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Born and raised in New Orleans, I went to school at St. Edwards in Metairie, Rummel High and on to LSU. I have been living "On The Air" in New Orleans for 20 years.
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Pedicabs now in the Quarter but some aren't happy
by stevenew
posted Sep 22 2011 1:28PM
French Quarter buggy drivers and Taxi owners are upset after "Pedicabs'' began operating in the French Quarter last week. I know your thinking, what's a Pedicab'? Well it's people-powered transportation. It's a seat with a person pulling it on a bike. (See Below)
But as is NawLuns tradition is corruption a foot? A business owner who applied for permission to operate some of the vehicles is appealing to the New Orleans City Council, saying the lottery process used to award permits was flawed. The rejected applicant says in his appeal letter to the council that some permit winners used multiple applications and proxy applicants to increase their chances of getting a permit. The council first approved the concept of using the pedal-powered rickshaws in September 2010. But legislative and bureaucratic complications followed, delaying the awarding of permits for months…let me guess all this will wind up in court…for years. Same story over and over.
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Pedicabs now in the Quarter but some aren't happy
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My sister and I just spent two days on the French quarter and loved the pedicabs. The only draw back was the ride during tbe cool nights. We had jackets but not prepared for the breeze.
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The 20 best smartphones available to buy in the UK right now. The best phones you can buy in the UK - Best Android phones, best iPhones, best Windows Phones - best mobile phone reviews. Keep reading to find out what is the best phone of 2015. Updated on 24/8/15.
Smartphones are an important and personal tech purchase so at PC Advisor we review all the major handsets available to buy in the UK. Here we rank them into the 20 best smartphones of 2015. See also: What's the fastest smartphone of 2015: processor, web and graphics performance comparison
We test and review smartphones in-depth and here are the best of the best from all the operating systems including iOS, Android, Windows Phone and BlackBerry. We update this story all the time as we review the latest smartphones. See also: Best Android smartphones in UK: What's the best Android phone you can buy in 2015?
If you've visited this page in the past you may notice that we've cut the number of smartphone in the list. There are now just 20 to help you get a clearer and more concise look at the best phones on the market. (See also: best smartphones for business.)
Best phones list: Smartphones to look out for in 2015 UK
Although we've ranked the best smartphones which we've reviewed, there are some upcoming handsets to be aware of. Once we've had them in, tested them fully, and reviewed them, they are likely to make this chart. This means it might be worth holding off your purchase for a little while. Take a look at: The best tablets of 2015: What's the best tablet in the UK right now?
Many of the big name smartphones for 2015 have launch including the Samsung Galaxy S6, HTC One M9 and LG G4 - We should also have a review sample of the Sony Xperia Z3+ very soon. However, we're still waiting for the arrival of the iPhone 7 (or iPhone 6S) and Samsung Galaxy Note 5 (which will launch alongside the Galaxy S6 Plus) plus expect new Nexus devices from Google at some point, too.
Adding to the list are the OnePlus 2 which is shaping up to be quite the phone and Motorola will announce new devices just a matter of hours later. We're expecting new models of the Moto G and Moto X.
See also: best new phones you should be most excited about in 2015.
Smartphone material poll
Best phones of 2015: How to choose which phone to buy
One of the biggest things you need to decide when choosing a smartphone is which operating system to use. Although there are others around, it's best to stick with the big names including iOS, Android, Windows Phone and potentially BlackBerry. If you're already using one then it might be best to stay in that camp – especially if you've invested time and money in its apps. However, it's not difficult to switch so you should consider them all. Note there aren't any BlackBerry devices on the market at the moment which we think are good enough to make this list but check out our BlackBerry Classic review.
Design will come down to personal taste and most of the top smartphones now have a very thin and light chassis. The best smartphones typically use premium materials like glass, aluminium or even steel and on this front you're best off trying a phone out in the flesh to see whether it feels good for the size of your hand.
It's worth pointing out that only a handful of the best phones on the market come with a waterproof design. It's mostly Sony offering this feature across its Xperia Z range.
The screen size of a high-end phone is typically 5in or above with a key exception being the Xperia Z3 Compact. You're looking at a Full HD (1080 x 1920) resolution typically or even higher at Quad HD (1440 x 2560).
These days, all the best phones have decent processors and plenty of memory. Some may be quad-core with 2 GB of RAM while others are octa-core with 3 GB of RAM. Despite benchmark scores, you're typically going to get great performance from these devices - you tend to get what you pay for.
What is more important to look at is storage as once you run out, that's it. If you want to store lots of apps, photos, videos and music then look for a phone with plenty of internal storage – 64- or even 128GB. Less is ok but check for a microSD card slot meaning you can add more by buying and inserting a memory card.
When it comes to cameras, more megapixels is a good sign but isn't the be and end all so make sure you click through to our full review of each phone for our thoughts as well as sample photos and videos. See also: Best phone camera 2015.
Whether you care about it or not, the best phones will typically come with some additional hardware. The latest iPhones have fingerprint scanners, and so do many of Samsung's Galaxy phones which also often have heart rate monitors and even UV sensors. Lots of top phones have an IR blaster so you can control other gadgets around your home such as your TV. Audio fans will enjoy the stereo speakers of the HTC One M8 and M9 while Sony's Xperia Z3 range and some other phones offers High-Res playback support.
Battery life will no doubt be important to you and there are still only a handful of phones which come with wireless charging built-in making it easier to keep your handset topped up. Battery life varies from device to device, so click through to our reviews to see how they got on in our tests.
Best Smartphones of 2015: best phones reviews
20. Moto X (2nd gen.)
- Rating:
- Reviewed on: 13 October 14
- RRP: £420 inc VAT
The standard, non-customised Moto X is a desirable smartphone, but it's a little overpriced especially if you compare it with the Nexus 5. So Google's phone may lack the premium build quality and hi-res camera, but in most other respects it's a match for the Motorola at a significantly lower price. What makes the new Moto X really attractive is Moto Maker, as it's unlikely anyone else will choose your combination of customisations. (But it may also make it harder to resell when it's time to upgrade.) It's just a shame that Motorola decided not to add a microSD slot: there's no such thing as too much storage.
Read our Moto X (2nd gen.) review.
19. YotaPhone 2
- Rating:
- Reviewed on: 13 May 15
- RRP: £440 inc VAT
There are a lot of things to like about the YotaPhone 2 and we applaud the company for doing something different. The design is excellent and if you want a dual-screen smartphone this is the one for you (ie. don't buy the original). Although the concept works pretty well and there's potential for great battery life, there are a few downfalls. We're mainly disappointed by the slow nature of using the e-ink screen and the awful ghosting. The price is also a barrier (even at £440) and means it comes short of rivals in areas such as photography and storage.
Read our YotaPhone 2 review.
18. Sony Xperia Z2
- Rating:
- Reviewed on: 8 May 14
- RRP: £599 inc VAT
Although not much has changed from the Xperia Z1, the Xperia Z2 is another solid effort from Sony. The smartphone is a good all-rounder with a great screen, camera, build quality and performance. We just wish it wasn't quite so bulky.
Read our Sony Xperia Z2 review.
17. HTC Desire Eye
- Rating:
- Reviewed on: 5 November 14
- RRP: £399 inc VAT
We are thoroughly impressed with the HTC Desire Eye: it's fast, it's great value (assuming it comes in around £350), it has a nice screen and it sounds great. Better still, it makes you look pretty.
Read our HTC Desire Eye review.
16. Samsung Galaxy Note Edge
- Rating:
- Reviewed on: 24 February 15
- RRP: £650 inc VAT
The Galaxy Note Edge is one of the most interesting smartphones around and while the edge screen is genuinely useful at times, it also remains a slight gimmick. Hardware is top notch and although we dislike the faux leather, build quality is good. The Note Edge is big and expensive so it might be worth waiting for the next generation before taking the plunge.
Read our Samsung Galaxy Note Edge review.
15. Samsung Galaxy Alpha
- Rating:
- Reviewed on: 28 January 15
- RRP: £342 inc. VAT
This really is the Samsung iPhone, and the South Korean firm has done a fantastic job of it. By putting build quality before specification it has produced a truly desirable, premium phone with a mid-range price. And still the Samsung Galaxy Alpha is still astonishingly fast.
Read our Samsung Galaxy Alpha review.
14. OnePlus One
- Rating:
- Reviewed on: 20 April 15
- RRP: From £229 inc VAT
There are only two, possibly three, bad things to say about the OnePlus One, if you are happy to buy online direct from OnePlus. We wish there was expandable storage, and it's bigger than other smartphones with similarly sized displays. And if we are being really harsh, we would hope for a better camera. But at the price the OnePlus One is an amazing deal. It's a flagship smartphone for a mid-range price. Bargain. Get them while they are hot.
Read our OnePlus One review.
13. Google Nexus 5
- Rating:
- Reviewed on: 23 September 15
- RRP: £299 inc VAT
Google and LG have done a fantastic job with the Nexus 5, producing a very desirable phone at an outrageously low price. It's the best value-for-money smartphone out there right now. Note: Google is set to launch the Nexus 5X on 29 September.
Read our Google Nexus 5 review.
12. Sony Xperia Z3
- Rating:
- Reviewed on: 8 October 14
- RRP: £515 inc VAT
The Sony Xperia Z3 is undoubtedly a decent and desirable smartphone but Z2 owners will have little reason to upgrade unless PS4 Remote Play or High-Res audio are must-haves. In terms of the wider market, the Z3 is up there with the best and a solid choice even if it doesn't have the amount of bells and whistles which others do.
Read our Sony Xperia Z3 review.
11. Honor 6 (by Huawei)
- Rating:
- Reviewed on: 6 November 14
- RRP: £249 inc VAT
We're seriously impressed by the Honor 6 which costs just £249 while providing specs you would normally pay a lot more for. It has a decent 5in Full HD screen, high quality cameras, good battery life, 4G support, good performance, expandable storage and wireless features like NFC and an IR blaster. The microSD cards slot is limited to 32 GB and Emotion UI isn't the best Android software but these don't stop the Honor 6 being the best value smartphone around.
Read our Honor 6 (by Huawei) review.
10. Samsung Galaxy Note 4
- Rating:
- Reviewed on: 5 November 14
- RRP: £599 inc VAT
The Galaxy Note 4 is a bit of a handful and is rather expensive but lovers of the Galaxy Note range will likely be enamoured with this edition. It is, on the whole, a great device with plenty of power and features. As long as you're aware that you're buying a huge phone and will get the most out of what it offers. Otherwise a smaller and cheaper handset is probably a better choice – the Galaxy S5 or one of its rivals.
Read our Samsung Galaxy Note 4 review.
9. Samsung Galaxy S6 Edge
- Rating:
- Reviewed on: 23 April 15
- RRP: £760 inc VAT
The Samsung Galaxy S6 Edge is a beautiful smartphone, one of the most attractive but the design has flaws such as sharp edges. While a non-removable battery is an inevitable outcome, we're surprised about the lack of waterproofing and a microSD card slot. Hardware is strong with a gorgeous screen, fast processor and great all-round camera. The key point here is that while dual edge display sounds like an amazing innovation it has very limited in functionality so simply isn't worth the extra money compared to the regular Galaxy S6.
Read our Samsung Galaxy S6 Edge review.
8. HTC One (M8)
- Rating:
- Reviewed on: 8 April 15
- RRP: £550 inc VAT
Like the Galaxy S5 and Xperia Z2, the new HTC One M8 isn't a big leap compared to the previous model. What HTC has done is taken a great phone and made it better. The M8 looks and feels gorgeous and with important upgrades including a microSD card slot and an innovative camera. This is one desirable smartphone. The HTC One M9 is now available but the M8 remains a good choice since the 2015 model is very similar.
Read our HTC One (M8) review.
7. OnePlus 2
- Rating:
- Reviewed on: 7 October 15
The lack of NFC, a microSD card slot, a removable battery, and quick- and wireless charging means the OnePlus 2 is not a flagship killer. It does have some killer new features though, including USB Type-C, 4G dual-SIM support and some powerful hardware. At £289 (we don't recommend the 16GB OP2), it's an unrivalled deal if you can get hold of one.
Read our OnePlus 2 review.
6. Apple iPhone 6
- Rating:
- Reviewed on: 23 September 15
If you are an iPhone user, and you specifically want an iPhone to be your next smartphone, the iPhone 6 is great, but of course the iPhone 6s is even better. It's going to come down to budget ultimately, as the iPhone 6 is a brilliant iPhone that'll save you a few pennies if you're set on getting an Apple phone. It's a slick, well-built, beautifully designed handset. Performance is good, the display is good, and the iOS eco-system is, well, good.
Where the choice becomes more difficult is in quantifying the value of the iPhone 6 in the wider market. Step over to the Android world and you could get a similar experience with a better display for a price tag that's almost the same. And you could expand the storage in most cases. There is no question that these days there is better value in the Android world, but value isn't really the point with an iPhone.
Read our Apple iPhone 6 review.
5. HTC One M9
- Rating:
- Reviewed on: 21 April 15
- RRP: £579 inc VAT
The HTC One M9 is a genuinely desirable smartphone with the best design and build available in Android land, even with Samsung upping the ante. It's good to see the powerful Snapdragon 810 and more memory, however, some key hardware remains the same meaning M8 users are unlikely to be tempted to upgrade – and the old model is now an attractive buy at around £350. The fact the Galaxy S6 is the same price with more impressive specs is also not a good thing for HTC.
Read our HTC One M9 review.
- Rating:
- Reviewed on: 1 June 15
- RRP: £259 inc. VAT
When the LG G3 came in at under £500 we were impressed. A year on and a phone that packs amazing features including a Quad HD display and a camera with a laser auto focus is one of the bargains of the market. The LG G3 is surprisingly small considering the 5.5in display and we like the more premium design. It's another winner from LG, and well worth your consideration in 2015.
Read our LG G3 review.
- Rating:
- Reviewed on: 19 August 15
- RRP: £500 inc VAT
LG has gone down an unexpected route with leather models which we like apart from a couple of colours. The so called ceramic model will be cheaper but feels cheap and plasticky. On the whole, hardware is once again strong - particularly the camera - but not massively different from the G3 and has tough competition. We feel build quality could be better with a metal frame and dimensions going down, not the reverse. This is the flagship to go for if you want a removable battery and expandable storage but it's a shame to see features like wireless charging dropped. (Remember the G3 is now a steal at under £300 SIM-free and the OnePlus 2 is now here)
Read our LG G4 review.
2. Sony Xperia Z3 Compact
- Rating:
- Reviewed on: 6 November 14
- RRP: £349 inc VAT
The Xperia Z3 compact is great little smartphone offering pretty much everything available on the full-size Z3 (including PS4 Remote Play and High-Res audio) apart from a Full HD screen. The new design is thinner and lighter plus the display is bigger than previously. At £349, this is not only the best mini smartphone you can buy, it's one of the best smartphones around.
Read our Sony Xperia Z3 Compact review.
1. Samsung Galaxy S6
- Rating:
- Reviewed on: 12 August 15
- RRP: £599 inc VAT (32GB), £660 inc VAT (64GB)
Samsung's Galaxy S6 is the best Android phone of 2015 so far, although we've yet to see what's to come from the LG G4 and Sony Xperia Z4. It's fast, it's well built, it has a gorgeous screen and the software isn't overly intrusive. The fingerprint scanner is vastly improved, the heart-rate scanner a potential draw for some users, and the wireless- and fast charging welcome inclusions. We'd like to see the price come down (which we are sure it will) and it's a shame we've lost the removable battery, waterproofing and microSD support, but these are all things we can live with.
Read our Samsung Galaxy S6 review.

subset: commoncrawl


text:
Crystal Cross Bracelet
Try this Crystal Cross Bracelet. It is very elegant and stylish bracelet. Made not only for fashion but for expressing our faith in a simple way. Very reliable and fashionable.
Crystal Cross Bracelet
- CZ crystal cross bracelet.
- Accented in clear CZ on a stretch band for a better fit.
- Circumference: 2"
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Union is one of the best for making blended images and double exposure shots, but don't download it if you're not willing to put in the work.
Link-Union's Link-U Hybrid SmartCam presents a promising alternative to server-based data plans, and any potential power-outage or Wi-Fi connectivity concerns.
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The search giant responds to EU claims it abused its search dominance, saying regulators failed to consider the impact of rivals like Amazon and eBay.
A breach revealed last week affected more people and grabbed more personal information than previously announced, the American Federation of Government Employees said Thursday.
A new deal between the two companies will allow consumers in China to pair their Apple ID with the country's most popular payment card to make purchases on its App Store.
Teamsters urge Mark Zuckerberg to support effort to improve working conditions and provide a wage that allows drivers to live near their jobs.
Backed by many tech firms and the ACLU, the privacy law hits the books but doesn't apply to federal law enforcement authorities.
Starting October 9, music streamed from Pandora, iHeartRadio and Slacker Radio won't count against Virgin's prepaid data bucket.
Scientists catch an unusual shark that looks like a cross between a blobfish and an electric eel. No wonder the poor species doesn't go out in public much.
Samsung Pay is now available in the US. Here's how it works and what you need to use the mobile payment system.


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D.1.2. Changes in MySQL 5.5.25a (2012-July-05) Note Due to MSI restrictions, the MSI packages of MySQL 5.5.25a will treat the version as 5.5.26 internally; for example, as displayed by the Installation Wizard. MySQL itself reports the version as 5.5.25a; for example, if you check the value of the VERSION() SQL function or the version system variable. Bugs Fixed * A regression bug in the optimizer could cause excessive disk usage for UPDATE statements. (Bug #65745, Bug #14248833) D.1.3. Changes in MySQL 5.5.25 (2012-May-30) Note MySQL 5.5.25 is superseded by MySQL 5.5.25a due to a regression bug that can cause excessive disk usage (for details, see Bug #65745). Current users of 5.5.25: Monitor disk usage and upgrade to 5.5.25a as soon as that is made available. Users contemplating upgrades to 5.5.25: Defer and upgrade to 5.5.25a instead when that is made available. Functionality Added or Changed * Important Change: Replication: The SHOW BINARY LOGS statement (and its equivalent SHOW MASTER LOGS) may now be executed by a user with the REPLICATION CLIENT privilege. (Formerly, the SUPER privilege was necessary to use either form of this statement.) * The --safe-mode server option now is deprecated and will be removed in MySQL 5.6. Bugs Fixed * Performance: InnoDB: Improved the algorithm related to adaptive flushing. This fix increases the rate of flushing in cases where compression is used and the data set is larger than the buffer pool, leading to eviction. (Bug #13990648, Bug #65061) * InnoDB: In a transaction using the REPEATABLE READ isolation level, an UPDATE or DELETE statement for an InnoDB table could sometimes overlook rows recently committed by other transactions. As explained in Section 188.8.131.52, "Consistent Nonlocking Reads," DML statements within a REPEATABLE READ transaction apply to rows committed by other transactions, even if a query could not see those rows. (Bug #14007649, Bug #65111) * InnoDB: The Innodb_buffer_pool_pages_flushed status variable was incorrectly set to twice the value it should be. Its value should never exceed the value of Innodb_pages_written. (Bug #14000361, Bug #65030) * InnoDB: The error handling and message was improved for attempting to create a foreign key with a column referencing itself. The message suggested a potential problem with the data dictionary, when no such problem existed. (Bug #12902967) * InnoDB: The CHECK TABLE statement could fail for a large InnoDB table due to a timeout value of 2 hours. For typical storage devices, the issue could occur for tables that exceeded approximately 200 or 350 GB, depending on I/O speed. The fix relaxes the locking performed on the table being checked, which makes the timeout less likely. It also makes InnoDB recognize the syntax CHECK TABLE QUICK, which avoids the possibility of the timeout entirely. (Bug #11758510, Bug #50723) * Replication: It was theoretically possible for concurrent execution of more than one instance of SHOW BINLOG EVENTS to crash the MySQL Server. (Bug #13979418) * Replication: Statements using AUTO_INCREMENT, LAST_INSERT_ID(), RAND(), or user variables could be applied in the wrong context on the slave when using statement-based replication and replication filtering server options (see Section 16.2.3, "How Servers Evaluate Replication Filtering Rules"). (Bug #11761686, Bug #54201) References: See also Bug #11754117, Bug #45670, Bug #11746146, Bug #23894. * Replication: An INSERT into a table that has a composite primary key that includes an AUTO_INCREMENT column that is not the first column of this composite key is not safe for statement-based binary logging or replication. Such statements are now marked as unsafe and fail with an error when using the STATEMENT binary logging format. For more information, see Section 184.108.40.206, "Determination of Safe and Unsafe Statements in Binary Logging," as well as Section 188.8.131.52, "Replication and AUTO_INCREMENT." Note Tables using the InnoDB storage engine are not affected by this issue, since InnoDB does not allow the creation of a composite key that includes an AUTO_INCREMENT column, where this column is not the first column in the key. (Bug #11754117, Bug #45670) References: See also Bug #11761686, Bug #54201, Bug #11746146, Bug #23894. * SHOW TABLES was very slow unless the required information was already in the disk cache. (Bug #60961, Bug #12427262)
|Written By
|MySQL Community Server 5.5.25a has been released
|Karen Langford
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Classic Album Review-George Strait "Something Special"
Today, we take a look back at what I think is one of the best albums to come out of the 1980's. It was August, 1985, when George Strait released his sixth album, "Something Special".
Two singles came from the album. "The Chair", is a great song, one of the best of that era, while "You're Something Special To Me" is also fine listening. Unlike some albums, where once you get past the single releases, the quality drops, this album is strong with every track.
"Last Time The First Time" is a song that will conjure up images of Bob Wills and His Texas Playboys. A very strong Western Swing number, it is, and is as good as anything he recorded in that era.
I recall some buzz about "Haven't You Heard", when this album was first released, and with good reason. This straight-ahead country number is one of the best songs on the album. How it never got released as a single, I do not know. They missed, there.
Back to the Western Swing sound for "In Too Deep" (no, not the same song as Genesis' from that period), another toe-tapper, George is always at his best, with these style of songs.
"Blue Is Not A Word", is a decent love ballad. However, the recording sounds, to me, like it should have been dropped a key or two, as it almost sounds at times, like it's too high for him to sing. That's about the only criticism I can give on the whole album.
Another outstanding cut is "You Sure Got This Ol' Redneck Feelin' Blue". This is what is called a country "tear-jerker".
The last of the swing numbers is "Dance Time In Texas", lyrically, the weakest song on the disc. That being said, one still finds themselves drawn in to the number, with it's infectious beat and again, that Bob Wills-style of arrangement.
"Lefty's Gone" is a tribute to the legendary Lefty Frizzell, written by Lefty's longtime songwriting partner, Sanger Shafer. Tribute songs can often times get too syrupy or sappy, however, both singer and songwriter avoid that with this one, and as a result, we get a fitting tribute to one of the most influential country music acts of the past sixty years.
"I've Seen That Look On Me (A Thousand Times)" wraps up the album in fine style, as a hard country ballad, that George sings as well as he does the dance numbers.
Availability-wise, you'll find used vinyl copies with just a little searching, but it is also still available, on CD, as well as being available for download on mp3.
Overall, this album is an easy 5 out of 5. I've said this before; the best albums leave you wanting more. This does just that. It's like a great meal; when you're done, you are full and completely satisfied with the quality, flavor, and depth. However, you'd love to have even more if it were possible. Even after twenty-five years, this album still feels fresh; it's one of the best of the 1980's.
MORE GREAT 1980's COUNTRY MUSIC
Randy Travis – "Storms Of Life"
Dwight Yoakam – "Guitars, Cadillacs, Etc., Etc."


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Ferndale police arrested two men and are looking for a third in connection with an alleged assault on a 16-year-old at the Taft Digital Learning Center.
According to police, the three went into a classroom Tuesday just before 2 p.m., demanded he turn over his cell phone and attacked the student leaving him unconscious. They took the cell phone, ran out of the building and the 16-year-old was rushed to Beaumont Hospital in an ambulance.
"It initially appeared that this attack was a robbery, but investigation shows that the assailants were retrieving a phone that was stolen from one of them about ...


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Loma Linda University
Loma Linda University Medical Center
Enrollment Information
Call us at: 909-558-1000
About LLU
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Danilo Boskovic
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Danilo Boskovic, PhD
Assistant Professor
, Basic Sciences
School of Medicine
Assistant Professor
, Earth and Biological Sciences
School of Medicine
, Faculty of Graduate Studies
Scholarly Journals--Published
Plank,M.S., Boskovic,D.S., Sowers,L.C. and Angeles,D.M. (2008.08.01)
Biochemical Markers of Neonatal Hypoxia.
2(4):485-501. ( 8/2008 )
Calderon,T.C., Wu,W., Rawson,R.A., Sakala,E.P., Sowers,L.C., Boskovic,D.S. and Angeles,D.M. (2008.07.01)
Effect of Mode of Birth on Purine and Malondialdehyde in Umbilical Arterial Plasma in Normal Term Newborns.
28(7):475-481. ( 7/2008 )
Danilo S. Boskovic, Thomas Troxler and Sriram Krishnaswamy. (2004.05.14)
Active Site-independent Recognition of Substrates and Product by Bovine Prothrombinase. A Fluorescence Resonance Energy Transfer Study.
279(20):20786-20793. ( 5/2004 )
The conversion of prothrombin to thrombin is catalyzed by prothrombinase, an enzyme complex composed of the serine proteinase factor Xa and a cofactor protein, factor Va, assembled on membranes. Kinetic studies indicate that interactions with extended macromolecular recognition sites (exosites) rather than the active site of prothrombinase are the principal determinants of binding affinity for substrate or product. We now provide a model-independent evaluation of such ideas by physical studies of the interaction of substrate derivatives and product with prothrombinase. The enzyme complex was assembled using Xa modified with a fluorescent peptidyl chloromethyl ketone to irreversibly occlude the active site. Binding was inferred by prethrombin 2-dependent perturbations in the fluorescence of Oregon Green488 at the active site of prothrombinase. Active site-independent binding was also unequivocally established by fluorescence resonance energy transfer between 2,6-dansyl tethered to the active site of Xa and eosin tethered to the active sites of either thrombin or meizothrombin des fragment 1. Comparable interprobe distances obtained from these measurements suggest that substrate and product interact equivalently with the enzyme. Competition established the ability of a range of substrate or product derivatives to bind in a mutually exclusive fashion to prothrombinase. Equilibrium dissociation constants obtained for the active site-independent binding of prothrombin, prethrombin 2, meizothrombin des fragment 1 and thrombin to prothrombinase were comparable with their affinities inferred from kinetic studies using active enzyme. Our findings directly establish that binding affinity is principally determined by the exosite-mediated interaction of either the substrate, both possible intermediates, or product with prothrombinase. A single type of exosite binding interaction evidently drives affinity and binding specificity through the stepwise reactions necessary for the two cleavage reactions of prothrombin activation and product release.
Danilo S. Boskovic, Laszlo S. Bajzar and Michael E. Nesheim. (2001.08.03)
Channeling During Prothrombin Activation.
J. Biol.Chem.
276(31):28686-28693. ( 8/2001 )
The plasma zymogen prothrombin (II) is converted to the clotting enzyme thrombin (IIa) by two prothrombinase-catalyzed proteolytic cleavages. Thus, two intermediates, meizothrombin (mIIa) and prethrombin-2 (P2), are possible on the reaction pathway. Measurements of the time courses of II, mIIa, P2, and IIa suggested a channeling phenomenon, whereby a portion of the II is converted directly to IIa without free mIIa and P2 as obligatory intermediates. Evidence for this was that the maximum rate of IIa formation preceded the maximum in the level of either intermediate. In addition, analysis of the data according to a model that included two parallel pathways through mIIa and P2 indicated that about 40% of the II consumed did not yield free mIIa or P2. Further studies were carried out in which II was continuously infused in a reactor at a constant rate. Under these conditions II, mIIa, and P2 reached constant steady-state levels, and IIa was produced at a constant rate, equal to that of II infusion. During the steady state, traces of II, mIIa, and P2 were introduced as radiolabels. Time courses of isotope consumption were first order, thus allowing the rates of consumption of II, mIIa, and P2 to be calculated. Under these conditions the rate of II consumption equaled the rate of IIa formation. Rates of consumption of the free intermediates, however, were only 22 (mIIa) and 15% (P2), respectively, of the rate of thrombin formation. Thus, both the time course experiments and the steady-state experiments indicate that an appreciable fraction of II is channeled directly to IIa without proceeding through the free intermediates mIIa and P2.
Danilo S. Boskovic and Sriram Krishnaswamy. (2000.12.08)
Exosite Binding Tethers the Macromolecular Substrate to the Protheombinase Complex and Directs Cleavage at Two Spatially Distinct Sites.
275(49):38561-38570. ( 12/2000 )
The prothrombinase complex, composed of the proteinase, factor Xa, bound to factor Va on membranes, catalyzes thrombin formation by the specific and ordered proteolysis of prothrombin at Arg323-Ile324, followed by cleavage at Arg274-Thr275. We have used a fluorescent derivative of meizothrombin des fragment 1 (mIIaDF1) as a substrate analog to assess the mechanism of substrate recognition in the second half-reaction of bovine prothrombin activation. Cleavage of mIIaDF1 exhibits pseudo-first order kinetics regardless of the substrate concentration relative to Km. This phenomenon arises from competitive product inhibition by thrombin, which binds to prothrombinase with exactly the same affinity as mIIaDF1. As thrombin is known to bind to an exosite on prothrombinase, initial interactions at an exosite likely play a role in the enzyme-substrate interaction. Occupation of the active site of prothrombinase by a reversible inhibitor does not exclude the binding of mIIaDF1 to the enzyme. Specific recognition of mIIaDF1 is achieved through an initial bimolecular reaction with an enzymic exosite, followed by an active site docking step in an intramolecular reaction prior to bond cleavage. By alternate substrate studies, we have resolved the contributions of the individual binding steps to substrate affinity and catalysis. This pathway for substrate binding is identical to that previously determined with a substrate analog for the first half-reaction of prothrombin activation. We show that differences in the observed kinetic constants for the two cleavage reactions arise entirely from differences in the inferred equilibrium constant for the intramolecular binding step that permits elements surrounding the scissile bond to dock at the active site of prothrombinase. Therefore, substrate specificity is achieved by binding interactions with an enzymic exosite that tethers the protein substrate to prothrombinase and directs cleavage at two spatially distinct scissile bonds.
Danilo S. Boskovic, Alan R. Giles, and Michael E. Nesheim. (1990.06.25)
Studies of the Role of Factor Va in the Factor Xa-catalyzed Activation of Prothrombin, Fragment 1.2-Prethrombin-2, and Dansyl-L-glutamyl-glycyl-L-arginine-meizothrombin in the Absence of Phospholipid.
265(18):10497-10505. ( 6/1990 )
In order to specifically evaluate the role of Factor Va in the prothrombinase complex, studies of the activation of prothrombin, Fragment l?2-prethrombin-2, and active-site-blocked meizothrombin were carried out, both in the absence of phospholipid and at concentrations of substrates and Factor Va sufficient to approach saturation in all components. Km values were independent of Factor Va concentrations, whereas kcat(apparent) values approached saturation with respect to Factor Va concentrations. The three respective substrates exhibited the following parameters of kinetics (Km, µM; kcat, 1/s at saturating [Factor Va]): prothrombin (9.0 ± 0.4; 31 ± 1); Fragment l?2-prethrombin-2 (5.4 ± 0.4; 13 ± 2); and meizothrombin (3.6 ± 0.3; 51 ± 5). Models of kinetics were constructed to interpret the results, and two of these were formally consistent with experimental results. Both models indicated that the variation of kcat(app) with concentrations of Factor Va reflects the formation of a Factor Va-Factor Xa binary complex. Analysis of kinetics indicated Kd values for this interaction of 1.3 ± 0.1, 3.0 ± 0.5, and 1.0 ± 0.1 µM for the three respective substrates. The models differed in the interpretation of Km. One indicated that Km reflects a binary interaction between Factor Xa and prothrombin, whereas the other indicated a binary interaction between Factor Va and prothrombin. Both indicated that two of the three possible binary interactions between the three components would be reflected in Km and kcat values but not the third. To distinguish these models, the binary interactions were studied by extrinsic fluorescence (Va*Xa), light-scattering (Factor Va*prothrombin), and competition kinetics (Xa*II). The first two interactions were detected and were characterized by Kd values of 2.7 ± 0.1 µM (Va*Xa) and 8.8 ± 0.8 µM (Factor Va*prothrombin). No active-site-dependent interaction between prothrombin and Factor Xa could be detected in the absence of Factor Va. The results of these studies suggest that Factor Va interacts with both Factor Xa and prothrombin and effectively presents one to the other in the formation of a ternary enzyme-substrate-cofactor complex. In addition, a comparison of the parameters of kinetics of conversion of prothrombin and its intermediates indicates that meizothrombin is the major intermediate of prothrombin activation in the absence, as well as in the presence of phospholipid.
Books and Chapters
Calderon,T.C., Boskovic,D.S., Sowers,L.S. and Angeles,D.M. (2008)
Use of Purines and Xanthine Oxidase as Markers of Neonatal Hypoxia-Ischemia. Chapter 8. In:
Advancements in Neurological Research
. Edited by Zhang,J.H. Research Signpost, Kerala, India, pp:209-227. ( 8/2008 )
Michael E. Nesheim, Russell P.Tracy, Paula B. Tracy, Danilo S. Boskovic and Kenneth G. Mann. (1992)
Mathematical Simulation of Prothrombinase.
Methods Enzymol.
215:316-328. ( 1/1992 )
Non-Scholarly Journals
D. S. Boskovic, T. Troxler and S. Krishnaswamy. (2005)
Using the Fluorescence Resonance Energy Transfer Approach to Demonstrate Active Site-Independent Recognition of Substrates and Product by Bovine Prothrombinase.
The RLBL Newsletter
30:8-10. ( 3/2005 )
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« Fixing the Patent System? |
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Posted by Derek
When I was talking about Steve Ley of Cambridge the other week, one of his research areas that I mentioned liking was his work on flow chemistry. This is the benchtop application of a type of reaction that's been done more often on large industrial scales.
Most of the work that medicinal chemists like me do is batch by batch. We weigh and syringe things into flasks, cool, heat, and stir them, and then pour the resulting stuff out of the flask and clean it up. There are all sorts of techniques that have come along to speed these steps up or to allow you to do more of them simultaneously, but all of them are still in "batch mode".
Flow chemistry is a bit different. The starting materials flow through an apparatus that (one way or another) causes them to react, and then out the other side. The business section of the machine can be a part that heats up the solutions as they go by, or puts them under high pressure, or forces them over a solid support that contains some catalyst. That last category is especially useful, since the number of metal-catalyzed reactions is increasing with no end in sight.
If the reaction isn't done, you can send the mixture back through for another pass. If the reaction's complete, you can (ideally) take the resulting solution on to the next step without necessarily having to clean it up – after all, the catalyst is staying behind on the solid support. If you treat it right, the catalyst should be reusable for quite a while as well.
One of the more widely adopted flow reactors so far has been the "H-cube". Its makers chose a reaction (hydrogenation) which is very useful, but one that a lot of chemists don't like to run. The opportunity to easily try out catalysts and conditions that aren't normally run has been another selling point. Now the company has come out with their X-cube, which is a more general flow reactor.
My question is: has anyone out there used this beast or its competition? I've had a little (generally positive) experience with the H-Cube, but none with any other flow reactor. There are a lot of homebrew setups out there, but the commercial space has been filling up recently, too.
Of course, as everyone knows, neat-looking equipment can end up gathering dust. For these flow gizmos to be useful, they'll have to do things that aren't easy to do in a flask, and do the flask reactions in a more convenient manner. The flow reactor people aren't competing with each other as much as they're competing with a drawer full of round-bottom flasks. I'd be interested to hear from anyone who's put that comparison to a real-world test. . .
Comments (23)
+ TrackBacks (0) | Category: Life in the Drug Labs
1. Matt on September 20, 2007 9:27 PM writes...
This sounds neat. I'm not a chemist, but from your description I'd be willing to bet (a very small amount of money) that it will catch on eventually.
P.S.: Your links don't work.
2. Handles on September 20, 2007 9:38 PM writes...
We had a microwave flow reactor once as a loan from the manufacturer. It worked fine, but we didnt end up buying one. It was faster to set up a whole bunch of reflux condensers in parallel overnight, rather than do the same reactions in series in the microwave.
3. Grubbs the cat on September 21, 2007 2:15 AM writes...
I only have H-cube experience and I can say that this is truly a blessing. Since I am an ex-Whiffenite (ie ex-Ley postdoc) and I saw him lecture and talk about it a few times, and just yesterday (what a coincidence) SigmaAldrich showed off their miniflow reactor kit at our company, I arranged with them to have a demo reactor in for a week or two. I also remember Peter Seeberger's last talk which made flow reactor chemistry sound like a must.
The are a few things that make me cautious:
- whatever if there is precipitation during the reaction (or due to cooling the reactor)...
- what about heterogeneous reactions...
...but then I guess these things can be sorted with some experience
4. Lars on September 21, 2007 6:35 AM writes...
No experience with the X-Cube either. Sounds interesting though...
One of the big benefits of the H-Cube is being able to move the hydrogenation-lab to your benchtop without baloons and giant tanks of explosive gas wobbling about. We're moving our chemistry labs into a new building in a couple of years and we're planning on buying an H-Cube.
BUT, we're still planning on designing and building a real, old-school, X-classed hydrogenation lab. Because in the end (and can I get an Amen here?) while catalytic hydrogenation, atmospheric hydrogenation in a baloon and flow-reactors often do the job of getting rid of that pesky alkene or insolent Bz-group you've got your sights on...sometimes the ONLY thing that works is a good old-fashioned Parr bomb at 10 atm.
5. befuddled on September 21, 2007 8:43 AM writes...
Grammar nit:
"Its makes chose a reaction (hydrogenation) which is very useful"
Was presumably meant to make more sense, though the meaning of the article is clear (and interesting).
6. Jose on September 21, 2007 8:45 AM writes...
H-Cube is amazing. Large amts of material, any silly pressure you want (much higher than a Parr) and easy to opmitize your conditions. Slick!
7. eugene on September 21, 2007 9:54 AM writes...
Hmmm... I wouldn't get the X-cube for now. It's flirting with litigation from two different video game console companies and you want to make sure you have customer support five years down the line.
The H-cube sounds like a good idea from all I've heard. If the company doesn't go out of business when sued by Nintendo and Microsoft of course.
8. Derek Lowe on September 21, 2007 9:57 AM writes...
Grammer fixed - thanks. It was a single-letter deletion, a DNA-level mistake.
9. Bacon on September 21, 2007 11:56 AM writes...
How much are these things? Just wondering if there was any chance of them catching on in academia (aside from niche groups whos focus is flow chemistry).
10. Anonymous on September 21, 2007 2:50 PM writes...
Check out Lab-on-a-Chip (if you have access to a technical Uni's library). It's the primary journal for those of us engineering "chip scale" chemical and biological research devices.
11. anon on September 22, 2007 3:38 AM writes...
There are a number of exciting things about continuous flow reactors. By combining flow methodology with Sharpless's Click chemisty (and telescoping), you go a long way to resolving, "For these flow gizmos to be useful, they'll have to do things that aren't easy to do in a flask, and do the flask reactions in a more convenient manner.".
The other thing is moving production from the hub to the spokes. At the moment, production is centralised: a chemical plant makes chemicals. With continuous flow reactors; the customer could make the drug by using a bespoke flow reactor. Repeat prescriptions at the flick of a switch.
12. eugene on September 22, 2007 9:04 PM writes...
"the customer could make the drug by using a bespoke flow reactor. Repeat prescriptions at the flick of a switch."
Now that's a disaster waiting to happen. Even if you get past the fact that the company would lose out when every user would become an (illegal presumably) generic competitor, but the litigation issues involved when the asymmetric hydrogenation part craps out on you and you get out some toxic byproduct would be a nightmare.
I agree that it's a good idea for swindling a few million bucks if you find a management team gullible enough to support research into this idea in any official capacity for a few years.
13. Polymer Bound on September 22, 2007 11:04 PM writes...
Local synthesis is how clinically used PET tracers are made. Positron emitters have short half-lives so imaging agents need to be made within a short drive of the radiation source and the hospitals where they're used.
Probably not useful for drugs though...
14. Flow-based Chemist on September 22, 2007 11:16 PM writes...
I use a microfluidic flow based instrument everyday. I see higher yields and fewer byproducts.
My research involves the preparation of PET imaging agents for medical research (mostly cancer) and molecular imaging compounds to study biochemical pathways. Typically, I work on the microgram scale and require in-line analysis as well as a timely synthetic scheme. Due to the fact that the most common positron emmiters, fluorine-18 and carbon-11, have short half-lives, 110 and 20 minutes respectibly, we have to work fast. This means that we have to have 1 simple purification at the end. Not between every step.
With my flow based system, I can optimize a synthesis in one morning. This may involve adjusting the reaction temperature, the flow rate, the stoichiometry, the concentration, and the number of serial reactions I perform to make one product. I have run as many as 72 different sets of conditions for a two step-process. Some of the preparations involve as many as 5 serial steps. Ordinarily, this quest would take months if I did it in a flask. Each day trying one adjustment. It's radioactivity so you have to be safe.
There are limitations, however. Any chemistry that involves cooling to generate stereochemistry or build upon chiral centers is difficult under flow based environments. Also, knowledge of the solubility of all compounds; reagents, products, and by-products is a must. You do not want a clog prevent you from achieving your goals for the day/week. A clog in a reactor, especially when radioactivity is involved, sucks.
I have been to Steven Ley's lab. In fact, I met with him and Ian Baxendale last spring at Cambridge. What they are doing with flow may one day revolutionize discovery chemistry. To be able to serialize many reactions across a bench-top, sequester impurities or incompaticle by-products and move on without further purification until the end expands all of our potential. To work in a (continuous) flow-based environment, with an endless supply of reagents allows the production of mg to g to kg of product, every day.
Use the same pumps but through parallel reactors and you have figured out the scale up procedure. Install in-line MS and you can follow a process. As some byproduct appears, adjust the temperature a little without starting over as you would in a flask. This work is part research, part production, and part chemical engineering.
Add a sample changer to the first reagent line and now you can create a library of compounds in short order. I hope that you can see where this technology is heading.
15. Flow-based Chemist on September 22, 2007 11:34 PM writes...
By the way, Lars, if you think that hydrogenations at 10 atm (147 psi) are the best way to do get the job done, you may like to know that flow based systems can achieve 68 atm (1000 psi) easily. You can also add HPLC back-pressure regulators and more to go higher.
16. eugene on September 23, 2007 12:47 AM writes...
Yeah, I meant that "lab on a chip" type systems are only bad from the point of view of making drugs in local pharmacies (without any, I would imagine, useful quality control). Not to mention that the application of flow based systems is still many, many years away.
But yes, I was very exited and interested in the possibilities of this system after a big name in the field gave a seminar on this topic in our department. It's not useful for drugs for sure. At least not in a 'local' sense. If this technology is used to make a drug on any sort of scale, it'll still be in a chemical plant.
I also don't think that this technology will revolutionize discovery chemistry. It might revolutionize chemical engineering methods, but we will not bother setting up a chip for every small reaction that we run. And since often a student will destroy a chip because of the problems mentioned (clogs developing; unknown stuff forming), it's not worth it. It's easier to run a reaction in a conventional manner from the start. Even for a methods group, no grad student is going to use a flow reactor to even optimize reaction conditions (too much strange stuff that can happen at different temperatures), not to mention trying out different substrates. From what I've seen, you have to known all the processes and they have to be very well behaved and that is a bit of an antithesis to discovery chemistry. So yes, I can see where this promising technology is heading, but I don't think I'm looking in the same direction as "Flow-based chemist".
And a personal pet peeve is that I've yet to see a flow reactor do one of either of my two favorite reactions: Grignard or Wittig.
17. Flow-based Chemist on September 23, 2007 9:48 AM writes...
Please don't get me wrong. I am not saying that we must change or die. Nor am I suggesting that labor intensive life of grad students in organic/natural product synthesis will improve.
Only that there is a resurgence of an old concept, made better by modern "small tools" and more powerful computers. As I mentioned in the negatives, we still need to know and understand the physical properties so that we do not clog the system.
There is a market and utility for these devices for they are simply a tool to get the job done. The chemist will forever exist.
18. Polymer Bound on September 23, 2007 12:11 PM writes...
"And a personal pet peeve is that I've yet to see a flow reactor do one of either of my two favorite reactions: Grignard or Wittig."
well, here's one of them:
I think the better way of doing flow chemistry is to set up a vial reaction just to make sure reagents are compatible with flow (don't crash out) then let the instrument do the automated optimization.
I find the concept of direct scale up of optimized conditions really appealing as it takes a lot of the thinking out of scale up. Even with microwave reactors, I've had issues going from 5 mg to 1-2 g. I think flow solves that problem once you get used to working with it.
19. Polymer Bound on September 23, 2007 12:14 PM writes...
The flow aqueous work-up device looks awesome too:
20. anon on September 23, 2007 12:47 PM writes...
eugene - "Now that's a disaster waiting to happen. " ...
Hi Eugene, your post and my post illustrate the distinction between an information society and an industrial society. In the system described by me; the value of the flow reactor is information - the shape of the channels, the pressures, the reagents: all the information that can be gleaned by experts such as those like the chap behind the name, "flow based chemist", above. Your model is the classical, industrial production model; you are controlling product rather than information.
All quite fascinating.
In terms of it being a disaster; consider the production of poisons (sarin, perhaps?; or easier for a chemist to visualise, phosgene) using hard wired, continuous flow apparatus. Therein is a larger disaster, or accident (in the Paul Virilio sense).
This is the future of chemistry especially when coupled with Sharpless's click chemistry idea.
We're looking at plug and play chemistry - massive de-skilling and blackboxification. Just as thick people who have no comprehension of electronics can make international telephone calls, these same people will be able to make sophisticated compounds.
21. eugene on September 23, 2007 6:29 PM writes...
Touche Polymer Bound, my comment was a bit hasty and I was proven pretty much wrong on that one. I myself take mass spectra of air sensitive compounds regularly; forgot that the Wittig can be a bit simpler at times...
FbC, I'm trying not to sell flow based chemistry short because the reactors do some quite amazing things.
I think I was trying to focus the negativity on the 'lab on a chip' concept for the purpose of simplifying chemistry as opposed to 'Flow Chemistry' in general and anon's comment that the price of a labchip reactor will make complex synthesis available to the layperson (in our lifetimes?). Apparently the common person will be able to perform complex synthesis of drugs without killing themselves in the process by consuming some seriously tainted batch.
And that anyways, is just a fun philosophical discussion that is not grounded in reality for now. I guess a good thing to say to that is" "by the time a lay person could make super toxins in gram quantities at home, the amount of information that the government has gathered on you via data mining, will make your attempts to poison others quite futile".
Although mind you, it would be quite expected for one of the 'normals' to snap and kill a bunch of fellow citizens in a suburban, mostly white, upper-middle class neighbourhood of Denver following the dictum: "A nation that would give up a little liberty for a little security will deserve neither and will lose both" and all that.
Futuristic thinking is quite fun on a Sunday night.
22. anon on September 24, 2007 4:43 AM writes...
Hi Eugene
Your latest post could easily be re-written to something like, "anon's comment that the price of a mobile telephone will make international calls available to the layperson (in our lifetimes?). Apparently the common person will be able to call anywhere in the world without understanding any of the complexities of the electronics. [etc etc]"
I do agree that "flow" chemistry is a lot more than lab-on-a-chip micro reactors. By expanding into the fourth dimension rather than the third, one can make large quantities of product in small spaces. Consider, a bog standard continuous stirred reactor, say 10 L volume. If you take the reaction to 98 % completion, then charge reagents and remove product at the same rate and at such a rate as to be slower than the rate of the reaction: you will have a continuous flow reactor. The rate of production of product being limited by the rate of the reaction (in the first instance) and if the reaction rate is fast, the rate of production will be limited by rates of addition etc. All of this from standard kit and a couple of pumps (depending upon work-up, of course).
This is before one considers: oscillatory flow reactors; spinning disc reactors; spinning tube reactors; microreactors.
Continous flow is also useful for work up. For instance, consider plant scale separations. You can have a batch sheet that says, 1) charge water x L; 2) stir (15 mins); 3) settle (30 mins); 4) collect lower layer; 5) repeat from step 1) twice. What about ... 1) configure vessel such that it has a circulation loop with a) an aspirator connected to a water source; and b) a cyclone separator such that the organic layer goes back to vessel and the aqueous layer goes to drum (or holding vessel); 2) circulate for 15 mins.
For an idea of what I'm talking about, there's a 1940s patent (Nobel industries) that uses the aspirator idea to nitrate glycerine. They pumped the nitrating mixture through the aspirator which sucked up the glycerine. Flow rates and such were that the proportions were appropriate and the aspirator provided excellent mixing. While oil/water separators are commonly available.
In short, continuous flow is misunderstood and much underused.
23. eugene on September 24, 2007 5:33 PM writes...
"Your latest post could easily be re-written to something like, "anon's comment that the price of a mobile telephone will make international calls available to the layperson (in our lifetimes?). Apparently the common person will be able to call anywhere in the world without understanding any of the complexities of the electronics. [etc etc]""
That's a non-starter because the two concepts are completely different. This is just creating an argument out of nothing. Since I am a chemist who has no basic understanding of the physics of molecular solvation and diffusion as well as bond forming processes, and I can make complex molecules, I will use my poor chemistry knowledge to tell you that your comparison is preposterous. Giving a cell phone (new phone version) to a lay person is very different from giving them another new version of a loaded gun which doesn't have a safety and is very prone to go off during cleaning.
Anyways, we are getting quite far away from the subject of this post, although I do like detours now and then.
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Books By David Powlison
Seeing With New Eyes: Counseling and the Human Condition Through the Lens of Scripture by David Powlison ,Published: P&R Publishing - 2003
Topics: Biblical Themes, Theology, Counseling Topics, Psychology and Christianity, Biblical Counseling, Pastoral Resources
Tags: biblical counseling, christian living, pastoral counseling, church ministry, counseling theory
The Biblical Counseling Movement: History and Context by David Powlison ,Published: New Growth Press - 2010
Topics: Counseling Topics, Psychology and Christianity, Biblical Counseling
Tags: biblical counseling, church history, ccef, psychology, history, nouthetic counseling
Recent Comments
That's a question that requires more than the space allowed in a comment post. For the differences between how people may see/perceive nouthetic counseling and biblical counseling, I would encourage you to read Heath Lambert's work, "The Biblical Counseling Movement After Adams." For differences between biblical counseling and Christian counseling, in terms of how those words are typically used, I would encourage you to read the "Five Views" book edited by Johnson.Read
Hi Bob,
What are the differences between nouthetic, biblical, and Christian counseling? Thanks!Read
Cinda, Without the scriptural and gospel basis for biblical counseling, it really isn't biblical counseling, is it? We in the "second generation" of modern biblical counseling must seriously consider our stewardship and be sure that our equipping is Christ-centered and biblically-focused with a robust and relational emphasis on the sufficiency of Scripture and progressive sanctification that is Gospel-centered.Read
3. I am very aware from studying under Powlison at Westminster and CCEF. He is a master in his art of biblical counseling and teaching, as he puts God's order in proper perspective within the secular camps. The book "Psychology ad Christianity; Five Views" compares these, and I recommend it. I believe we can intelligently, with God's grace, use secular terms and prevailing science in psychology to bring the presenting spiritual root to the surface during counseling.Read
1. Yes, I do think the biblical counselors who are young and just learning are not getting the scriptural and gospel basis for their specialty. It may become too secular and just like other camps if we continue to trend more towards cultural and worldly dictates. We cannot forget Who the counselor is; Jesus Christ through the transforming Holy Spirit, alive and well in a believer's therapy. Cinda Marturano, Biblical CounselorRead


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I enjoyed watching the quilt with the Pear design created by Ana Buzzalino.
Do you need a special machine to do the stiffling ?
I need someone who could help me with similar quilt design for my daughter's bedroom.
It is a picture of a little girl in a flower garden. If someone can start it for me, then I could
continue painting or hand embroidering it as needed.
If anybody can help me, please respond to: Leeladill.
hi leela
i am not familiar with the pear quilt. but someone else may be able to help you.
and what is stiffling? if a typo - are you talking about stuffing ? (like trapunto) or stipple quilting? or is this a new method i don't know about yet ?
i am starting a baby quilt for my niece - a toddler standing in a field of flowers, holding baby birds on her tummy while talking to the mom and dad birds. she has a picture that she loves and wants to capture the essence of. but she is gonna let me do some dimensional embellishing and make some changes to the picture. the clothes will be embellished with lace and whatever fun trims and buttons we find. sunflowers will be ruched , with either textured fabric or beads for the seeds in the center. there will also be hollyhocks and pansies, and some other generic flower shapes.
the toddlers face will be painted with the tsukineko ink. i have not decided if the hair will be fabric and thread or inked.
i need some more info, before i could offer any help. do you have a picture of what you want to make? or a line drawing? and what size?
let us knowsome more details and specifics, and we will see what we can do to help. ckquilter
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With their towering, highly visible locations, empty (and otherwise) commercial billboards have always been a prime spot for graffiti and street artists to 'get up', albeit illegally. The 'Public Works' project flips the script on the status quo by having street artists work directly with major outdoor media outlets to create billboards in LA that will not advertise the latest blockbuster or the hottest jeans, but rather showcase street art. Organized by Daniel Lahoda of LaLa Arts / La Freewalls and Rick Robinson of Macdonald Media, the project will feature printed and hand-painted signs from a top-flight roster: How & Nosm, Insa, Push, Revok, Risk, Ron English, Seen, Shepard Fairey, Trustocorp, WCA Crew, Uglar, and Zes.
The project will kick off with a gallery show @ LaLa Arts (8.3 –8.17) and continue with periodic installation of the outdoor signs beginning in August through the end of the year. This milestone project will benefit Art Share LA, a charitable organization engaging youth through arts education. After the jump, we have a small preview of some of Public Works billboard designs. Also to get a better feel for the project, check out a teaser of an upcoming short-film by Jason Wawro.http://www.vimeo.com/46712036
Public Works
Outdoor Installation — Throughout LA from 8.1 through the end of the year.
Gallery Opening: Friday, August 3rd (7 to 10 PM)
LaLa Arts


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South Carolina's Punter Patrick Fish Makes Crazy FG Trick Shot
November 12, 2013 1:28 PM
By: Evan Jankens
The best thing to hit the internet since Sports Illustrated swimsuit photos via dial up 56k Internet has to be Vine. Vine is a service that allows you to do video for 15 seconds and post it online. Vine has come through with some of the better quick videos I have seen on the Internet.
South Carolina's punter Patrick Fish may have won the Internet for the day in my opinion. A Vine the punter posted shows a trick field goal that should make even Kickalicous jealous. In the video, Fish does some type of soccer move to get the football off the ground and spinning. Once the ball is spinning, then he kicks a field goal.
Who does their trick shot better… Fish or Kickalicous?


text: [ Survey: Small Biz Optimism Took A Dive In November By Associated Press December 11, 2012 NEW YORK (AP) — Small business owners grew more pessimistic in November after the presidential election and Superstorm Sandy. That's the finding of a survey by the National Federation of Independent Business... Read More|Comment Category: Associated Press, National News Tags: November, small businesses, survey Send to a friend! Share on Facebook Share on Twitter Pin it! Reddit This! Share on Tumblr!


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Boardman House (1875)Monday, January 6th, 2014 Posted in East Haddam, Houses, Italianate, Second Empire | No Comments »
In 1842, Luther Boardman invented and patented an improved mold for creating britannia silverware. He established a factory in East Haddam where he produced britannia spoons. In 1864, Luther Boardman entered a partnership with his son Norman S. Boardman, under the name L. Boardman & Son. This successful business peaked in the 1860s and 1870s. Norman Boardman had already built the Italianate house at 8 Norwich Road when another grand residence was constructed next door circa 1875. A more eclectic house than its neighbor, it features an Italianate design and an octagonal rear tower on west side with a mansard roof and Eastlake-style iron cresting. There is some confusion over who built the house. The National Register of Historic Places nomination for the East Haddam Historic District lists the house as the Norman S. Boardman House, while an 1880 bird's-eye-view of East Haddam lists it as the residence of his father, Luther Boardman. An online collection of images from the Boardman Collection at the East Haddam Historical Society has a photo of the house with the description "The Lawton House owned by the Boardman Family."
Neptune Twine Mill Office (1899)Friday, October 25th, 2013 Posted in East Haddam, Greek Revival, Industrial | No Comments »
Down Johnsonville Road from the Emory Johnson Homestead in Moodus, East Haddam, is a surviving building of the Neptune Twine Mills, owned by Emory Johnson and then, after his death in 1896, by his son, E. Emory Johnson. The area around Johnson's mills was known as Johnsonville. In the "Nineteenth Annual Report of the Bureau of Labor Statistics for the Year Ended November 30, 1903" (printed in Public Documents of the State of Connecticut, Vol. I, 1903; published in 1904), a picture of the building is captioned "Neptune Twine and Cord Mill, No. 3, Moodus." The report describes the other two mill buildings as follows:
The Neptune Twine and Cord Mills, Inc., property consists of two mills, the upper one of which was constructed by Emory Johnson. In 1862 he constructed this mill, and began the manufacture of twines, and though the civil war was then in progress this mill did a successful business, and was the only one in town in operation during the entire period. The lower mill, in which Mr. Johnson had formerly an interest, again came into his possession in 1867. This mill, which was erected by Mr. Johnson's father-in-law (Stanton S. Card), is now known as the Neptune. The name of "Neptune," as applied to these mills, was adopted in 1864. The upper mill is 34×80 feet on the ground floor, and has two stories. On the first floor is done the carding. Its motive power is a 36-inch turbine water wheel of seventy-five horse power. The lower mill is 36×80 feet, and has four floors: on the first floor, carding, etc.: second floor, the spinning; third floor, the twisting, winding up, and on the fourth floor, the packing, baling, etc. The motive power is water, and has a force of one hundred horse power. The mills employ forty hands and consume 19,000 pounds per week. They manufacture soft and hard twines, cable cords, etc., etc.
The firm was incorporated in 1902, and the present officers are as follows: E. Emory Johnson, president and treasurer; Matthew W. Plumstead, vice president; Elsie S. Johnson, secretary and assistant treasurer.
The upper mill, known as Triton, was destroyed by fire 1924 and the lower mill, dating to 1832, was also lost in a fire in 1972. The surviving mill building (No. 3) was built in 1899 and included the mill's office and a Post Office. As related in Fibre and Fabric, Vol. XXXV, No. 908 (July 26, 1902):
Mr. Johnson takes great pride in the appearance of his property, and the village of Johnsonville is a model of neatness. The main offices of the mills are located near the Neptune mill and are sumptuous in their appointments. In the office building is the Johnson library, containing 3,000 volumes, opened in the fall of 1899, which is free to all the employees of the mills as well as to the employees of the other factories. There is also a smoking room in the building and a room where the records of the mill for 70 years are kept. All are neat and tasty in their appointments. Mr. Johnson's enterprise is commendable and thoughtful in promoting the welfare of the employees of the Neptune mills and is appreciated.
It was later part of the Johnsonville village tourist attraction and, vacant for a number of years, has recently acquired a new owner.
Emory Johnson Homestead (1842)Thursday, October 24th, 2013 Posted in East Haddam, Houses, Italianate | No Comments »
On Johnsonville Road in Moodus, East Haddam, is an Italianate-style house built (according to the sign on the house) in 1842. It was the home of Emory Johnson, who owned twine mills near the Johnson Mill Pond across from his home. In the nineteenth century, Moodus was the "Twine Capital of America," with twelve mills in operation. Johnson's father-in-law, Stanton S. Card, owned the Neptune Twine Mills, which he left to his son-in-law at his death in 1867. Johnson had already opened his own mill, called Triton, in 1862. The area of worker housing that grew up around the mills became known as Johnsonville. The two mills continued to be operated by Emory Johnson and then by his son, E. Emory Johnson, who died in 1905. In the 1960s, the house and other Johnsonville properties were acquired by Raymond Schmitt and became a Victorian era attraction. Closed in 1994 and vacant for many years, the property was recently sold.
Gilead Chapel (1876)Sunday, September 8th, 2013 Posted in Churches, East Haddam, Folk Victorian, Gothic | No Comments »
In 1836, Henry P. Haven (1815-1876; A biography of Haven by Henry Clay Trumbull, entitled A Model Superintendent, was published in 1880) established the Gilead Sunday School in Waterford. In 1876, Gilead Chapel was built at the corner of Foster Road and Parkway North to serve as the home of this interdenominational school. After the school closed in the early 1940s, the building was used for a decade by the Church of Jesus Christ of Latter Days Saints. Vacant several years thereafter, in 1969 it was purchased by Raymond Schmitt for his his Historic Johnsonville Village in Moodus in East Haddam. The building was taken down and reassembled in Moodus at the intersection of Johnsonville Road and Neptune Avenue.
Atlantic Duck Company Mill House (1855)Friday, August 9th, 2013 Posted in East Haddam, Greek Revival, Industrial | No Comments »
Cotton duck (also called canvas) is a type of heavy cotton fabric. The Atlantic Mill, originally called the Atlantic Duck Company, was first leased in Moodus (in East Haddam) in 1852. Destroyed by fire in 1854, the mill was rebuilt and operational again by 1857. Closed during the Civil War, the mill later reopened and continued in operation until 1894. In 1898 it began operating as a twine and textile mill until it burned down in 1939. Surviving today in Moodus is the "Atlantic Duck Co. Mill House," built c. 1855.
Hyde Schoolhouse (1863)Friday, July 26th, 2013 Posted in East Haddam, Greek Revival, Schools | No Comments »
Yesterday I featured the Carriage House at Johnsonville, a now abandoned Victorian-themed village attraction in East Haddam originally created by Raymond Schmitt, founder of of AGC Corporation. One of the buildings that Schmitt brought to Johnsonville is the Hyde Schoolhouse. It was originally built in Canterbury between 1853 and 1863 and was said to have been discovered by Schmitt's wife Carole in an abandoned state, surrounded by overgrowth.
Johnsonville Carriage House (1870)Thursday, July 25th, 2013 Posted in East Haddam, Italianate, Outbuildings | 1 Comment »
In the 1960s, Raymond Schmitt, owner of AGC Corporation, an aerospace equipment manufacturer, purchased the former nineteenth-century mill village of Johnsonville in East Haddam and began to transform it into a 100-acre open air museum celebrating the Victorian era. As an attraction, Johnsonville did not keep regular hours, but was open to the public several days a year (most notably during the Christmas season when holiday decorations were on display) and for charity functions. For his recreated period village, Schmitt purchased historic structures from other places and moved them to Johnsonville. One of these was the Carriage House (built between 1870 and 1900) and an adjacent Livery Stable (built around 1920). They were moved by Schmitt from Winsted. Inside, he stored his collection of antique horse drawn carriages and sleighs, which were often used in carriage rallies and in rides for the public. After a disagreement with the town of East Haddam in 1994, Schmitt shut down Johnsonville and put the property up for sale. After his death in 1998, his estate sold off much of his antiques collection (including his carriages), several pieces of the property and even individual buildings. The remainder of the village has long sat abandoned and up for sale to potential developers. Thanks to Luke Boyd for introducing me to Johnsonville.


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Fix The FDA, Fix Patents, Save Lives
May 13, 2014
Yevgeniy Feyman
Bringing life-saving drugs to market isn't cheap the capitalized cost of bringing a typical drug to market is around $1.2 billion and continues to grow every year. And thanks in no small part to heavy-handed FDA regulations, this cost is slated to keep growing, especially for new, highly targeted medicines for diseases ranging from cancer to type 2 diabetes.
Much of the cost of drug development lies in what economists refer to as fixed or sunk costs this covers the gamut of everything from machinery to rent to regulatory costs (filing fees and time spent conducting clinical trials for example). This situation creates a classic underinvestment problem companies invest significant amounts of money to develop a product (with large social benefits) where they will be unable to capture much of the total benefit (social+private); in economic terms, an externality. The way that we overcome the problem of large sunk costs is by granting companies a temporary monopoly on production and sale of a product (in essence, a patent that creates intellectual property), that allows society to encourage investment in high-value, high fixed cost products that may not have been developed otherwise. Patents are granted for a 20 year period in all countries that have signed the World Trade Organization's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPs).
The problem is that not all industries are created equal. When Apple unleashes the newest iWidget, the engineers who designed it don't need to prove to the FCC or any other government body that the device is safe and effective.
But pharmaceuticals aren't smartphones. And ensuring the purity, safety, and efficacy of drugs put out on the market serves a tremendous public interest (particularly in light of the significant information asymmetries between the general public and drug manufacturers). Nevertheless, FDA clinical trial requirements that help prove safety and efficacy in large populations also create a long lag between invention (when patents have to be filed) and commercialization (when the product can be sold). This doesn't happen with other industries Apple can profit from the iPhone as soon as it is working reasonably well and does well with focus groups. This commercialization lag has resulted in an effective patent life of around 12 years in the 90s, which has likely fallen even more since then.
And the shortened effective patent life has potentially dire consequences for U.S. pharmaceuticals. Potentially promising ventures (which may sometimes involve blue-sky research), with enormous social value (estimates of the value of a cure for cancer have been as high as $50 trillion) but extensive clinical trial requirements may not get developed or commercialized. Take for example a hypothetical preventative drug for Alzheimer's given to individuals at age 30. Because typically, Alzheimer's develops after age 60, standard clinical trial protocols focused on clinical endpoints would prevent the drug from being developed the 20 year patent life would be exhausted before any clinical effects could be documented.
In fact, just looking at cancer drugs, researchers from Harvard Law School, the University of Chicago, and MIT found that in one year 2003 fixed patent term distortions resulted in a loss of life-years valued at about $89 billion.
So what are we to do?
Fortunately, the research quantifying these distortions also offers a glimpse of the path forward. Generally speaking, the commercialization lag is minimized when drugs are approved based on surrogate (non-mortality based) endpoints. (The researchers note that all FDA-approved cancer prevention drugs, which would suffer from under-investment, were approved using surrogate endpoints or through publicly-financed trials.) Surrogate endpoints (this can include molecular changes like the level of the HIV virus in the blood to physical measures like tumor size) tend to shorten the FDA approval process significantly, reducing the cost of clinical trials. To expand the use of surrogate endpoints (especially beyond cancer and HIV), however, requires significant reform at the FDA.
In simple terms, this would mean expanding the agency's accelerated approval designation, to most (if not all) drugs (or at least those drugs where there is a well-established link between surrogate markers and clinical results).
But here's the catch many surrogate endpoints aren't well-vetted. And the value of surrogate endpoints is only relevant insofar as they can accurately predict positive clinical effects.
The other approach, noted by the researchers, would be targeted R&D subsidies. While we currently have a temporary R&D tax credit that helps spur pharmaceutical research, the tax credit has to be renewed each year (creating uncertainty) but it also isn't targeted (that is, it doesn't change the cost of developing a high-value medicine relative to the cost of a lower-value drug). The general idea would be to focus subsidies (perhaps through public financing of clinical trials) on drugs that may not have well-established surrogate endpoints, but may have promise in curing early stage diseases or preventing them altogether.
Both solutions have their share of potential stumbling blocks. For starters, because validating surrogate endpoints can be challenging, increasing federal support for doing so should be a first-order concern. As I've written elsewhere, funding for the National Institutes of Health is critical in this regard, as it is one of the agencies best positioned to help do so.
And while in theory, targeted subsidies can help defray much of the cost of developing high-value drugs, determining which inventions should qualify (generally they should target early-stage diseases and diseases prevention) would likely be on a case-by-case basis (again, increasing uncertainty).
Looking further, while eliminating the commercialization lag would help incentivize firms to invest in areas where the current system discourages spending, the high prices of some drugs would still be an issue. $100,000 cancer drugs, even if developed, can become a substantial cost burden even for some Americans with otherwise generous insurance coverage. (The ACA's annual out of pocket limits will help to some extent, but by mandating coverage of many benefits, the ACA also puts increased upward pressures on deductibles and co-pays, including for high cost medicines, as well as tighter formularies. This is, in fact, the opposite of what you'd like to achieve routine, one-off costs, should be paid out of pocket, while large costs should be exactly what is covered by insurance.)
One way to address this (that would avoid innovation-killing price controls) is through a tactic initially pioneered by (now) Harvard economist Michael Kremer and endorsed by George Mason University economist, Tyler Cowen patent buyouts. Under this approach, the government could purchase patents of approved drugs from companies and place them in the public domain, immediately making the drug generic.
Leaving technical details aside (for interested readers, however, the price would be based on second-price sealed-bid auctions), the idea is that the government would pay the inventor the private value of the drug, plus some markup. (The sale of the patent would still be entirely voluntary, and the patent holder could always decline the sale.) The private value would be determined through an auction where other companies would be allowed to bid on the patent, and in a small number of random cases, the government would award the patent to the auction winner (this is to ensure that bidders don't bid randomly, but actually reveal their preferences). All in all, for drugs with very large differences between the competitive equilibrium price and the monopoly price (generally drugs with very high social value), this would eliminate the temporary price distortions created by monopoly patents, making life-saving drugs much more widely available (and affordable) than would otherwise be the case.
A few serious caveats: Such a system would necessitate some large government outlays (possibly to the tune of hundreds of billions of dollars, though this cost could be slashed with reforms of the FDA approval process). There is also the problem of follow-on innovations: typically, first in class products will still be on patent when follow on products launch a few years later. With patent buyouts, such drugs would face generic competition immediately, and companies may decide to avoid development new products in this case.
Indeed, the revenues that accrue to first in class drug incentivize additional research. Putting a first-in-class product directly into the public domain after FDA approval, creating an instant generic, would put strong downward pricing pressure on follow-on innovations, reducing incentives for further research. And there's always the danger that public and private insurers would just reimburse for these generic-first drugs; the VA, for instance, doesn't cover many newer medicines. This is far from an insurmountable concern, however.
Under Kremer's model, the price paid would likely be greater than the private value of the drug incorporating a good deal of social value as well, in order to avoid this exact problem. Moreover, for some categories of medicines, where research is especially risky or time consuming, or demand is low (i.e., a malaria vaccine) this approach could effective act as an advanced purchase commitment, similar to those used by non-profits today. The long and the short of it is that we are almost certainly underinvesting in new medicines that have enormous social benefits, and driving up their costs once they reach market. As such, thinking carefully about existing patent incentives and FDA regulatory reforms would be necessary to both spur more innovation and assure broad patient access within a reasonable time frame. (as Alex Tabarrok has noted, FDA reform and patent reform could be complementary strategies).
Still, patent buyouts would eliminate much of the monopolistic distortions inherent in all patents, without dampening incentives to innovate.
Of course, this is all easier said than done. Over the long run we need to generate more new drugs, for the people who need them the most. We'll need creative solutions that are sustainable for patients, payers, and industry.
Original Source: http://www.forbes.com/sites/theapothecary/2014/05/13/fix-the-fda-fix-patents-save-lives/
America's Legal Order Begins to Fray Heather Mac Donald, 09-14-15
Ray Kelly, Gotham's Guardian Stephen Eide, 09-14-15
Time to Trade in the 'Cadillac Tax' on Health Insurance Paul Howard, 09-14-15
Hillary Charts the Wrong Path on Wage Inequality Scott Winship, 09-11-15
Women Would Be Helped the Most By an End to the 'Marriage Penalty' Diana Furchtgott-Roth, 09-11-15
A Smarter Way to Raise Paychecks Oren Cass, 09-10-15
Gambling with New York's Pension Funds E. J. McMahon, 09-10-15
Vets Who Still Serve: After Disasters, Team Rubicon Picks Up the Pieces Howard Husock, 09-10-15
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|Date & Location
|Travis Tritt
|Thursday, November 5, 2015 at 7:30 PM
Salem Civic Center
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|Saturday, November 14, 2015 at 10:30 PM
Billy Bobs
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|Friday, December 4, 2015 at 8:00 PM
Count Basie Theatre
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|Saturday, December 5, 2015 at 8:00 PM
Hard Rock Rocksino - Northfield Park
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|Saturday, December 12, 2015 at 8:00 PM
Cypress Bayou Casino
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|Thursday, January 7, 2016 at 6:30 PM
Beacon Theatre - VA
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|Tuesday, January 12, 2016 at 7:30 PM
Birchmere Music Hall
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|Thursday, January 14, 2016 at 8:00 PM
The Ridgefield Playhouse
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|Friday, February 19, 2016 at 8:00 PM
Atlanta Symphony Hall
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Mahaffey Theater At The Progress Energy Center
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Travis Tritt Northfield - Hard Rock Rocksino - Northfield Park
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Travis Tritt Melbourne - Melbourne Auditorium
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