole purpose of displaying text onto your computer screen. Since then, web has come a long way with more complex navigation & and also designs. The World Wide Web is "still in its infancy" but as the technology has evolved, it has now become difficult to handle the balance between practicality as well as compatibility, and in between esthetics and accessibility. These artificial limitations are not impossible to cross; we only have to look past them & deal with the drawbacks, if any kind of. Go through the points pointed out listed below to take a preview into the future of web design.
Simplicity - It's the most important attribute of a web site. The freelancers dealing with online web designing projects can no more ignore this fact. The relatively overcrowded websites, filled with unnecessary and also confusing details tend to sidetrack the users resulting in total customer dissatisfaction.
Speed - Freelancers dealing with web site style projects have to create & maximize website to ensure that they are downloaded and install swiftly. Likewise when it comes to website ecommerce, the customer wants to shop quickly without being bombarded with unnecessary advertisements or prolonged purchasing procedures. An intelligent & effective website is one that fixes all the demands of an end-user and is quick in doing it.
Attractive Style - Internet site designing, especially ecommerce making is more than just pictures as well as text or data. An ecommerce site is an advertising and marketing system that represents your firms business and also its gears. A shoddy looking internet site will certainly drive away any kind of prospective consumer. An internet site should have a character & must mirror feelings. Consequently, freelancer endeavor online web designing jobs need to try and also keep the styles eye-catching.
Standardization - Standardization of website design is going to be the substantial step forward on the Internet. It's going to have to do with use & functionality.
Web designing has evolved from being primitive to intricate & will certainly now move to being easy and very easy to use. The objective, becomes to produce visually appealing as well as substantially unique website design which work with all kinds of browsers as well as accessible to one as well as all.
External Links:-


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Stylish luxury Italian leather crocodile style business briefcase ladies handbag by Maxwell Scot Bags
Stylish Italian leather croco style ladies business briefcase handbag by Maxwell Scott
Stylish fine Italian leather ladies business briefcase tote handbag by Maxwell Scott
Over time we guarantee this striking slim briefcase will gain its own individual character and become a trusted business companion.
A stylish investment for the discerning professional! The interior provides a safe and organised haven for your working essentials with a padded laptop section large enough to fit a 15" Macbook


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Dick's Sporting Goods
Dick's Sporting Goods is a big site. They have tons of sporting goods, ball sports equipment, racquet sports supplies and outdoor gear as well. Plus they have lots of name brand apparel and footwear. For paddling supplies, try their Boating section of their Water Sports Department.
Boating Equipment at DicksSportingGoods.com
Paddling Online Online Paddling Stores Manufacturers A-O Manufacturers P-Z
Picking a Kayak Kayak Opinions Used Equipment Paddle Makers
Pick Your Paddle PFD shopping Kayaker Helmet Outerwear Other Gear
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Wednesday, February 4, 2009
UPdate on the Credenza
Just an update on the credenza, it sold in one week. I put a piece of paper on the top with the measurements of the HUGE plasma TVs, like 52 inch up to 72 inch. Also put a picture from a retail store where they pictured 3 units shoved together (in red) to hold a huge TV. There were 2 people that had the piece on hold. Of course only one got it, but I am so glad someone did cause it was a great piece.
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Marion Energy Fires Up Gas Production in Utah
Marion Energy reported that gas production operations have now commenced at a second Clear Creek well, the 100% owned RR 13-17 well located at Clear Creek, Utah, USA.
Ridge Runner 13-17
Marion's operation team have commenced production operations at the RR 13-17 well. RR 13-17 is located approx. 8 km from Marion's producing Oman 2-20 well and benefits from excellent access to infrastructure and also being tied into existing pipeline and gas distribution networks.
The well is the second to commence production operations under the well rehabilitation program designed and being implemented by recently appointed Chief Operating Officer Jay Stratton.
The RR 13-17 well was drilled prior to Marion acquiring the Clear Creek project. The well was completed and underwent limited production testing in 2007 but was then shut in to allow the construction of the Clear Creek gathering and distribution system.
Following extensive recent diagnostic analysis undertaken by operations management, a program of work has commenced with first gas sales targeted for mid February 2010.
Management is firmly of the view that this well has the potential to produce in the range of 1 to 4 million cubic feet per day, given the well flowed at approximately 2 million cubic feet per day previously during a limited test period.
Oman 2-20
The Oman 2-20 successfully commenced production operations in December 2009.
The well has now been in operation for over six weeks and since that time has flowed uninterrupted with consistent good quality, clean gas. Operations management are closely monitoring and managing flow rates, and as the back pressure is gradually pumped down and fully released, these rates will increase above the initially reported level of 280 mcf per day. Gas is currently being sold into the distribution network at prices close to the prevailing Henry Hub benchmark price.
Multi Well Rehabilitation Program
Operations management are currently implementing a multi well rehabilitation program that is focussed on bringing a further two wells into production by April 2010, currently planned to be the RR 11-17 and RR 2-19. Both the RR 11-17 and RR 2-19 wells were previously production tested by Marion achieving flow rates of over 5 million and 2 million cubic feet per day respectively.
Management believe that with the successful implementation of the multi well rehabilitation program all four of these Clear Creek wells will be back onto production by late April 2010 with the wells expected to increase production rates to targeted maximum productivity within a further two months.
Management is targeting a production level from each of these four wells to be in a range of 1 to 4 million cubic feet of gas per day with a combined production target for the four wells of 8 million plus cubic feet of gas per day. It is management's aim to further extend this program to bring onto production the other 14 Clear Creek and Helper wells over 2010 and 2011.
- Marion Energy Fires Up Gas Production in Utah (Jan 27)


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Cufflinks, socks, a new wallet... uninspired, dull and definitely not the sort of gifts dads are going to want or need this Father's Day. If you want a gift that will actually make a difference, Colgate has the answer!
The new Colgate ProClinical A1500 electric toothbrush is the only toothbrush in the UK with smart sensors that automatically adjust the speed and direction of the brush strokes for healthier teeth and gums! It has many features which make this the perfect must-have gadget gift for Father's Day – including the sonic wave cleaning action which removes 5x more plaque along the gumline compared to a manual brush, the dentist recommended 2-minute timer and even a handy travel case. This is the gift to get in any Dad's good books! Find out more at www.colgateproclinical.co.uk
Give the perfect gadget this Father's day with the Colgate ProClinical A1500 electric toothbrush by entering this competition to win one of the brushes. Just answer the following question:


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Time limit meant they had to reapply every time they went home.
Filipinos welcome change to clearance certificate rules
ABU DHABI // Filipinos living in the UAE will no longer need to apply for clearance to leave their country each time they return for a holiday.
The Philippines plans to overhaul the system of overseas employment certificates (OECs), the country's labour secretary, Rosalinda Baldoz, told the website InterAksyon at the weekend.
The documents, which prove a worker has been hired legally, are currently valid for only 60 days, meaning Filipinos need a new one each time they return home.
The new certificate will be valid for as long as a worker's contract, removing the need to reapply each time, said Ms Baldoz, who also heads the governing board of the Philippines Overseas Employment Administration (POEA).
The paperwork is available from the Philippine overseas labour office in Abu Dhabi or Dubai, and at POEA offices in the Philippines. The agency is also testing an online application process.
Ms Baldoz said the change would officially be announced on Migrant Workers' Day, June 7.
Nasser Munder, the labour attache in Dubai, said his office had yet to be formally notified of the change, but added that it would be welcome.
On any given weekday the labour office in Abu Dhabi processes 200 applications for employment certificates - and in busy months that number can double.
In December last year, Mr Munder said he had to help out the lone member of staff who issues OECs.
"At that time, people got angry at us and wanted to jump the queue because they were flying on the same day," he said. "But why did they wait until the last minute to apply for their OECs?"
Some do think further ahead. Jonathan Apiado, 35, a clerk in Abu Dhabi, was at the labour office on Sunday to apply for a certificate ahead of a trip home on Thursday.
A resident for 15 years, he said it was time the government addressed the slow processing of these certificates.
"Many have to ask permission from their employers just to come here," he said. "Others even live and work in Al Ain and Ruwais and have to face long queues."
Cerlina Dalaguete, 44, a maid in Abu Dhabi, said she was lucky that she did not have to queue for long.
She is flying home on Saturday to spend a month with her two children in Cebu City, about 600 kilometres south of Manila.
"Last year, there were so many people applying for an OEC," she said. "If the government changes the system, then things will be a lot better and convenient for us."


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16" Corvette® C6 Tiffany - style Lamp Fixture. Rev - up your rec room with America's favorite speedster!
Now THIS is interior design you can get behind! Handmade with stained glass and detailed with the Corvette name and classic race flag logo, it'd look great hanging above your pool table or bar.More:


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Someone linked onto my blog today by searching for "Can crack taste like bananas?" on Google.
Just thought I'd throw that out there.
Happy New Year!
Someone linked onto my blog today by searching for "Can crack taste like bananas?" on Google.
Just thought I'd throw that out there.
Happy New Year!
I went to visit my family in Charlotte, NC for Christmas this year.
To be honest, I was way too busy eating, wrapping presents and hanging out to take many photos, but I did manage to get a few in there!
Sorry it took so long to post these… had some strange computer/photo/Wordpress issues, but I think we're back now!
After today, I won't be blogging until Monday. You know… Christmas and all that 🙂
Jorge and I got all our Christmas shopping done this weekend. Plaza las Americas was pretty crazy, but nothing compared to US malls the week of Christmas. (I made the mistake of going to the mall on Christmas Eve once when I lived in Virginia… 45 minutes to get out of the parking lot. Never again.)
The weather continues to be in the 70s during the day, and much cooler at night. I've thoroughly enjoyed going out in the evenings with jackets and scarves 🙂 It is more challenging for me to get into the Christmas spirit when it's not freezing outside, though.
I've been listening to Christmas music all month. My two favorite kinds of music are Glee songs and Christmas songs, so obviously I've been listening to their Christmas album.
Jorge's family normally doesn't exchange gifts on Christmas, but this year we decided to do it. I already know what I'm getting from his parents, and I'm pretty excited about it! I just hope his brothers don't peak inside their gift bags, which are already under my in-laws' tree.
My company had it's annual "posada" (the Mexican term for Christmas party) at a resort in the Hotel Zone last week. It was a good night for me… I won employee of the year for my department, and I won a bar mixing set in the raffle!
And last but not least, the long overdue photos of the Christmas lights at our house! I think it turned out nicely! (Except for some of the colored lights not working… oh well.) We're actually planning on leaving up the lights in the tree for a few more months, just taking down the colored lights after Christmas. I'd like to point out that I fought hard for the last 5 boxes of white Christmas lights at Walmart. I got the evil eye from a few ladies, and I had to dig through about 20 stacks of colored lights… but it was worth it to find them all smushed against the back corner of the shelf.
**Please ignore the crazy dogs in the background**
Merry Christmas!
Good news: Despite craving something sugary, I resisted buying the chocolate-filled rolls from the machine at work today.
Bad news: I bought a bottle of Coke instead.
Good news: I only drank half the bottle.
Bad news: The real reason I stopped drinking Coke was to save room for the massive amounts of sushi I plan on eating after I get home from work.
As you can see, the diet is going well.
When I first came to Mexico, I had a hard time expressing myself 100%. I always wished I could speak English, which gave me more opportunities to use more colorful expressions.
After a few years in Mexico, however, I've become familiar with using many of the local idioms and expressions used here, which allows me to express myself sometimes even better than an English!
One of my favorites is "engentarse". (You probably won't find this in a dictionary.)
When conjugated to "Me engento", it roughly translates to "being in a crowd of people really puts me in a bad mood".
It comes from the word "gente", which means "people".
I use this one a lot. It's the main reason I avoid concerts and why I always want to leave nightclubs early.
If there's one thing I hate, it's going grocery shopping. I don't mind making my list, picking things out, pushing the cart around, or waiting in line. What really bothers me is the massive amount of people, and weaving my way through masses of shopping carts. I will do everything I can to get out of Walmart as quickly as possible.
I'd like to take this opportunity to apologize to Jorge for being mean at Walmart last night… and pretty much every time we go grocery shopping. Jorge, you should be able to buy oranges, a chocolate bar and even hot dogs without me rolling my eyes. Thanks for loving me anyway.
Me engento.
Turns out that over the last 2 weeks or so, Cancun has had a few record-breaking low temperatures.
The days have been beautiful, usually in the 70s with a cool breeze and lots of sunshine. (I wish it were like this all year!) At night, however, it has gotten down to 50 degrees. I know those of you who have been experiencing blizzards and snowstorms this winter are probably saying "What are you complaining about?" but hear me out…
-Houses in Cancun have no heating system.
-Houses in Cancun are made of concrete, which is designed to make things cooler.
-Houses in Cancun usually have all-tile floor. Great for the heat, but not too cozy for 50-degree weather.
-Windows and doors in Cancun aren't usually airtight, letting in a bit of the cold.
So what does this mean? We have basically been sleeping in 50 degree temperatures.
I love it sometimes, so long as I have good blankets and PJs. We borrowed 2 fleece blankets from my brother-in-law yesterday. I grew up sleeping under heavy blankets and comforters, and I think it's the best way to sleep! Jorge, however, is having a difficult time with the cold. This is a guy who sleeps at most with a thin blanket… although usually he will sleep on top of the covers or in a hammock.
The dogs usually sprawl out on the tile floor to stay cool while they sleep. Lately they've been making use of their doggie beds to cuddle up from the cold. Yesterday I washed the doggie beds and they hadn't dried, so last night we had to improvise. Suki slept on my laptop bag by my side of the bed (her favorite spot). Dolly snuggled up with one of Jorge's old t-shirts under the bed. Konan used a doggie bed cushion (the only part that had dried by then) under the bed, as well. I would love to shave their fur to keep them cleaner, but with this weather that won't be an option until March or April.
The upside is that I've been thoroughly enjoying some Salted Caramel Hot Chocolate from Starbucks, we'll save a ton on the electric bill by not using the AC, and I get the chance to wear my cute jackets, scarves and long-sleeved shirts that spend all year in my closet. Plus it feels more like Christmas!
How cold is it where you are?
I came across another dream house online yesterday, and I can't stop thinking about it! It's located in Merida.
Ya'll are gonna think I'm insane, but here are some photos:
If I had money, here's what I would do:
1. Put in a down payment on the house
2. While saving money to renovate, I'd rent the house out as a site for filming horror movies, because DANG it's creepy right now
3. Renovate it for a relatively small cost because everything in Merida is cheap (I'm thinking beam ceilings, traditional colorful tiles on all floors, and maybe opening up a few doorways)
4. Move in, or sell it for profit because it has potential to be GORGEOUS. Look at that 2-story room! Beautiful.
It only costs $45,000 US.
*sigh* Someday.
First of all, a little explanation. Here in Mexico, when you get married, you have to get married twice. One is the religious ceremony, which is the big ceremony and reception, like an American wedding. Second is the civil ceremony, where you have to say your vows and sign a paper, to show you're legally married.
Jorge and I did the religious ceremony back in July, and we'll be able to do the civil ceremony soon.
Our friends Juan and Viri, however, did it the other way. They had their civil ceremony last Saturday, and the big formal wedding will be in August.
Some Mexicans just go to the courthouse for their civil ceremony. Others have a small, informal ceremony and party.
Juan and Viri hosted a party at La Europea, a wine and liquor shop in the Hotel Zone. La Europea has a small tasting room in the back for events, along with a beautiful garden and balcony overlooking the lagoon. It's a great spot. Seriously, the next party I throw will be here! haha
And now for the ceremony photos (please overlook my poor nighttime photography skills)…
After dinner, a bunch of us stayed out on the balcony for some drinks. I was lame and went home at 1 a.m., but Jorge didn't get home until 4! Must have been quite a party 🙂
Some of you may have noticed I haven't been blogging as much the past few weeks. Nothing to worry about! I've just been busier than usual at work. Anyway, here are some updates as to what's going on in my life lately:
-I finally finished reading They Came to Baghdad by Agatha Christie. What a fun spy novel! This is the 2nd Agatha Christie book I've read, and I really enjoy them. Mysterious, but light-hearted, with lots of twists and turns! Now I need to find something else to read…
-Jorge and I hung Christmas lights at our house last night! It looks very pretty. I forgot to take pictures because we were in a rush, but hopefully I'll have them by tomorrow. I don't think we'll get a Christmas tree this year because we have no living room furniture… so it seems kinda sad to just have an empty room with a tree. But the lights look incredible!
-Jorge and I have to write a Christmas list to give to my family this week, but we don't really need anything! We have tons of clothes, lots of stuff to decorate the living room with eventually (even though there's no furniture yet haha) and more kitchen items than we have room for. We'll have to get creative, I guess.
-Two of my best friends are getting married this weekend! Not the official wedding yet, but they're signing papers and having a dinner with friends. I'm very excited 🙂 Congrats, Juan and Viri!
-I won't be seeing Mario Lopez on Saturday because it's the same night as my friends' marriage. Sorry, ladies.
-Ever since we got married, I've been having super intense and often violent dreams. Jorge has no dreams. I think I'm stealing his dreams. Can that happen?
-The company I work for blocked Facebook. Sooo I can only use it on weekends. This has hurt my blog stats because normally a lot of my visitors link in from Facebook, but I can only post links on weekends. Not cool. (Other than that, I'm kind of glad to have Facebook out of my life.)


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IntrepidTravel: Take or Make a Friend Sweepstakes
Ended: 11/30/2014 23:59 ET(18+)
Intredpid Travel is celebrating friendship by offering a $20,000 trip to one winner and a friend. This includes $5000 spending money!
PRIZESPrize includes:
- one Travelex Multi-Currency Cash Passport Card loaded with USD$5,000
- one credit with Intrepid Travel up to the value of USD$10,000
- accommodation (up to a maximum of two nights of pre- and post- trip accommodation booked in conjunction with an organised Intrepid trip
- transfers available through Intrepid Travel
- one credit for airfares up to the value of USD$5,000
NOTESValid in Australia, New Zealand, United Kingdom, the United States of America, member countries of the European Union, Switzerland, South Africa and Canada. Void in Quebec.
Your Comment Here:


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Talk to your local Valley dealer about irrigation systems today!
Sign up now for your free PivotPoint magazine subscription!
We want to hear from you!
Sometimes, a center pivot requires a bit more "oomph" to keep itself going through difficult field situations. If you're a grower with a field that develops deep wheel tracks or other difficult challenges, the Valley® 3-Wheel Drive floatation option may be the solution for you. The 3-Wheel Drive will help keep your center pivot afloat and therefore limit your downtime.
Valley Irrigation offers a superb selection of irrigation tires and irrigation parts to help you get the most out of your fields. For more information about our irrigation equipment, contact your local Valley dealer.
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2786Call for Participation: CHI 2007 Workshop: "Beyond Current User Research"
Expand Messages
- Jan 3 1:10 PMHi there,
Thought that this workshop would be of interest to those working in
Agile Usability.
Find out more info here: http://depts.washington.edu/uwtclute/CHI2007/
Beyond Current User Research: Designing Methods for New Users,
Technologies, and Design Processes
A workshop at CHI2007, San Jose, California
This workshop focuses on the challenges of creating or adapting user
research methods for use with new user groups, technologies, and
design processes. For example, how do you assess the usability of a
mobile, multi-user social-network system? We want to hear your answers
to challenges like this.
We invite user researchers who have created/modified user research
methods to submit case studies describing and analyzing their
experience. Successful submissions must address these questions:
(1) What was the impetus for creating the new method or revising
an existing method? What circumstances created the need for the
method? What goals did the method have to meet? What data was needed?
(2) How was the method implemented? What process was followed to
develop the method? How were problems addressed when applying it? How
was its quality assessed?
(3) What was the impact of the method on the design process? How
was impact tracked? What circumstances, if any, limited the method's
impact on design?
This one-day workshop will focus on analyzing your case studies to
identify guidelines for improving future work.
Submit a 4-page paper plus a short bio to jramey@... by
12 January 2007. At least one author needs to register for the
workshop and for one day of the CHI 2007 conference.


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Value My Trade-In
against current vehicle
2016 Toyota Camry Altise ASV50R MY16
$21,910 Ex. Govt. Charges
|6 SP Automatic
|3,120 Kms
|2.5 Litres Petrol
We're sorry, but this vehicle has been sold.
2016 Toyota Camry Altise ASV50R MY16
Ex. Govt. Charges
Dealer Comments
Great value scoop purchase. Limited stock available. Excellent condition both inside out and covered by the remainder of their Toyota Factory Warranty. Reliable. Efficient and comfortable Camry. Do not miss out, limited numbers at this price. We are the Competitors for more than 30 years our friendly staff have been selling and servicing used vehicles in Canberra and the surrounding region. Instant finance tap. Any trades welcome. Guaranteed title on all vehicles. Extended Australia wide warranty and roadside service available. All vehicles workshop and safety tested. Over 250 Vehicle in stock. Australia wide transport available or fly down and enjoy one of the many Canberras attractions like War memorial, Parliament house, National Museum, National Art Gallery or sleep with a Tiger at Jamala the award winning luxury accommodation at Canberras Zoo. Our 190 friendly staff are specialists, whos focus is on providing excellent representation for our brands while also ensuring our customers feel their Purchase and After-sales experience is unequaled.
12 Volt Power Outlet
Dual Front Airbag Package
Airbag Knee Driver
Anti-lock Braking
Air Conditioning
Adjustable Driver Seat - Manual
Alarm System/Remote Anti Theft
Adjustable Steering Wheel - Tilt and Telescopic
Ambient Temperature Display
AUX/USB Input Socket
16 Inch Alloy Wheels
Brake Assist
Body Coloured Bumpers
Body Coloured Exterior Door Handles
Body Coloured Exterior Mirrors
Bottle Holders - Front and Rear
Cruise Control
Centre Console Box With Sliding Armrest
Centre Courtesy/Dome Light(s)
Cup Holders - Front and Rear
Central Locking Remote Control
Child Proof Rear Door Locks
Child Seat Anchor Points
Child Seat - ISOFIX Anchorage System
Cloth Trim
Door Pockets - Front and Rear
Daytime Running Lights - LED
Dusk Sensing Headlights
Electronic Brake Force Distribution
Grab Handles - Front and Rear
Headrests - Adjustable on All Seats
Head Airbags
Halogen Headlights
Illuminated - Entry/Exit with Delayed Fade
Engine Immobiliser
Intermittent Wipers - Variable
Luggage/Cargo Area Light(s)
Low Fuel Warning
Lockable Glove Box Compartment
Multi Function Control Screen
Multi Function Display
MP3 Compatible Audio/CD Player
Mobile Phone Connectivity
Map/Reading Lights - Front
Power Mirrors With Indicators
Power Steering
Power Windows
Rear Centre Armrest
Remote Boot/Hatch Release
Radio CD with 6 Speakers
Remote Fuel Lid Release
Rear Lights - LED
Reversing Camera
Side Airbags
Seatbelts - Height Adjustable Front Seats
Seatbelts - Load Limiters Front Seats
Seatbelts - Lap/Sash for All Seats
Seatbelts - Pre-tensioners Front Seats
Seatbelts - Reminder for All Seats
Speed Sensing Auto Door Lock
Split Fold Rear Seat
Sunglass Holder
Seatback Pocket - Front Passenger Seat
Sunvisors with Vanity Mirrors and Illumination
Steering Wheel-mounted Audio Controls
Spare Wheel - Full Size Steel Wheel
Steering Wheel - Urethane Type
Trip Computer
Traction Control System
Vehicle Stability Control
Dealer Details
National Capital Motors - Canberra Fleet & Wholesale - Belconnen
16-18 Josephson Street, Belconnen, ACT 2617
(02) 6256 3300
Similar Vehicles


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Green Zebra
It's no secret that Melbourne is a city that loves to brunch, with gourmet breakfasts available throughout the day at the many eclectic cafés. The trend has now spread further afield with brunch venues in regional Victoria evoking the spirit of St Kilda or Fitzroy.
LiveFast – with a reputation for the best coffee in Halls Gap, Live Fast also serves up a great brunch seven days a week to satiate even the biggest outdoor adventurer's appetite.
Green Zebra – a long time favourite of locals and visitors to Albury. If the food isn't made from scratch or harvested from the kitchen garden, it will have been purchased from a local producer who is fanatical about flavour and freshness.
The Black Pudding is located in the port area of Echuca, a great little spot to soak up the history of the town over a perfect cup of coffee. The menu is adjusted seasonally to deliver what locals dub the best breakfast in town. Open seven days for brunch.
Yellow Espresso – newcomer Yellow Espresso is bright, bustling and the latest place to be for brunch in Ballarat. Serving all day breakfast and one of the best coffees in town.
Elk Horn Roadhouse – a cafe, restaurant and gift store with its own range of gourmet products, all housed in what was formerly a tin shed in the middle of a horse paddock. Inspired by US roadhouses, visitors will find delicious breakfasts worth the road trip. Open seven days.
Percy and Percy – step into this old grocers in Bendigo and feel as though you're in a destination cafe in Fitzroy. Offering a seasonal breakfast menu, open Wednesday to Sunday for breakfast.
Run Rabbit Run – popular brunch spot in the heart of Castlemaine, known for great coffee and provincial fare served in a relaxed atmosphere. The gallery space upstairs plays host to temporary exhibitions. Open Wednesday to Sunday.
Coral Lee – a favourite with Bright locals and visitors-in-the-know, this is a quirky 1950s-inspired café dishing up modern food made with love. Enjoy Honeybird coffee roasted locally with a delicious brunch in the sun-filled courtyard. Generous and earthy dishes fill the blackboard menu, including Coral Lee's signature dish, the pesto toast with feta, beetroot and poached eggs. The house-baked cakes hero local produce in season.
Coombe – The Melba Estate is home of world famous opera singer Dame Nellie Melba and a property with an unrivalled provenance. Located at the gateway to the Yarra Valley wine region in Victoria, the historic estate includes a cellar door, providore, gallery and restaurant. The modern, spacious yet intimate restaurant overlooks the market-style courtyard of the beautifully restored facilities.
Burnham Bakery and the adjoining Piggery Café offer enchanting in-house breads and pastries. The Piggery Café has been designed in a warm and rustic manner with touches of modernity, while Burnham Beeches sources sustainable and ethically-caught andharvested produce, which is reflected in its menu.
1 Sherbrooke Rd, Sherbrooke VIC 3789