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Breast Reduction in San Diego – Dr. Gary H. Manchester
Reduction mammoplasty, or breast reduction as it is more commonly known, is a surgical procedure which removes fat and glandular tissue and tightens the skin of large breasts to make them smaller, lighter and more proportionate to the body. Breast reduction can relieve a number of physical ailments caused by large or heavy breasts including back and neck pain, skin rashes, breathing difficulties, improper posture, and skeletal deformities. The result is firmer, more youthful breasts with the nipples in a more elevated position.
You may be a San Diego breast reduction candidate if you are physically healthy and have realistic expectations for improving large, heavy or pendulous breasts. If you intend to breast feed in the future, you may be advised to postpone the surgery as many of the milk ducts leading to the nipples are removed. Younger patients may also be advised to postpone surgery until the breasts are fully grown.
Dr. Manchester may perform your breast reduction procedure in the hospital or at his clinic located in San Diego, California. Surgical times range from two to four hours and general anesthesia is most commonly used. The incision for breast reduction runs around the nipple, extends down vertically to the fold beneath the breast and runs horizontally along the fold. This will result in a scar that will be concealed by most bikini tops and bras and will fade to a fine line in time. Working through the incision, Dr. Manchester will remove excess fat, skin and glandular tissue and reposition the nipples. During this process the areola will be reduced to normal size without loss of nipple sensation.
After your breast reduction surgery, your breasts will be numb for several weeks. Pain medication will help to relieve your discomfort. A bandage or surgical bra will be worn for the first few days. A return to work is usually anticipated within two weeks, though you will need to take it easy for the first month. Your wounds will require a minimum of six weeks to fully heal.
What is breast reduction?
Breast reduction, which is referred to as reduction mammaplasty in the medical field, is a surgical procedure which improves very large or pendulous breasts by making them smaller, lighter, and more proportionate to the body. During surgery, fat and glandular tissue are removed and the breast skin is tightened.
How do I know if I'm a candidate for breast reduction?
If you are in good physical health and have realistic expectations for improving large, heavy, sagging or pendulous breasts, then the breast reduction may be right for you. Women seeking breast reduction are often bothered by a variety of physical ailments including back and neck pain, skin rashes, breathing difficulties, improper posture, and skeletal deformities. Younger patients may be advised to postpone the surgery until the breasts are fully grown, as well as women who are planning to breast feed in the future.
Where is the breast reduction procedure performed?
Dr. Manchester performs breast reduction procedures in the hospital or at his clinic in San Diego, California.
Dr. Gary H. Manchester is a highly regarded plastic surgeon in San Diego, California. He has several decades of experience performing intricate breast enhancement procedures, including breast reduction, breast lift and breast augmentation in San Diego.
Breast Reduction Side Effects Web Marketing powered by Ceatus Media Group LLC


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Games & Hobbies
Chasing Geek S4 Ep. 10: It's Gaiman Time!
Hey folks, it's time for another episode of Chasing Geek! This week PintSize and Knight go over the big panels and reveals from New York Comic Con, including a lot of Neil Gaiman related shows like American Gods and Good Omens. Let us know which one you are looking forward to most by either commenting below or hitting us up on Twitter!
As always you can find Selina Angotti as PintSizeGinger on Twitter, Tumblr, Instagram, Twitch as well as on the PlayStation Network!
You can find Matt Mueller on ComicBook.com, and you can reach him on Twitter and PSN!
As for Chasing Geek, you can follow us on Tumblr, Twitter, or Facebook!
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As I'm about to take leave after our lunch together, Terrence leans in conspiratorially. "I wrote a joke for when I get together with my friends," he says. "How many New Yorkers does it take to change a light bulb?"
When I say I don't know, he says, "'Well, the next two weeks are shot because of work, and then I'm out of town for the weekend, so you want to try for the first week of next month?'"
Saturday, May 23, 2015
Posted by Scott Lee Williams at 12:18 AM
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A bit of housekeeping: 1) Orange County hardcore heroes Social Distortion never, ever had a hit. 2) Six of the nine songs on this record have been re-recorded by the band's present line-up, meaning you don't get to hear 1996's 'When The Angels Sing' driven by the drumming of hardcore's greatest ever drummer, Chuck Biscuits (the Social's drummer that year). 3) If you come round to our house, we'll burn you a better 'best of' than this (and we'll include 'The Creeps (I Just Wanna Give You)', the band's best song which is bizarrely absent here). That said, Social Distortion are one of the greatest punk rock bands ever and in Mike Ness (the only member who's made it through from their inception in 1978) they possess one of the greatest songwriters the genre has known. This is a flawed starting point, but whatever gets you on the road to discovery is fine with us.
James McMahon


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Amy's Whack a Nik – The game is based on arcade style 'whack a mole' type games. In this game, you are trying to hit various robots created by Dr. Robotnik that pop up briefly out of various holes on the game board. There are three different types of robots, and they each have a different point value attached to them, ranging from one to three points. You must also avoid hitting Sonic or Sally, who also pop up randomly, as hitting either of them will cost five points. Score 50 points or more to advance to the next level!
Game Stats19,566 Plays
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8 votes, average: 3.25/5


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Lolo's Surf Cantina is now open for lunch and dinner service, bringing Baja-inspired Mexican eats to Miami Beach's South of Fifth neighborhood. Created by chef/partner Richard Ampudia and Plan Do See, a global hospitality brand based in Japan, the beachside space is located inside the recently refurbished Stanton South Beach Hotel (161 Ocean Dr.).
Conceptualized by Ampudia, often referred to as the "godfather of Mexican street food," Lolo's caters to locals as well as out-of-towners, bringing affordable and inventive dishes designed for both a sit-down meal or grab-and-go. Lourdes Herman — a Mexican native who has worked at the Setai, 1 Hotel South Beach, and R House — joins Lolo's as Ampudia's chef de cuisine.
When dining at Lolo's, begin with its raw bar offerings ($15 to $16), which include Sinaloa-style ceviche topped with cucumber, fennel, and sesame, as well as tostada de pulpo, Spanish octopus served with guacamole and chile de arbol. Next, add a few small shareable plates to your order ($5 to $13), such as Mexican-style grilled corn on the cob topped with queso cotija, chili powder, and lime, or quesadillas with corn masa, wild mushroom, espazote, salsa verde, and crema.
All tacos ($10 to $14) at Lolo's are served with warm, house-made tortillas and paired by fresh salsas and sauces made in house too. Three come per order, allowing diners to mix and match rib eye, mahi-mahi, carnitas, and mushroom.
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For something heartier, try the Doña Lolo's burger ($16), a sirloin brisket blend with cheese, tomato, caramelized onions, and jalapeños, or the torta ahogada ($15), a Mexican dip sandwich served on a crisp baguette with carnitas and pickled onions. There are meats prepared a la plancha too, including steak, chicken, and shrimp platters served with grilled onions, avocado, tortillas, and house salad. The menu also includes gluten-free and vegetarian dishes such as grains and greens ($14) mixed with lentils, red quinoa, purslane, carrots, cherry tomatoes, cucumber, and salsa macha, and the Martinez kale salad ($14), topped with walnuts, aged Gouda, apples, and maple-mustard vinaigrette.
Indulge in a selection of traditional Mexican sweets for dessert ($7), including homemade flan, warm cajeta pudding with bananas, and pastel de elote — Mexican corn cake — with crème fraîche ice cream.
Wash it down with a drink by Mexico City mixologist José Luis Leon, who offers everything from beer cocktails to margaritas, along with an extensive list of tequilas and mezcals plus nonalcoholic alternatives.


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Overnight MoTweets, my personal favorite wp7 twitter app, was updated to 2.9 and now supports mango multitasking.  You can get the update through both the  free ad supported version and MoTweets Pro, the premium app.  From a quick look over settings and the new feature list it doesn't look like anything else has been changed in this version but I look forward to any upcoming changes especially more live tile settings.
I personally appreciate app developers pushing out app switching support even when their other mango features are not ready for prime time.  The ability to instantly pull up a full featured twitter client changes the equation for me when it comes to usability.  What app are our readers most excited to get quick switching support?  My personal vote is for Netflix.


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Call: (727) 785-0589
Insurance & Payment
We are happy to discuss how much our various services will cost out of pocket, verify your benefits, or discuss the financing option we offer here. You never need to worry about money as a patient of ours, because there are so many options for payment and coverage. We accept Visa, MasterCard, American Express, Discover, and we also offer no interest financing through Care Credit and Spring Stone.
CareCredit & The Lending Club
The office of Dr. Krawczyk works hand-in-hand with CareCredit and The Lending Club Patient Payment Plans. Both CareCredit and SpringStone offer special financing options to patients at a reasonable rate through use of a credit card. The credit card allows you to make easy monthly payments for dental treatments, rather than delaying treatment for financial reasons. Please contact our office for more details.


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1. Introduction
The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTKs) that also include ErbB2, ErbB3 and ErbB4 [1]. EGFR can bind at least seven ligands, of which the most widely studied is epidermal growth factor (EGF) [1]. Regulated activation of the EGFR requires high affinity ligand binding and involves homo- and/or hetero-dimerization with other ErbB family members [2]. Dimerization is essential for activation of its intrinsic kinase activity and subsequent autophosphorylation [3-6]. These events activate a number of different downstream signaling pathways that regulate multiple cellular processes such as proliferation, differentiation and development. The EGFR is commonly overexpressed or mutated in many cancer types and its presence promotes tumor progression and survival.
In glioblastoma multiforme (glioma), a highly malignant and lethal neoplasm of the brain, amplification of the EGFR gene leads to overexpression of the receptor and is associated with a number of mutations. The most common EGFR mutation in glioma is the de2-7EGFR, a 267 amino acid deletion of the extracellular domain (ECD) [7]. It is constitutively active, unable to bind known ligand, cancer specific, and is not detectable in normal tissue [8]. The clinical importance of de2-7EGFR is evident as its expression is closely linked to increased tumor aggression, invasion and poor prognosis for survival [7].
The antibody mAb806 which was raised against the de2-7EGFR, also binds the full length EGFR but only when it is activated through overexpression, mutation or autocrine activity [9,10]. Since the EGFR is not constitutively active in normal tissue, the mAb806 is cancer-specific. Epitope mapping has shown that the mAb806 epitope is located in short cysteine loop of the EGFR (amino acids 311-326) [11].
Recently, several novel glioma-specific missense mutations in the ECD of the EGFR were identified [12]. Two of these mutations, R324L and E330K, are located within or close to the region of the mAb806 binding site. Importantly, a similar corresponding region in ErbB2 has also been found to be mutated [13]. Given the location of these mutations and their proximity to the mAb806 binding site, we sought to understand the function of these missense mutations in NR6 cells as these do not express any ErbB family members. Interestingly, the N-terminus of the de2-7EGFR ECD also starts in this region and contains a free cysteine adjacent to the mAb806 epitope. Using the de2-7EGFR as a model we examined the role of cysteine residues in this region with respect to mutant EGFR activation.
2. Results
2.1. Expression of the ECD Mutations
The expression of two EGFR ECD mutants (R324L and E330K) was examined in a cell-free system and NR6 cells. The R324L mutation is located within the disulfide loop containing the mAb806 epitope and the E330K mutation is located within an adjacent disulfide loop. Characterization of the A289V has been reported previously [12] and was included as a control in several experiments.
The cell-free translation of mutant EGFR demonstrated that Mw and expression levels of the proteins were similar to the wtEGFR, indicating that the mutations did not affect translation efficiency (Figure 1A). Both the wtEGFR and mutant EGFR were expressed on the cell surface of NR6 cells as determined by Fluorescence Activated Cell Sorting (FACS) (Figure 1B). Since the mAb528 antibody is highly conformation dependant, its ability to recognize the mutants suggests that they are folded correctly. The mAb806 recognized a portion of the overexpressed wtEGFR as expected (Figure 1B), but a greater shift was evident for wtEGFR and A289V than the R324L or E330K mutants, suggesting that the latter two mutations may affect the binding of the mAb806. This was also observed in our Western analyses (Figure 1C) where mAb806 displayed reduced binding especially to the R324L mutation relative to wtEGFR (upper panel). Binding of a C-terminal EGFR antibody was unchanged (lower panel) when comparing the fully glycosylated upper EGFR band. Thus the R324L and E330K mutations are expressed on the cell surface and have a minor, but reproducible, impact on mAb806 binding.
2.2. ECD EGFR Mutations Are Constitutively Active and Retain Response to Ligand
To examine if the EGFR mutants were constitutively activated or could respond to ligand, Whole cell lysates (WCL) from transgenic NR6 cells were blotted with a panel of pY EGFR antibodies (Figure 2). Basal phosphorylation of the EGFR (Figures 2A and 2B) was enhanced in the absence of ligand stimulation for both the R324L and E330K mutants slightly at Y1173 (2 fold and 5 fold increases when corrected for total EGFR, respectively) and dramatically at Y992 (3 fold and 10 fold increases, respectively) relative to wtEGFR. Examination of the Y1086 and Y1148 sites also showed enhanced basal phosphorylation for the mutants, particularly R324L, relative to wtEGFR (Figure 2C). However, Y845 basal phosphorylation, a target of Src phosphorylation and not autophosphorylation, was only increased slightly (Figure 2C). EGF stimulation resulted in increased phosphorylation at Y1173 and Y992, the two sites examined, for both R324L and E330K (Figures 2A and 2B). Thus the R324L and E330K mutants are constitutively active and respond to ligand.
2.3. Downstream Signaling by EGFR Mutations
We determined if the EGFR mutations affected the activation of the extracellular signal-regulated kinase (ERK) 1/2 and Akt. Although ERK was phosphorylated in response to EGF stimulation (data not shown), basal levels of pERK were significantly decreased for both the R324L and E330K mutants compared to wtEGFR (P < 0.01 for both; Figure 3A). Basal pAkt:total Akt ratios were similar for wtEGFR and mutant EGFR (Figure 3B). These results suggest that these constitutively active EGFR mutants down-regulate pERK1/2 but do not activate Akt.
2.4. EGFR Mutations Bestow an In Vitro Survival Advantage to NR6 Cells
The survival of NR6 cells expressing the EGFR mutants was examined under serum-free and low serum conditions at various time points to determine any in vitro survival advantages. The NR6 cells expressing R324L showed enhanced proliferation within the first 24 h of culture (Figure 4A). Also, while the number of wtEGFR and A289V NR6 cells decreased substantially over 48 h in serum free conditions, the number of NR6 cells expressing either R324L or E330K remained steady (Figure 4A), indicating a retention of cell viability. When grown in 2% fetal bovine serum (FBS) over 96 h (Figure 4B), the cell numbers for the R324L and E330K mutants continued to increase and were significantly higher than the wtEGFR and A289V cells, which began to die, at the 96 h time-point. These data show that the R324L and E330K also provide a survival advantage to cells in low serum conditions.
The ability of the transgenic NR6 cells to form colonies in anchorage-free conditions was examined (Figure 5). All of the cells tested formed colonies, with the R324L mutant forming significantly more colonies than the other cell lines (P = 0.009; Figure 5). The E330K mutant did not form significantly more colonies than wtEGFR-expressing cells. When the data was grouped into the percentage of colonies greater than 120 μm (Figure 5B) and 150 μm (Figure 5C), it was clear that both the mutant EGFR-expressing cells formed colonies that were significantly larger in size than wtEGFR. Thus, the ECD EGFR mutations significantly enhanced in vitro survival in serum free conditions and soft agarose when compared with wtEGFR.
2.5. EGFR Mutations Increase Tumorgenicity of NR6 cells In Vivo
Transgenic NR6 cells expressing wtEGFR, R324L or E330K were injected s.c. into BALB/c nude mice and tumor development was followed for 50 days. Expression of the EGFR mutations in NR6 cells caused an accelerated growth rate over time compared to the wtEGFR (Figure 6A). The R324L and E330K tumors at day 40 were 4–5 times bigger than that observed for wtEGFR tumors (1.15–1.5 cm2 vs. 0.25 cm2 for the mutant EGFR and wtEGFR respectively). Examination of the tumor appearance after surgical resection revealed that the mutant EGFR tumors were bulbous and heavily vascularized, whereas the wtEGFR tumors were flat, pale and possessed little vascularization (Figure 6B). These results show that the R324L and E330K mutants conferred a significant growth advantage and enhanced tumorgenicity of NR6 cells in vivo.
2.6. de2-7EGFR Undergoes Reduction-Sensitive Dimerization Utilizing a Free N-Terminal Cysteine
The de2-7EGFR truncation breaks the EGFR cysteine pairing of C295-C307 and removes the C295 residue, creating an unpaired cysteine at C307 (identified by us here as C16 in the mature de2-7EGFR sequence). This cysteine maps to the same region as our missense mutations. In addition, it is possible that this free cysteine could lead to dimerization and activation of de2-7EGFR via formation of an intermolecular disulfide bond. To investigate this, we mutated the C16 to serine (C16S) in the de2-7EGFR. Both the de2-7EGFR and the C16S were successfully expressed in U87MG cells (Figure 7). Under non-reducing conditions (upper left panel, Figure 7A), a de2-7EGFR dimer was clearly observed but was virtually absent in the C16S mutant even when the blots were overexposed (left panel, Suppl. Figure 1) proving that de2-7EGFR dimerization requires this free cysteine. Quantification of the dimer: Monomer densitometry ratios for total protein (lower left graph, Figure 7A) showed the de2-7EGFR dimer formed a high proportion of the total species (∼25%). As expected, the dimer disappeared in the reducing mAb806 blot (left panel, Figure 7B). When non-reducing blots were probed with the pY1173 EGFR antibody, the de2-7EGFR dimer was strongly phosphorylated whilst no phosphorylated dimer was detectable for C16S (upper middle panel, Figure 7A). Densitometry analyses confirmed that the de2-7EGFR dimer was the active form of the receptor as it was 4.1 times more intense than the monomer (lower right graph, Figure 7A). Reduction of the samples and probing for pY1173 showed that the overall phosphorylation of the C16S mutant was markedly decreased compared to the unmodified de2-7EGFR (middle panel, Figure 7B). These data demonstrate that the free cysteine created as a consequence of the de2-7EGFR mutation is critical for the formation and stabilization of the active de2-7EGFR dimer.
2.6. The C16S Modification Displays a Reduced Tumorigenicity In Vivo
In order to see if the ablation of the free cysteine in de2-7EGFR has any in vivo consequences, U87MG cells expressing unmodified de2-7EGFR or the C16S variant were injected s.c. into BALB/c nude mice and tumor development followed. The survival of each population was then compared by Kaplan-Meier survival analysis (Figure 7C). Animals injected with C16S variant survived significantly longer (P < 0.05) than those injected with unmodified de2-7EGFR, demonstrating that the reduction observed in in vitro activity translates into a reduced tumorigenicity in vivo.
3. Discussion
Glioma specific single point missense mutations in the cysteine rich region of EGFR near the mAb806 epitope lead to autoactivation and enhanced tumorigenicity. There were pronounced differences with respect to the tyrosine phosphorylation pattern seen for each mutant and neither R324L nor E330K strongly activated pY1173, previously identified as the key phosphorylation site for activity of the de2-7EGFR [14]. This suggests that clonal selection within the tumor might result in EGFR mutations with differing signaling properties. The preponderance of ECD mutations in glioma, in contrast to the kinase mutations that dominate lung cancer, further supports the idea that mutations arise in a context specific manner. Both mutants, but especially E330K, showed increased phosphorylation at Y992. Phosphorylation at this site reduces ligand-induced receptor endocytosis, increasing the lifetime of the activated receptor in the plasma membrane and therefore enhancing signaling capacity [15]. Recently, an Akt-independent PLCγ-PKCα-mTOR pathway was identified in glioma [16]. It is possible that our mutations preferentially activate this pathway and may partially explain the lack of Akt activation. The decrease in pERK mediated by the R324L and E330K mutant is consistent with recent findings showing pERK is negatively correlated with de2-7EGFR [17].
Various reports suggest that the de2-7EGFR only forms transient homodimers [14,18,19]. An early publication showing robust dimerization of de2-7EGFR has not been reproduced [20] and a second paper reporting significant dimerization used non-physiological conditions including a lengthy purification [21]. However, de2-7EGFR homodimers must exist as auto-phosphorylation of the EGFR always occurs in trans through the formation of an asymmetric dimer [22]. Indeed, we used differentially tagged de2-7EGFR molecules to demonstrate this transient interaction [18]. Using the drug iodoacetamide during lysis to protect disulfide bonds, we could reproducibly show significant levels of dimerized de2-7EGFR. Importantly, detection of the de2-7EGFR dimer in our system was totally dependent on the presence of the free cysteine at position 16. The previous confusion about the presence or absence of de2-7EGFR dimers seems to be caused by the use of differing techniques. Detection of these dimers requires the addition of reagents that protect the intermolecular disulfide bond as it appears extremely labile during cell lysis. Finally, the intense phosphorylation of the de2-7EGFR dimer, especially when the phosphorylated receptor is compared to total receptor (Figure 7), clearly demonstrates that this is the active conformation.
Unfortunately, while we were able to show that the missense mutations were present as dimers using the techniques described here (data not shown), we were unable to definitively determine their nature because of their low abundance and the presence of alternative inactive dimers as previously reported [23]. Also, the ability to mutate the exact cysteine residue in the de2-7EGFR made the definitive experiments relatively straight-forward in this receptor. Obviously this approach is not possible in full-length receptors. We have postulated that the region around mAb806 must be locally misfolded during receptor activation [10]. As noted, the R324L mutation is found within the mAb806 epitope and the E330K mutation is in the adjacent cysteine loop (Figure 8A). Our results show that these mutations cause conformational changes that enhance receptor activation in the absence of ligand. The R324L mutation abolishes two salt bridges with adjacent E317 and E319 residues. These salt bridges appear to stabilize the C311-C326 disulfide loop (Figure 8B). Their removal should increase the flexibility and dynamic behavior of the loop and place strain on the C311-C326 disulfide bond. This would make the bond more susceptible to breaking and possibly prevent its formation, leaving a free cysteine for intermolecular bonding as for the de2-7EGFR. Indeed, the cysteine at 311 is only a few amino acids away from the free cysteine in de2-7 EGFR which is cysteine 307 (or C16 in the de2-7EGFR). Molecular modeling has suggested that a G336R ECD mutation found in zebra fish EGFR also disrupts a nearby disulphide bond resulting in the formation of disulphide linked homodimers [24]. Taken together these results suggest a general mechanism of activation, whereby mutations in this cysteine rich region lead to disruption of disulfide bonds which become available for stabilizing dimer interactions.
Mutations in other RTKs have been shown to create free cysteines that mediate receptor dimerization. The ECD mutations W290G or T341P within FGFR-2, which are directly linked to the initiation of Crouzon and Pfeiffer syndromes, release a free cysteine by disrupting a nearby intramolecular disulfide bond, triggering intermolecular bonding, activation and conferring tumorigenic properties in NIH3T3 cells [25]. Other examples of free cysteine-linked activation include the R129C ECD erythropoietin receptor mutation [26,27], C342Y ECD FGFR-2 mutation [28] and the c-RET MEN-2A ECD germline mutation C634R [29]. All of these mutants are dimerized, constitutively active and directly linked to induction of various diseases or cancers.
4. Experimental
4.1. EGFR Numbering
Through-out the paper we have numbered EGFR based on the initiating methionine, as per the original mutation paper. However, numbering of phosphospecific antibodies is based on the mature EGFR as per common use. The difference between the two numbering formats is 24 amino acids.
4.2. Antibodies and Reagents
mAb528 and mAb806 were produced and purified at the biological production facility at the Ludwig Institute for Cancer Research, Melbourne, Australia. The anti-C-terminal EGFR mAb R13 was from BD Biosciences (San Jose, CA). The anti-C-terminal EGFR polyclonal antibody 1005 and the Protein A/G beads were from Santa Cruz Biotechnology (Santa Cruz, CA). All anti-phosphorylated EGFR antibodies (pY845, pY992, pY1068, pY1086, pY1148 and pY1173), as well as the anti-mouse IgG conjugated to Alexa Fluor 680, were from Invitrogen (Carlsbad, CA). The anti-phosphorylated Y1173 EGFR (clone 53A5) and the anti-β-actin polyclonal were from Cell Signaling (Danvers, MA). The anti-pan actin mAb ACT05 was from ThermoFisher Scientific (Waltham, MA). Horse radish peroxidase (HRP)-conjugated anti-mouse or anti-rabbit secondary antibodies were from Millipore (Billerica, MA). Anti-mouse IgG whole molecule-R-phycoerythrin (PE) conjugated secondary antibody, human recombinant EGF and iodoacetamide were from Sigma Aldrich (St Louis, MO). Anti-rabbit IgG polyclonal antibody conjugated to IRDye800 was from LiCor Biosciences (Lincoln, NE). Site directed QuikChange mutagenesis XL kit was from Stratagene (La Jolla, CA). All primers were synthesized at Sigma Aldrich or at Micromon (Monash University, Clayton).
4.3. Cell Lines
The human glioma cell line U87MG (HTB-14) and the human epidermal carcinoma cell line A431 (CRL-1555) were sourced from the American Type Culture Collection (ATCC, USA). The NR6, U87MG.Δ2-7 and U87MG.EGFR cell lines have been described by us previously [30]. The NR6.EGFR, NR6.A289V, NR6.R324L and NR6.E330K cell lines were constructed as follows; mutations were introduced into the EGFR ORF, subcloned in pGEM-4Z (Promega), by site-directed mutagenesis using the primer sets detailed in Suppl. Table 1. Next, the mutant EGFR ORF's were cloned into the pBABEpuro retroviral vector and transfected into a viral packaging cell line using Fugene (Roche), with subsequent viral supernatants used to infect NR6 cells. Transfected cells were selected in the presence of puromycin (2 μg/mL) and surviving cells FACS sorted for high EGFR expression using mAb528.
The U87MG.Δ2-7C16S cell line was constructed using primers detailed in Suppl. Table 1 and site-directed mutagenesis to incorporate a Cys-Ser mutation at amino acid position 16 (the equivalent amino acid is C307 in wtEGFR) within the de2-7EGFR ORF also using the pBABEpuro retroviral vector. Cells were FACS sorted with mAb806 to obtain a surface expression level similar to U87MG.Δ2-7. All cell lines were maintained in DMEM/F12 containing 5% FBS, 2 mM Glutamax and 100 units of penicillin/streptomycin in the presence of suitable selective drug.
4.4. In Vitro Cell-Free Protein Expression
EGFR-related cDNA's were translated into 35S-cysteine labelled proteins from pGEM-4Z using the TNT-coupled reticulocyte lysate kit according to manufacturer's protocol (Promega, Madison, WI).
4.5. Fluorescence Activated Cell Sorting (FACS) Analysis
2–3 × 105 cells were incubated with the indicated antibody at 10 μg/mL in 0.1% human serum albumin/PBS (HSA-PBS) for 1 h at 4 °C and then incubated with 1:20 anti-mouse IgG-PE secondary antibody in HSA-PBS at 4 °C for 30 min. Cells were resuspended in FACS fix solution (PBS; 3.2% D-glucose; 1% formaldehyde) and run on a Guava flow cytometer (Millipore).
4.6. Immunoprecipitation and Western Blotting
Immunoprecipitation of EGFR from 1–3 × 106 transgenic NR6 cells was carried out essentially as previously described [30] using 1 μg/ml of mAb528 to capture the EGFR. Bead pellets after washing were resuspended in reducing LDL loading buffer containing 100 mM DTT. Reducing SDS-PAGE and western analysis were essentially as previously described [30].
4.7. MTS Cell Growth Assays
Transgenic NR6 cells expressing wtEGFR or mutant EGFR were seeded in triplicate at 5000 cells/well in 96 well plates and allowed to adhere overnight. Cells were washed in serum-free medium after which cells were incubated in serum-free medium at 37 °C, 5% CO2 for 48 h. At 0 h, 24 h and 48 h, MTS was added to the wells. After 3 h of incubation at 37 °C, the assay was read at 490 nm using a FLUOstar Optima plate reader (BMG Labtech, Offenburg, Germany).
4.8. Anchorage-Independent Growth Assay
Using 6-well plates, a bottom layer of 0.8% low melting agarose (LMA) was made by combining equal quantities of melted 1.6% LMA and 2 × media (DMEM-F12; 10% FBS; 4 μg/mL puromycin). The top layer of 0.4% LMA was made by combining equal volumes of melted 0.8% LMA and 2 × media containing the transgenic cells, at 1000 cells/well. Plates were incubated at 37 °C, 5% CO2 overnight, then 500 μL/well of media was added and plates incubated for 20 days. Wells were washed twice with PBS and 500 μL of 1 mg/mL MTT was added for 24 h after colonies photographed and counted.
4.9. Dimerization Analysis of de2-7EGFR
This was conducted using an established protocol [31] with minor modifications. Confluent cells were harvested, washed twice in ice cold PBS (pH 8.0) containing 10 mM iodoacetamide and lysed in ice cold RIPA buffer [50 mM Tris (pH 7.5); 150 mM NaCl; 5 mM EDTA; 0.5% sodium deoxycholate; 0.05% SDS; 10 mM NaF; protease inhibitor cocktail set 1 (Calbiochem, USA); 200 μM Na3VO4; 10 mM iodoacetamide] for 10 min on ice. Lysates were sonicated and clarified at 21,100 × g for 20 min at 4 °C. Equal protein amounts, as determined by BCA assay (Sigma), were resuspended in either non-reducing Laemmli buffer or reducing Laemmli buffer containing 0.8 M of β-mercaptoethanol and analyzed by SDS-PAGE and western blotting.
4.10. Bioplex Assay
Transgenic NR6 cells plated at 2 × 105 cells/well were serum-starved for 24 h prior to stimulation with EGF at a final concentration of 100 ng/mL for 15 min, at 37 °C. Whole cell lysates (WCL) were prepared using Bioplex cell lysis buffer (BioRad, Hercules, CA) and pAkt and pERK1/2 were quantified according to the manufacturer's instructions.
4.11. In Vivo Xenograft Models
2 × 106 transgenic NR6 cells in PBS were injected subcutaneously into both flanks of six week old female BALB/c nude mice. Tumors were monitored and measured as previously outlined [30]. This research project was approved by the Animal Ethics Committee of the Austin Health, Heidelberg, Australia.
5. Conclusions
Our previous studies with mAb806 have clearly identified a critical role for the cysteine-rich region around amino acids 311-326 in EGFR activation [10,11]. We now show that glioma-associated missense mutations in this region lead to ligand independent activation of EGFR. Significantly, a recent report identified activating mutations in the same cysteine rich region of ErbB4 in melanoma [32]. These studies and our current observations strongly suggest that local misfolding in this cysteine rich region is important to EGFR activation. Ongoing studies into the nature of this local misfolding, and the potential role of transient disulfide bond cleavage, should be informative with respect to the mechanisms associated with activation of the ErbB family.
This work was supported by the National Health and Medical Council of Australia (Program Grant 280912), the James S. McDonnell Foundation (#220020173), a research grant from Amgen Inc and the Victorian Government's Operational Infrastructure Support Program. T.G.J is a recipient of a Clinical Fellowship from the Victorian Cancer Agency.
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Supplementary Files
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Made to be loved, cherished and to stand the test of time, these dolls are absolutely perfect for every age. Suitable from birth, our gorgeous rag dolls are made from poly-cotton with recycled polyester wadding. Dressed in a white dress adorned with pink flowers, with a striped waist band and tights. This adorable keep-sake features brown hair bunches with striped bows and pink shoes. Our adorable dolls can be personalised for someone special, making the perfect gift for any little girl.
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Marcy Coate
Hi! My name is Marcy Coate. I enjoy creating clipart and digital designs for the web, digital scrapbooking, hybrid scrapbooking, paper crafts and printables. My designs reflect my life-long love of crafts and sewing. I particularly enjoy playing with colors and textures to create unique products that will make your life more beautiful. My customers and subscribers are very important to me, so if you have any design requests feel free to send me a message or post your request on my Facebook Page.


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Passionately Helping Accident Victims in Luzerne County, PA
At Rogan Law, a personal injury lawyer can meet with you to review your claim, advise you of your rights, and explain your legal options. With the help of an expereienced Scranton personal injury attorney at Rogan Law, you can file a lawsuit against the person responsible for your injuries, and seek damages for your pain and suffering, emotional distress, medical expenses, future medical bills, lost wages, and decreased enjoyment of life.
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(First of all, thank you all so much for your feedback on my Negative post. I debated on whether or not to post it, mostly because it reveals that as much as I struggle against it, I still wrestle with fear. Sharing that goes against my natural tendency to package myself up a lot more neatly than that, but my ever-growing desire to be real and unpackaged won out. For those who have asked, I may test again, but it could really all just be me misreading my body's signs.)
So, going back to my problem with Stuff. And how God is dealing with me about Stuff. And how I want to be free from my bondage to Stuff.
As my dear friend Shaila would ask, What does that look like? Freedom from stuff? And how can I connect that to my desire to leave behind a more gentle impact on this planet?
Most of the time, I'm all about big ideas and little follow-through. I find big change to be more manageable in small steps. So I wanna break this down into something that is real and lasting. Each week, let's talk about some ways we can live Another Way. A way that is outside the consumerist paradigm. A way that speaks of financial integrity and resource responsibility. A way that make us, yes, a little uncomfortable, but perhaps also encouraged that if a lot of us make some little changes, something bigger than ourselves might take place.
My first Another Way Wednesday challenge to myself - *deep breath* Buying mostly (if not all?) gently used children's clothing.
This is huge for me, girls. Huge. Oh gosh, this is about to get ugly. You might wanna hide your eyes. But there is this awful, vain, shallow voice somewhere in my mind that has been known to say disdainfully, "But your girls deserve better than that!" Yuck. There is just no way to package that. It's as ugly as it is true.
To be given gently used clothes? Sure, I'll take 'em! (Seriously, if you're reading Ali, I'll take anything you clean out from your girls' closets!) But to intentionally buy used clothes? My pride . . . it wants to stand up and say NO!
But watching the Story of Stuff movie challenged me on that. I have shopped at Once Upon a Child and The Children's Orchard and there is really cute, nice, unstained and untattered clothing to be found. There really is no reason I have to keep feeding into this broken consumerist system by buying brand new clothing for the girls when I can buy clothing someone else's little girl has already broken in. And you know, this is the time to begin training my girls in a different way of looking at clothes shopping, one that might help to ward off future self-esteem problems caused by materialism. And maybe discourage any training I might unintentionally but inevitably be doing to cause them to have their own problems with Stuff.
The timing is right for me to take on this first challenge to myself because D really does need clothes as she woke up one morning having outgrown her 3Ts. The grandparents were generous with birthday money and mama needs to go shopping. Just not *gulp* at The Children's Place.
So, how about you? Anyone wanna start down Another Way path? If changing your clothes shopping ways isn't where you want to start, maybe you could check out this article my sweet reader Elizabeth emailed me about Green Grocery Shopping. Or check out Jen's list of her goals.Whatever small steps you are taking, I want to hear about it! Share in the comments or link me to your own Another Way post(s).
Labels: Another Way, general natural family living, stuff


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Tee-off in this fantastic free golf game for real courses, real-time multiplayer duels, tournaments and our unique Golf Royale mode!
Red Riot, your mission is to destroy the enemy flying drones, tanks, radar towers and more. Go through multiple mission-based scenarios and upgrade your super powers – increasing damage and versatility – while laying waste to everything around you.Help
There are 3 awards in Red Riot. View All Awards


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August 26, 2010
Sundance Institute Composers Lab: Park City, UT
Sundance Institute Composers Lab - August 11-26, 2010.
Six composers have been selected as Fellows to the Sundance Institute Film Composers Lab. This year's Composers Lab Fellows are Sherri Chung, John Hancock, Mark Orton, Arturo Rodriguez, Kareem Roustom, and Rani Sharom. Composers Tyler Bates, George S. Clinton, Randy Edelman, Blake Neely and Aaron Zigman and director Kasi Lemmons are this year's Creative Advisors.
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Each week, Learn, Listen, Watch, Discover and Share with BMI! From must-see videos, to creative inspiration and dynamic playlists we're excited about, BMI's The Weekly is dedicated to delivering specially curated content designed for music creators and music fans alike!


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Seven Questions for Arem Duplessis, Design Director of The New York Times Magazines (All of Them!)
Among our first priorities on any Saturday is opening the door to UnBeige HQ and locating our freshly delivered copy of The New York Times, bloated with all manner of colorful weekend inserts. We shuffle furiously through the Best Buy circulars and Macy's coupons to find The New York Times Magazine (and, if we've been especially good that week, T: The New York Times Style Magazine as well), and it's distinctive cover has a way of setting the tone for the weekend, whether with exploding produce, a gilded manhole cover, a killer sugar cube, or most recently, conjoined twins that may share a mind. Meanwhile, the creative mind behind all of the New York Times magazines is award-winning design director Arem Duplessis, a veteran of Spin, GQ, and Blaze. He made time to answer our seven questions, and we detected a pleasing ocean/aquatic theme to his answers, which include mentions of drowning and sharks!
1. You'll be presenting at next week's ABSTRACT Conference in Portland, Maine. Can you give us a sneak preview of your talk?
I'll be discussing our new content and our most recent redesign. How we approach design problems, and more importantly how we solve them.
2. What is your greatest graphic design or publication design pet peeve?
Magazines that are so clearly design derivatives of other magazines. A successful magazine/brand has an immediate identity that belongs to them. We all "borrow" from time to time but when it's so bad that you cannot even tell which magazine you are in, there's a real problem.
3. What is your best or most memorable design-related encounter?
A decade ago, I was on a shoot and was accused by an overbearing publicist of trying to "drown" her client. Literally. It wasn't the best moment, but certainly the most memorable.
4. What is your proudest design moment?
I once designed a poster for my wife for an anniversary present. It had some personal writing in it, and it made her cry and laugh all at the same time. Sappy I know, but I'm keeping it real here.
5. What's on your summer reading list?
I'm three-fourths of the way through The Man from Beijing by Henning Mankell
Demon Fish: Travels Through the Hidden World of Sharks by Juliet Eilperin
Guns, Germs, and Steel: The Fates of Human Societies by Jared Diamond
6. Last film you saw?
Adrift, which is fantastic. And just to be clear, the Portuguese film starring Vincent Cassel and Laura Neiva, not the shark movie…although I did see that one as well.
7. You have just received $100,000 that must be used for a single dream project. How would you spend it?
The appropriate answer would be that I would design a revolutionary iPad app that would make the world wonderful and happy but in reality…I'd buy a plot of land somewhere warm, right on the ocean, and spend the rest of my time dreaming about the day I can move there, build a little house and fish and dive all day. Selfish, I know.
Motion graphics by Erick Fletes


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As home and business owners, energy efficiency is our Holy Grail. We spend thousands of dollars on utility bills in the pursuit of powering our appliances, heating and cooling systems and electronics; among others.
We often blame external factors for higher than average electricity bills, rather than looking at ways to increase our home's energy efficiency. In reality, we can all realize increased savings simply by installing the proper insulation.
At Banker Insulation, our Lake Havasu City Insulation Contractors can insulate you from the elements by assessing whether or not your property has any air leaks as well as if you're lacking the proper amount of insulation.
The right kind of insulation with the right number R-value when installed correctly in the right region for that value will boost your property's energy efficiency and significantly increase your comfort; not to mention your savings.
The importance of increased sound control, energy efficiency (see the pattern?) and moisture control is critical. You need these benefits for your home to remain comfortable and function at its best.
High quality insulation materials such as fiberglass, cellulose, spray foam and rigid foam can provide you with all of the above benefits and more. They all have their own set of advantages and disadvantages, which is something your contractor will discuss with during assessment.
Hiring the right insulation contractor in Lake Havasu City can make all the difference on a project. Our skilled contractors wish to provide you with best commercial insulation services regardless of your project's scope. We service:
We take great pride in meeting and exceeding all of your insulation needs by providing you with high quality and professional services. With a wide variety of insulation products and services, we are your one stop shop for insulation. Contact Banker Insulation at (928) 680-4888 to get insulated today!


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People are funny. And they don't necessarily respond in ways that academics and experts might predict, particularly when it comes to health issues. I'd like to discuss three recent counter-intuitive or paradoxical results in health policy. I don't have a good explanation for these results — but neither do the experts. But these results do suggest that we should be cautious about predicting health outcomes, even when (or especially when) an expected outcome seems intuitively obvious.
The three paradoxical results are as follows:
1) If you have a serious heart problem, you might be better off not being treated by the top experts.
In 2014, Dr. Anupam Jena and colleagues studied what happened to heart patients if they needed emergency treatment during the weeks that top cardiologists were away at one of the two big national cardiology conferences vs. the other weeks of the year.
To their surprise, they found that survival rates were higher for high-risk patients who suffered from cardiac arrest or congestive heart failure during the times the top doctors were away. In general, the patients were being treated by more junior physicians than on the weeks that the top doctors were in town.
Ars Technica writer John Timmer summarizes:
At teaching hospitals, the rate of death after heart failure was 24.8 percent on non-meeting days. While the cardiologists were out of town, it dropped to 17 percent. A similar trend was apparent with cardiac arrests, where death rates fell from 68.6 percent to 59 percent while cardiology meetings were happening. There was no significant difference with acute myocardial infarction patients.
So, having specialists in town appeared to make matters worse for patients — the exact opposite of the hypothesis the researchers set out to examine. The various controls suggested the effect was robust, and it persisted after adjusting for other potential influences, like age and sex.
The reasons for this difference aren't clear, although some speculate that the more junior doctors may be less aggressive about certain advanced invasive treatments, and this may actually be better for patients.
2) Increasing Medicaid insurance coverage doesn't decrease utilization of emergency rooms by the previously uninsured.
In 2008, the state of Oregon expanded Medicaid coverage for low-income adults. But because they couldn't afford to cover everyone who qualified, they took the unusual step of holding a randomized lottery to offer coverage to as many people as the budget allowed. In effect, the state of Oregon created an inadvertent "natural experiment" that would allow health policy researchers to track medical utilization and outcomes between identical groups of people who differed only in whether they had Medicaid or were uninsured.
One of the big surprises was that now-insured Medicaid patients continued to use the emergency rooms (ERs) as heavily as the uninsured patients.
This result is important because one argument for providing "universal" coverage is that giving patient insurance would allow them to see their own personal physicians for non-emergency care, rather than relying on the ER.
(ERs are typically the health providers of last resort for many uninsured patients. ERs are legally required to admit and evaluate all patients regardless of ability to pay, at least long enough to assess if they are stable to be treated elsewhere. This results in tremendous overcrowding of ERs, as well as increasing global health spending. ERs are specialized to provide acute care for serious problems, and are a very expensive way to provide non-urgent primary care services.)
Many experts expected that increasing Medicaid coverage would reduce ER utilization and decrease ER-related costs. But that didn't happen. And experts don't really understand why.
(Other paradoxical results from the Oregon experiment have also spawned broader debates over the merits of government health insurance. For some typical commentary from the political Right and Left, see "Oregon Study: Medicaid 'Had No Significant Effect' On Health Outcomes vs. Being Uninsured" by Avik Roy and "Here's What The Oregon Medicaid Study Really Said" by Ezra Klein.)
3) Using a wearable fitness device doesn't make you more fit.
Writing in the New York Times, Dr. Aaron Carroll described a recent weight-loss study where patients were all put on healthy diets, given weight loss counseling, and advised to exercise more.
But here's the twist:
[H]alf were also given wearable tech devices that monitored their activity and connected to a website to help provide feedback. All participants were followed for 18 more months.
At the end of the two years, which is pretty long for a weight loss study, those without access to the wearable technology lost an average of 13 pounds. Those with the wearable tech lost an average of 7.7 pounds.
Dr. Carroll emphasizes:
It's hard for many to accept, so I'm going to state the results again: Those people who used the wearable tech for 18 months lost significantly less weight than those who didn't.
Furthermore, Dr. Carroll notes, "[T]hose who employed the technology were no more physically active than those who didn't. They also weren't more fit."
So if you want to lose weight, the study authors conclude, "Devices that monitor and provide feedback on physical activity may not offer an advantage." In other words, wearable fitness monitors may lighten your wallet, but may not make much difference in lightening your weight.
I don't have a good explanation for these three paradoxical health results. And neither do the experts. So it's hard to draw definitive conclusions.
But these paradoxes do increase my skepticism that experts can reliably predict how health outcomes will be affected by expert medical staffing, government health programs, or adoption of new technologies. Those who advocate more central planning in health policy might wish to keep these lessons in mind, before proposing "obvious" ideas to improve Americans' health. People are funny, and they don't always respond the way experts might predict.
I am a physician with long-standing interests in health policy, medical ethics and free-market economics. I am the co-founder of Freedom and Individual Rights in Medicine…
I am a physician with long-standing interests in health policy, medical ethics and free-market economics. I am the co-founder of Freedom and Individual Rights in Medicine (FIRM). I graduated from University of Michigan Medical School and completed my residency in diagnostic radiology at the Washington University School of Medicine in St. Louis (where I was also a faculty member). I'm now in private practice in the Denver area. All my opinions are my own, and not necessarily shared by my employer.


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In the last post on building fences we talked about the physical and psychological barrier we want to build between ourselves and our opponents. This time let's talk about what we are prepared to do once they attempt to cross this barrier.
Folks will often begin to ask all the "what if" questions at this point however, my question to them is; have you done everything a reasonable person can expect you to do to avoid, deter and deescalate this situation? Is there an imminent threat of serious bodily injury or death? If the answer to either of those questions is yes then there is no what if. The time to have talked to an attorney regarding a plan for the legal battle after the physical battle was long before you found yourself in a fight for your life. There is no time now for second guessing, which is why I can't stress enough; talk to an attorney immediately if you haven't already. You need to understand the in's and out's of the fight on every level so you can move with audacity and abandon when the time comes. Okay, with that out of the way…
I'm a big fan of going to a weapon as soon as possible during a violent criminal encounter. No ands, ifs, or buts. We have to understand this isn't an honorable match or duel. We're dealing with violent criminal actors who have chosen to commit a violent criminal act against us.
One of the benefits of having opposable thumbs is the ability to use tools to achieve our objectives. In a violent criminal encounter our objective is to keep them away from us and disrupt their ability to function long enough to allow us to get away. We don't need to win, we need to survive. This means breaking contact as soon as possible and getting the heck out of there. The first tool I recommend to everyone is Red Sabre Spitfire or something similar. Easily palmed so you can have it in your hand as you verbally engage your opponents .
This is how I regularly carry mine. I grab it with the spray ready to rock. Craig Douglas refers to OC as an "eyejab in a can" for good reason. This stuff is HOT. You can hold this in a more discreet manner if you'd like, this is just a way I've found to work fairly well. Aim for the forehead but even getting close to the face with this stuff is going to be a distraction for the opponent. Keep in mind you will also be affected, just not as bad. Indirect exposure can be a bear but you're tough and you'll fight through it.
Another tool I like for this range is impact weapons. Saps, jacks, and improvised impact weapons will do the trick here. This is where all your time in the gym lifting heavy things in a ballistic manner comes into play. The ability to generate force and do so repeatedly is going to help us immensely now. Also the time you've invested in full contact stick fighting will give you a superior sense of distance, timing, power generation, and weapons familiarization. Take a moment and look around you. Do a quick inventory of all the improvised weapons available to you. If something happened right now what would you pick up and how would you use it? This is a simple mental exercise you can do regularly as you go about your day. You might be surprised at how easily and quickly you can arm yourself. If you can't recognize items you could use as an improvised impact weapon or you're not sure you have the ability to use an impact weapon, fix that ASAP. We don't get to choose where the fight goes but we can train to have the skills to handle whatever is thrown our way.
Next post we'll get into in-fight access of edged weapons and firearms. Until then focus on the positive, train hard, and stay dangerous.


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home: nice price [ Kenwood Stand Mixer ]
This week there are bargains galore leading up to and including Friday – thanks to us borrowing the American idea of a one off huge sale day 'Black Friday' – which seems to have grown to a week and even a fortnight with some brands.
It's not the nicest invention for small brands who can't compete with big brands on discounts and lose custom, but also leaves brands who have huge discounts with little or no profit – but it without a doubt for the consumer a day to grab a bargain. However it's only a bargain if you actually needed it in the first place.
Electronics and appliances are the best products to take advantage of on such a day and our NICE PRICE find is this Kenwood Stand Mixer with a huge discount at Amazon
They say;
If you're short of space or just starting out, you'll need a small and simple food mixer that does it all. Our Prospero compact food mixer is the ideal match – just perfect for small batches and everyday family use
The Kenwood Prospero Mixer will work hard for you, perfectly kneading, whisking, and beating the ingredients you need to create fabulous breads, cakes and pastries
Was £154.99 Now £74.99 saving £85!


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I hate to brag, really I do, but this year I made a major contribution to the world of crosswords. All I had to do was quit trying to make a major contribution to the world of crosswords.
It's a little humbling to realize that the best thing I could do was nothing, but that's exactly how it worked out. I started XWord Info in 2007 as an attempt to archive and organize NYT crosswords, highlight ones I thought were special, and run a few interesting statistical queries. The site was moderately successful, it got lots of traffic, and importantly to me, there was an effort to display each puzzle as close to the canonical print version as possible. No other site did that. No other site tracked puzzles by constructor either. There were plenty of other unique features.
Still, the site never really became part of the daily puzzle conversation. Bloggers and commenters mostly ignored it. Traffic was steady but stuck at around 2 million hits per month. Income was never quite enough for me to quit my day job. More importantly, it continued to be work. Will Shortz and his cadre of constructors kept innovating and XWord Info had to scramble to stay on top of each new wrinkle A small contingent of readers kept insisting on telling me my site sucked for one reason or another. I assured them the web had plenty of other URLs they would enjoy visiting.
Finally, I had enough. I wanted to go back to enjoying puzzles for their own sake, so I quit. More precisely, since a few people actually relied on the site to do their jobs for one reason or another, I announced the site was shutting down at the end of this year, giving them enough time to make alternate plans.
I got a few nice emails from people thanking me for the work I'd done and one or two from people who wondered if someone else could take over the project. The scope of XWord Info is huge, though, and it uses about a dozen different technologies. Nobody sane would want to dive in.
Enter Jeff Chen. He not only wanted to take it over but since he's a writer as well as a constructor, he wanted a forum to comment on each puzzle and saw this as an opportunity. Our conversation went something like this:
Me: So tell me, Jeff, what do you know about HTML5, CSS3, JavaScript, jQuery, jQueryUI, C#, SQL, or LINQ? What do you know about optimizing code for the disconnected HTTP protocol, about caching strategies and performance optimizations for complex websites, or about running a web service?
Jeff: Not much. But it's all just a big puzzle, right? I like puzzles.
I was sold. I handed the digital keys to Jeff, and let him run with it.
We have a shared OneNote where I write down ideas I think might be useful, and where Jeff keeps track of questions he needs to understand, but otherwise it's his show now, and I couldn't be more pleased.
My dry old site is suddenly vital. There are well over 9 million hits a month now. In my assuredly biased opinion, it has become the best crossword site on the planet. Jeff is an engaging new voice. He adds his own commentary to every puzzle from the perspective of someone who deeply understands and who deeply loves crosswords. On top of that, he has been able to get constructor comments most days as well. (One of the standard blogs has begun doing that too. I don't think Jeff intentionally copied that idea, he had talked to me about constructor comments from our earliest conversations, so it's rather a case of simultaneous invention.)
The site now combines many of the best features of a database and a blog. There are no reader comments and there never will be on XWord Info. I like to think that benefits the other blogs because readers who disagree with Jeff will have to go elsewhere to say so. WordPlay is the most likely blog to benefit. The vast majority of non-search inbound links come from WordPlay. Very few come from other blogs.
Even better, Will Shortz contributes his own thoughts to each puzzle. That turns out to be fascinating and unique and it will be the subject of my next blog post.


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How I learned to stop worrying and love Contra Dance.
This coming weekend is the Dandelion Romp—Oberlin's annual one-weekend Contra Dancing festival. It's been pretty much the highlight of my spring semester for the past three years, so in anticipation of all the dancing I'm going to do this weekend, I'm reflecting a little on where this whole dancing thing started for me.
I have never felt one with my body. Intellectually, when it comes to the mind-body problem, I'm a monist—I believe that there is no distinction between my mind and my body. And yet, in practice, I've always lived in my head, treating my body as some external object which I have only rudimentary power over, like an awkward puppeteer1. Before I came to college, I was convinced that I was incapable of displaying any rhythm or smoothness of motion. The extent of my social dancing experience was a few graceless school dances.
People who know me now might find this hard to believe. I dance all the time these days. I go to as many dances as I can fit into my schedule. But people who knew me back then can tell you it's true. When it came to dancing, I was awkward.
My friend Allison periodically reminds me that when we met freshman year in the 'Sco, I told her that I didn't know how to dance, but now that I was in college, I intended to learn. I don't remember what I was thinking in that moment, but I guess I meant it.
The first time I went Contra Dancing, I don't think I even took the beginner's workshop they offer at the beginning of each dance, though the charming and beautiful girl who had invited me showed me a couple moves beforehand. For this reason, I tell people that you don't really need to take a lesson—it's just one way to help you feel more comfortable on the dance floor.
People love to wear skirts while Contra Dancing because they twirl so wonderfully! Photo by Ma'ayan Plaut.
Despite skipping that lesson, I remember the feeling of wonderment that passed over me midway through the evening as I thought, "GOOD GOD, I'm dancing! I am actually making my body move in the way that I want it to." I still remember the amazement at discovering a dance that I understood—that I was not only capable of, but felt like it came naturally.
My two favorite dance forms these days are Contra and Blues, for similar—yet also opposite—reasons. Contra I love because you always know you're doing it right because there's a caller at the front of the room who is telling you what to do at all times. Blues I love because you always know you're doing it right if you're dancing to the music. I could write a whole separate love post about Blues, but Aries has already done so2. As she says, "There are gentle suggestions of what might work, but in the end of the day, you make the rules."
Contra is more approachable than blues for most beginning dancers because you don't have to make things up unless you want to. As you gain experience you'll find that you can add in plenty of your own flourishes to make things fun, interesting, and your own—but when you're just starting out it's sufficient to follow directions.
I've progressed3 a lot since that first dance. Though I still feel that body-mind disconnect, it's less when I'm dancing. I've moved from Contra into other forms of dancing4. And in the Contra community, I'm a caller now as well as a dancer, not only better puppeteering my own body, but helping to orchestrate the entire room in dance.
Sometimes I make ridiculous faces while I dance. Also, check out Aries glancing worriedly in the other direction. Photo by Ma'ayan Plaut, from the Dandelion Romp last year.
As part of this role, I've also been the instructor for those short beginner workshops (yes, the one that I myself skipped the first time I went dancing) and I'm discovering how difficult it is to explain what Contra is and how it's done. It's nearly impossible in words (though I've read some very valiant and funny attempts) but even with the people right there and the ability to walk them through moves, I can tell that they don't quite get it until the music has started and the dance has begun.
My task, then, if I'm not to teach them how to dance, is twofold: 1.) to persuade them that Contra dancing will be an enjoyable experience for them—that they really should stick around after the lesson and try it out and 2.) to make them more comfortable on the dance floor. Once they're on the dance floor, the dancing will speak for itself.
If I'm not going to explain to you what Contra Dancing is, at the very least I can give you some idea of why I love it. To me, these are the important points of Contra:
- There is always someone telling you what to do. As a beginner, this is reassuring. As an experienced dancer, this is not stifling—you can always progress your technique and there are an infinite number of flourishes and variations that you can throw in.
- Contra is the most social of social dances. It is the only form of dance where I can virtually guarantee that you will have danced with everybody in the room by the end of an evening. You will meet a lot of people.
- There's always a live band.
- Contra dancers, in my experience, are some of the friendliest, most unpretentious people I have ever met. We're very welcoming to beginners and everyone always takes it in stride when someone makes a mistake. Experienced dancers are almost as likely to make a mistake as beginners and it's never a big deal.
- Contra dancing breaks barriers of all sorts. At Oberlin the dancers are largely students, but there are more than a few regulars from town as well as the occasional faculty/staff. President Marvin and Amy even show up from time to time. (Amy, incidentally, is a great dancer.)
This year's Dandelion Romp poster. Bet you can guess who made it.
The Dandelion Romp starts this Friday evening. As special as Oberlin's monthly Contra Dances are, the Dandelion Romp is more.
We bring great bands and callers from out of town—who are always outstanding. Lots of out-of-towners come visit for the weekend. Many of them (both the attendees and the musicians) are Oberlin alumni. Some are from such far off locales as Maine, Virginia, and Washington state. One of the band members this weekend is even coming all the way from Ireland!
There will be three dances and numerous dance and music workshops such as "Scandinavian Turning Dances," "Gender Bender Contras," and "Shapenote Singing." If you're in town, check the website for the schedule. We'll dance.
Happy dancers at the Dandelion Romp. Photo by Ma'ayan Plaut.
This is how deep my disconnect with my body goes:
Once, at an informal contact improv workshop, the instructor was using me to demonstrate some position, but my body was not cooperating. "Relax your arm," she said to me. I relaxed my arm. Or so I thought. "Relax it," she said.
"It is relaxed!" I replied.
"No," she said, "It isn't." I looked over as she tugged on my arm and to my surprise, she was right. My elbow joint was totally tensed up. Embarrassed, I relaxed my arm, this time for real. ↑
Aries actually also already wrote a post about Contra, but I couldn't stop myself from writing another. ↑
This is a Contra Dance pun. Learn to Contra Dance and you will get it. ↑
Waltz, polka, swing, and a little Irish set dancing, among others. After Contra and Blues, I highly recommend waltzing. So beautiful. 3/4 time feels like home to me.
Something interesting you learn about dancing when you do lots of kinds is how they're all connected. Besides skill in each dance contributing to skill in the others, many of them have some historical basis together. For instance, in Contra there's a move called a Petronella twirl, which involves spinning over one's right shoulder. In Irish there's a whole dance called Petronella which contains a similar move. There's clearly some historical connection in the dances' pasts. And did you know that early Swing clubs also played waltzes and Latin songs in addition to jazz tunes? No dance is an island. ↑
Responses to this Entry
A wonderful reflection on dancing. I agree that the contra dance community is amazingly warm and welcoming, not just at Oberlin, but anywhere. I am really looking forward to the Romp (What an understatement!)
If any prospective students reading this are going to be visiting April 16-18th, I strongly recommend coming to the Dandelion Romp. It was the highlight of my revisit experience.
Posted by: Nora on April 12, 2010 5:09 PM
You chose some of my favorite contra dancing photos. This year I think I'm absorbed with the design dysprosium for most of it, but Daniel will be there practically the entire time.
And I'm completely in love with the poster this year, by the way.
I loved reading this. Things that involve dancing exude love and adoration :)
Posted by: Ma'ayan on April 12, 2010 8:55 PM
When someone asks me what I'm doing this weekend, I'm going to send them this entry.
Posted by: Aries on April 13, 2010 10:16 AM
I didn't start contra dancing until about a year and a half after I left Oberlin, but this captures the experience pretty well.
I am hoping to get back for the Romp one of these years....
Posted by: Ryan on April 13, 2010 2:30 PM
Contra rocks !!!!! :)
Posted by: ricky on September 11, 2010 7:50 PM
Great post. It inspired me to share it in a post at the Country Dance and Song Society blog:
Max Newman
CDSS Youth Intern
Posted by: Max Newman on January 18, 2011 11:40 AM
Harris, this post makes me so happy. I think that when I look back on how I spent my time at Oberlin, contra dancing will be way up on the list.
Posted by: Anna V. E. on January 30, 2011 10:51 PM
Hey Harris, tis I- Tracy from the Flurry. Very cool that you have this blog. We seem to have much in common aside from contra; tea, for instance. I am going to sleep now, since I haven't yet. Later, I intend to read the rest of your blog. So much better than Facebook stalking, right?
Posted by: Tracy on February 21, 2011 3:58 PM


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One of the biggest tourist draws in the area will soon be welcoming a new addition. During the last round of Washington County Riverboat Grants, the Kalona Chamber of Commerce was bestowed with nearly $40,000 in funds to buy a new bus for their By-Ways Tour. They'll also be receiving matching $5,000 donations from the Kalona Historical Society and the Chamber of Commerce.
Norma Yoder with the chamber says the new step on bus will offer additional passenger room and will replace their current bus that has around 264,000 miles.
The By-Ways Tour is open April through October and follows country roads through Kalona's Amish country.


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La nostra storia
We are an international Think Tank focused
Founded in 1992, on initiative of a small group of intellectuals and professionals, as a research and study center oriented to international relations and economy, geopolitics and to promote international cultural exchanges and studies. The CSI is independent, free from religious or ideological constraints. Over the years the CSI has expanded its activities and interests towards innovative sectors of research and the promotion of new generations creating a permanent laboratory for training, the GeoLab (in 2007) and also expanding interests in the most innovative fields of study of humanities and social sciences: the applied neurosciences and integrated medicine. Today the CSI has some thematic sectors, each of which operates with a wide range of autonomy, by free initiative of scholars and researchers.
Read more about our themes of discussion and work.
The CSI has a wide range of themes of discussion and work that tries to face the modern world and its global challenges. Find out more about these themes.


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China defends deal to build 1000 MW nuclear plant for Pak
Tacitly confirming reports of signing of an agreement with Pakistan to build a huge 1000 MW nuclear power plant, China on Monday defended the deal saying that it confirmed to safeguards of the IAEA and rejected allegations that it has violated Nuclear Suppliers Group (NSG) norms.
Beijing: Tacitly confirming reports of signing of an agreement with Pakistan to build a huge 1000 MW nuclear power plant, China on Monday defended the deal saying that it confirmed to safeguards of the IAEA and rejected allegations that it has violated Nuclear Suppliers Group (NSG) norms.
"China has noted the relevant report," Chinese Foreign Ministry spokesman Hong Lei told a media briefing in Beijing on Monday.
He was replying to a question on reports from Washington that Beijing has secretly entered a deal with Pakistan to construct the plant at Chashma in Punjab province.
On allegations that the deal violated the norms set by 46-member NSG, which regulates the issues relating to nuclear proliferation and commerce, Hong said, "I want to point out that relevant cooperation between China and Pakistan does not violate relevant norms of the NSG."
In recent years, China and Pakistan have had some cooperation in the field of civilian nuclear cooperation, he said.
All this cooperation is for peaceful use and this cooperation is in compliance with our respective international obligations and subject to the safeguards of the IAEA, Hong said.
A Washington-based news report had said two days ago that China has secretly signed the deal to construct a new power plant at Chashma.
China has so far aided and assisted Pakistan in constructing four power plants at Chashma.
Chashma I and II were stated to be 300 MW each and as per the previous plans the III and IV were stated to have 340 MW each.
While I and II were already commissioned, three and four were expected to be commissioned in 2016.
It is not clear whether the 1000 MW reactor would be a fifth one to be constructed there or the third reactor would be upgraded.
Find latest and upcoming tech gadgets online on Tech2 Gadgets. Get technology news, gadgets reviews & ratings. Popular gadgets including laptop, tablet and mobile specifications, features, prices, comparison.
also read
Misbah-ul-Haq to step down as Pakistan chief selector, focus on role as head coach
Misbah accepted the dual role of head coach and chief selector last year, but he said he wants to focus on coaching the senior Pakistan team.
Zimbabwe coach Lalchand Rajput to skip Pakistan tour after Indian embassy in Harare requests his exemption
In head coach Rajput's absence, bowling coach Douglas Hondo would take charge of the team during the tour.
NBA: China state broadcaster CCTV hints Houston Rockets executive Daryl Morey 'paid price' for Hong Kong tweet
CCTV suspended NBA broadcasts last October after Morey tweeted "Fight for freedom, stand with Hong Kong", referring to protests Beijing calls separatist and seditious.


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Lego Compatible Building Bricks Set
My kids are huge fans of Lego's. They spend hours a week building different creations and are constantly begging me to get them more building bricks. This has gotten to be quite an expensive hobby with as many sets as Lego has come out with. I have purchased them other brands hoping that they would fit with their Lego sets and have had no luck.
I recently had the opportunity to work with a company called Click n' Play. Click n' Play sent me one of their Lego compatible building brick sets free of charge to review in my home in exchange for my honest opinion. The building blocks set currently retails for about $29.99. The building blocks set contains 1000 different building blocks. There is an assortment of 10 colors and 14 different shaped pieces.
The building bricks come in various colors and sizes that are guaranteed to fit tight and compatible with Lego and other major building blocks manufacturers. The kids were so excited when the mail man dropped off their latest addition of building brick and could not wait to get the bag open and start building. The building bricks are the perfect size and shape to match their other building blocks.
If you would like more information or to purchase the building blocks set, please visit the Click n' Play Website. Be sure to stay up to date on all of the latest news and products from Click n' Play by following their social media pages on Facebook. While you are there, be sure to follow Mommy and Baby Reviews on Facebook, Instagram and Twitter.
Disclaimer: (These bricks are not affiliated with or endorsed in any way by Lego, a registered trademark of Lego Systems. A special thank you to Click n' Play for sending Mommy and Baby Reviews Lego Compatible Building Bricks Set free of charge to review. Mommy and Baby Reviews follows all FTC guidelines. All opinions stated in our review are our own truthfully opinion and were not influenced by the sponsor or from getting the review product free of charge. We were in no way compensated for our review or opinion. Mommy and Baby Reviews only recommends products and services that we feel are a good fit for our readers.)