text:
A bipolar transistor in which the emitter possesses a double "mesa" structure so as to achieve the maximum avoidance of the phenomena of electron/hole recombinations that have a deleterious effect on the current gain. The double mesa emitter can be made out of an alternation of materials MI /MII having different types of behavior with respect to a pair of etching methods. These materials may be GaInP and GaAs.
1. A heterojunction bipolar transistor including Group III-V semiconductor materials, said transistor comprising:
a substrate having a respectively superimposed collector, base and emitter, wherein the emitter has a double mesa structure comprising at least a first layer, a second layer and a third layer that are superimposed starting from the base, said first and said second layer having a greater section than a section of said third layer, the sections of the first, second and third layers being defined in parallel to the substrate, wherein said first layer and said third layer are made of a first semiconductor material and wherein said base and said second layer are made of a second semiconductor material with said first and second semiconductor materials exhibiting different behavior with different etching methods.
2. A heterojunction bipolar transistor according to claim 1, wherein the first material is GaInP and the second material is GaAs.
3. A heterojunction bipolar transistor according to claim 1, wherein the emitter also has a fourth layer superimposed on the third layer, said fourth layer being more weakly doped than said third layer so as to constitute a ballast resistor integrated with the transistor.
4. A heterojunction bipolar transistor according to claim 1, further comprising at least one layer facilitating the setting up of an ohmic contact with higher doping than the layers constituting the emitter.
5. A heterojunction bipolar transistor according to claim 1, further comprising electrical insulation trenches formed by ion implantation at the collector, on either side of the superimposition of the collector, base and emitter.
1. Field of the Invention
The field of the invention is that of bipolar transistors and especially vertical structure heterojunction bipolar transistors in which the current is conveyed perpendicularly to the surface of the substrate, these transistors being used for microwave applications.
They are formed by a stack of layers of semiconductor materials, at least one surface layer of which is etched in "mesa" form, namely in a raised or embossed pattern. FIG. 1 describes the conventional structure of a heterojunction bipolar transistor or HBT whose emitter, base and collector are at three different levels. Conventionally, a contact CE is made on the surface of the emitter by the superimposing of matched layers. Laterally, two contacts CB1 and CB2 are made in the base on either side of the emitter and two contacts CC1 and CC2 are also made in the collector on either side of the base.
This type of vertical structure raises a problem of electron/hole recombinations at the free surfaces s1 and s2 shown in FIG. 1. These recombinations play a major role in the deterioration of gain in current.
The smaller the transistors, the greater is this phenomenon (through leakage of electrons at the edges). The microwave applications of vertical structures of this kind are therefore highly penalized by this problem. Indeed, for operation in microwave applications, a bipolar transistor consists of several parallel-connected elementary transistors (also called fingers) and in order to limit the base resistance of an elementary transistor, it is necessary to limit the width of the emitter. Typically, the width of a finger must be in the range of 2 μm for applications at frequencies below 100 GHz while the length of the emitter finger may be about 30 microns.
2. Description of the Prior Art
There have already been certain solutions brought to bear on this problem, especially for HBT transistors made with GaAlAs/GaAs materials. In particular, one approach envisaged has been that of introducing a passivation layer between the emitter and the base creating an intermediate depopulated zone in which the electron/hole recombinations are made practically impossible because of the disappearance of the free carriers in this zone. More specifically, FIG. 2 shows a structure in which the emitter has a particular architecture obtained by partial etching of a GaAlAs layer deposited on a p doped GaAs layer constituting the base. Two contacts CB1 and CB2 are made at the emitter level on the surfaces s'1 and s'2. Then, by an appropriate processing operation, these contacts may be diffused over the thickness eo. In this configuration, the electron/hole recombinations in the base, which were earlier fostered on the free surface of the base, are limited because of the emitter thickness eo kept above the base. The problem with this type of structure however lies in its poor stability inasmuch as the diffusion made for the contacts cannot be entirely controlled and may therefore continue to develop with time and temperature.
This is why the invention proposes an optimized heterojunction bipolar transistor structure in which the surface recombinations are minimized through a particular emitter architecture.
More specifically, an object of the invention is a heterojunction bipolar transistor based on group III-V semiconductor materials comprising a substrate on which there are respectively superimposed a collector, a base and an emitter, wherein the emitter has a so-called "double mesa" structure comprising at least three layers (1), (2) and (3) of semiconductor materials MI, MII, MIII, that are superimposed starting from the base, the layers (1) and (2) having a greater section than the section of the layer (3), the sections of the layers being defined in parallel to the substrate, the layer (1) being weakly doped to provide for the passivation function.
Preferably, the layers (1) and (3) are formed out of the same semiconductor material MI, the materials MI and MII having different types of behavior with respect to a pair of etching methods.
In the bipolar transistor according to the invention, the material MI is preferably GaInP, the material MII being preferably GaAs.
The heterojunction bipolar transistor may furthermore advantageously include a layer (4) integrated between the emitter itself and layers providing access to the contact CE. This layer may typically be prepared out of the material (III) more weakly doped than in the layer (3) to form a ballast resistor integrated into the emitter.
The presence of this layer (4) may prove to be particularly valuable in power applications that particularly use parallel-mounted heterojunction bipolar transistors, these being applications for which the phenomenon of thermal racing is crucial.
Indeed, the fundamental mechanism of thermal racing arises out of the difference of about -1.5 mV/K in the characteristic IE (VBE) (emitter current as a function of the voltage applied between the emitter and the base). This means that a fraction of the elementary component drains most of the emitter current. If for example the base current is fixed, the greater the heat of the component the more the current gets concentrated in the hottest zones which are increasingly localized. This mechanism finally induces the formation of a hot point which leads to the destruction of the device.
The use of an integrated resistor as compared with the conventional approach in which an external resistor is added to the emitter makes it possible to reduce the value of the resistance needed to overcome thermal racing by about 30% (assessed experimentally), which consequently leads to a substantially higher level of performance.
The invention will be understood more clearly and other advantages will appear from the following description, given by way of a non-restrictive example and from the appended figures, of which:
FIG. 1 illustrates a standard bipolar transistor structure;
FIG. 2 illustrates an architecture of a bipolar transistor according to the prior art;
FIG. 3 illustrates the bipolar transistor structure according to the invention;
FIG. 4 illustrates an exemplary epitaxial structure, used in a heterojunction bipolar transistor according to the invention;
FIG. 5 shows a general sectional view of an exemplary bipolar transistor according to the invention.
FIGS. 6(a)-6(c) detail steps in making the device of FIG. 1.
The invention proposes a novel bipolar transistor architecture, and especially a heterojunction bipolar transistor architecture in which the emitter has an original structure. FIG. 3 illustrates this structure consisting of at least three layers (1), (2) and (3) superimposed on the base B which is itself superimposed on the collector C. By using materials MI and MIII such that their etching is very well controlled on the base B and the layer (2) respectively, it is possible to achieve the "double mesa" architecture of the emitter on the base. This makes it possible therefore to prepare the base contacts CB1 and CB2 without resorting to processes of diffusion in the emitter medium as proposed in the prior art.
The invention shall be described in the precise case of a heterojunction bipolar transistor made with GaInP and GaAs semiconductor materials. Indeed, this pair of materials is particularly valuable as compared with the more conventional GaAl/As/GaAs system for several reasons.
There are several etching methods, either by aqueous chemical means or by dry etching, that can be used to selectively etch the pair GaInP/GaAs. Thus, it is possible to entirely etch a layer made of GaInP and stop at a layer of GaAs with an infinite degree of selectivity.
More specifically, using an epitaxially grown transistor structure having all the functional layers of semiconductor materials, it is possible to obtain the geometry illustrated in FIG. 3.
The heterojunction bipolar transistor can thus be made out of a succession of the following layers illustrated in FIG. 4.
On a semi-insulator GaAs substrate S, the following are made in a standard way:
a sub-collector layer (SC) which is typically made of GaAs (Si) with n doping in a concentration of 4.1018 cm-3 and a thickness of the order of 800 nm;
a collector layer (C) made of GaAs (Si) with n doping in a concentration of 2.1016 cm-3 and a thickness of the order of 1,000 nm;
a base layer (B) made of GaAs (carbon) with p doping in a concentration of the order of 7.1019 cm-3 and a thickness of the order of 120 nm.
Then, the following layers of the emitter structure to which the invention pertains are made:
a layer (1) made of GaInP (Si) with n doping in a concentration of 3.1017 cm-3 and a small thickness of about 30 nm;
a layer (2) made of GaAs (Si) with n doping in a concentration of 3.1018 cm-3 and a very small thickness of about 5 nm;
a layer (3) made of GaInP (Si) with n doping in a concentration of 3.1017 cm-3 and a thickness of about 120 nm.
Preferably, a ballast resistor layer is integrated into the emitter structure. This is a layer (4) with a doping concentration lower than the doping of the layers (1) to (3), namely:
a layer (4) made of GaInP (Si) with n doping in a concentration of 7.1016 cm-3 and a thickness of 250 nm.
The following are also integrated in a conventional way:
a layer (5) of GaInP (Si) with high n doping in a concentration of 3.1018 cm-3 and a thickness of about 100 nm. This layer is used as a transition layer between the emitter which is formed mainly by GaInP and an upper layer made of GaAs, making it easier to set up the ohmic contact of the emitter;
a layer (6) of GaAs (Si) with high doping in a concentration of 3.1018 cm-3 and a thickness in the region of 200 nm;
an optional layer (7) made of Ga1-x Inx As (Si) with doping in a concentration of 3.1018 cm-3 and a thickness of 20 nm on which the emitter contact CE is made.
Using the stack of all these layers, the desired architecture is made by the selective etching of the pair GaInP/GaAs. The lateral dimension of the "mesa" comprising the layer (3) is fixed by a dry etching method such as reactive ion etching (RIE) which uses the emitter ohmic contact as an etching mask; the emitter contacts CE are made beforehand on the upper layer (7). The metallizations used to make the metal contacts may be an alloy of AuGe/Ni/Au.
In a second stage, the entire unit may be covered with a positive resin, subsequently etched at the position where it is desired to demarcate the lower "mesa" corresponding to the layers (1) and (2). In the zones not covered with resin, the layers (1) and (2) are etched up to the surface of the base.
By ion implantation of boron, it is possible to prepare electrical insulation trenches (Cl) so as to limit the base-collector capacitance values. The boron gets diffused in depth beneath the base layer, on which it is possible subsequently to define the base contacts CB1 and CB2 by metallization (illustrated in FIG. 5).
The removal of the resin on the protected zones leads to the obtaining of the desired structure.
The entire unit is covered with a protective passivation layer (P).
Patent Citations
Non-Patent Citations
Referenced by
Legal Events
Original Image


text:
HTC Mobile Phones Online @ MobileCiti
HTC mobile phones are products that Australians have come to know and trust for superb functionality, a multitude of applications and consistently good performance. HTC phones are the must have accessory for the modern world and at MobileCiti, we are proud to stock a huge range of the very latest unlocked HTC phones models.
We offer unrivalled discounts to ensure you get the best deal on network unlocked HTC phones! That includes the HTC Velocity, HTC Wildfire, HTC Desire, HTC Salsa and HTC Sensation - you can even buy an HTC One for less! MobileCiti is committed to the very best products at the lowest possible prices, which is why we offer such an extensive range of HTC mobiles.
MobileCiti is renowned for offering the best possible service when it comes to shopping for mobile phones online, and our unlocked HTC One offerings are no different. We strive to make it quick and easy to browse and buy HTC mobiles online so you can enjoy your new purchase sooner.Read our HTC mobile phone reviews to find out more about our cheap unlocked Australian stock or check out our latest specials on our clearance page.
HTC Desire 310 Blue
Regular Price: AUD199.00
Special Price AUD129.00
HTC Desire 320 Matte Blue
Regular Price: AUD199.00
Special Price AUD155.00
HTC Desire 510 4G/LTE Grey
Regular Price: AUD249.00
Special Price AUD179.00
HTC Desire 510 4G/LTE Grey
Regular Price: AUD249.00
Special Price AUD171.00
HTC Desire 510 4G/LTE White
Regular Price: AUD249.00
Special Price AUD171.00
HTC Desire 820 (4G, 5.5" HD display) Grey
Regular Price: AUD499.00
Special Price AUD408.00
HTC One M7 801s 32GB Silver
Regular Price: AUD599.00
Special Price AUD419.00
HTC One M7 801s 32GB Silver
Regular Price: AUD599.00
Special Price AUD399.00
HTC One M7 801s 64GB Silver
Regular Price: AUD699.00
Special Price AUD449.00
HTC One M8 4G Amber Gold
Regular Price: AUD999.00
Special Price AUD549.00
HTC One M8 4G Metal Grey
Regular Price: AUD899.00
Special Price AUD579.00
HTC One M8s (2015) - Metal Grey
Regular Price: AUD899.00
Special Price AUD589.00
HTC One M9 Gold on Silver
Regular Price: AUD1,099.00
Special Price AUD859.00
HTC One Max 803s 16GB (2GB RAM, 5.9") - Silver
Regular Price: AUD899.00
Special Price AUD419.00

subset: commoncrawl


text:
Miguel Angel Jimenez's second hole-in-one in two weeks defied ...SHARE TWEET SMS SEND EMAIL Most golfers play their whole life in search of a hole-in-one. Miguel Angel Jimenez — dubbed the world's most interesting golfer — just made his second in two weeks. That brought the ... USA Today, 1 month ago
Jimenez enjoys record ace - Sky Sports, 1 month ago
Jimenez's record-breaking hole-in-one - BBC, 1 month ago
225 images for miguel angel jimenez
Golf - Francesco Molinari and An lead PGA Championship
Francesco Molinari and An Byeong Hun shared the lead at the PGA Championship but it was Miguel Angel Jimenez and Tommy Fleetwood who produced the real third-round fireworks on Saturday. 9 minutes ago Reuters . View photo Francesco Molinari ...Yahoo! UK and Ireland Eurosport, 1 month ago Molinari and An lead European PGA Championship, Jimenez and Fleetwood sparkle ABC Online, 1 month ago Golf-Molinari and An lead but Jimenez and Fleetwood steal glory Yahoo! UK and Ireland Eurosport, 1 month ago Molinari and An lead but Jimenez Fleetwood steal glory MENAFN, 1 month ago
Fleetwood and Jimenez provide fireworks
Rory McIlroy's absence was barely noticed as an albatross from Tommy Fleetwood and a hole-in-one from Miguel Angel Jimenez lit up the third round of the BMW PGA Championship. Rory McIlroy's absence was barely noticed as an albatross from Tommy ...Irish Independent, 1 month ago Video: Tommy Fleetwoods makes an ALBATROSS and Miguel Angel lands ANOTHER hole-in-... Irish Independent, 1 month ago Fleetwood, Jimenez thrill crowds AOL UK, 1 month ago Barcelona - Deportivo La Coruna Betting: Back the Blaugrana to shade a high scoring affair at the Camp Nou Fnews.com, 1 month ago
Westwood, Poulter join Chambers Bay field
Lee Westwood, Ian Poulter and Miguel Angel Jimenez highlight the field of 24 players who earned exemptions on Monday to next month's US Open Championship. Westwood was runner-up in the British Open and Masters tournaments in 2010 while fellow ...CHINAdaily.com.cn, 1 month ago Westwood added to US Open field Asian Connection, 1 month ago (Golf) Westwood, Poulter join US Open field Hong Kong Standard, 1 month ago Westwood, Poulter get nod Shanghai Daily, 1 month ago
Miguel Angel Jimenez is going to feature in EA Sports' new golf video game
SHARE TWEET SMS SEND EMAIL (EA Sports) Rejoice! Thethe 51-year-old, cigar smoking, most interesting golfer on tourMiguel Angel Jimenez, is going to feature in EA SportsRory McIlroy PGA Tour when it is released on ...USA Today, 3 weeks ago
Video: 'You're my hero' - Rory McIlroy is clearly fond of Miguel Angel...
Sports fans love the cool man of golf Migeul Angel Jimenez and clearly world number one Rory McIlroy shares the sentiment. Sports fans love the cool man of golf Migeul Angel Jimenez and clearly world number one Rory McIlroy shares the sentiment.Irish Independent, 1 month ago Different Strokes: Rory McIlroy's charming Irish Open, Miguel Angel Jimenez wins a BMW and Colin Montgomerie tastes major glory Yahoo! Maktoob News, 1 month ago McIlroy frustrated as Molinari grabs two-shot lead Taipei Times Online, 1 month ago Wentworth: 1st round highlights Sky Sports, 1 month ago
Harrington fighting fit for Irish Open challenge at Royal County Down
Three-time Major champion gets extensive treatment to overcome a shoulder injury Miguel Angel Jimenez in lighthearted form during practice for the Irish Open at Royal County Down GC yesterday. Photo: Matt Mackey/Inpho/Presseye Philip Reid Topics: ...Irish Times, 1 month ago Irish Open 2015: Pictures from Tuesday's Practice Round Irish Mirror, 1 month ago PGA European - Lyoness Open Preview Miami Herald, 3 weeks ago Dubai Duty Free Irish Open Leading Scores MySanAntonio, 1 month ago
More from: ESPN.com, Irish Mirror...and 5 other sources
Golf-Poulter and Jimenez among 25 players exempt for U.S. Open
May 26 (Reuters) - England's Ian Poulter and Lee Westwood, Spaniard Miguel Angel Jimenez and Frenchman Victor Dubuisson are among 25 players who have booked their places at next month's U.S. Open via this week's world rankings. The quartet ...Reuters Africa, 1 month ago Ian Poulter and Miguel Jimenez among 25 players to book places at the US Open Stuff.co.nz, 1 month ago Poulter and Jimenez among 25 players exempt for US Open MENAFN, 1 month ago Ian Poulter and Anirban Lahiri among 25 players exempt for US Open IBNLive India News, 1 month ago
Anirban Lahiri set to live his Augusta dream
Indian paired with former World No. 1 Lee Westwood and flamboyant Spaniard Miguel Angel Jimenez at first major of the seasonDNA, 2 months ago Lahiri to pair with Westwood, Jimenez at Masters Rediff.com, 2 months ago Lahiri soaks in atmosphere, to pair with Westwood, Jimenez Jagran Post, 2 months ago
Maui Jim Signs Pro Golfer Miguel Angel Jimenez as Ambassador
Maui Jim Inc. has added Professional Golfer Miguel Angel Jimenez to its team of ambassadors. The announcement was made at the BMW PGA Championship at Wentworth Club for which Maui Jim is the Official Eyewear Supplier. With 23 tour victories ...Sports One Source, 1 month ago Jimenez Joins Maui Jim's Team of Ambassadors Industrial Info Financials, 1 month ago
Realtime News
on your WebpageAdd Widget >Get your members hooked!


text:
Skype opens door to real-time translation feature
Microsoft-owned Skype on Tuesday cleared the way for anyone to use a new feature that translates video chats or instant messages in real time.
It's good to talk: app aims to spur voice renaissance
Two former Google employees are hoping an innovative new phone application will trigger a renaissance in an increasingly unfashionable method of human communication: talking.
Skype to unveil group video chat function
(AP) -- Internet calling service Skype plans a public "beta" test of a group video chat function that lets up to five people participate in a video call simultaneously.
Most NSA data from regular Internet users, report says (Update)
Nine out of 10 people identified in a large cache of online conversations intercepted by the National Security Agency were ordinary Internet users and not foreign surveillance targets, a news report says.
UK: Surveillance devices to monitor Web traffic (Update)
The U.K. plans to install an unspecified number of spy devices along the country's telecommunications network to monitor Britons' use of overseas services such as Facebook and Twitter, according to a report published Tuesday ...
Skype replaces Microsoft Messenger for online calls
Microsoft on Tuesday announced that recently-acquired Skype will replace its Messenger online chat service.
IBM Researchers Lower Language Barrier With Text Translator
IBM Researchers are helping to break the language barrier with the advent of technology dubbed "n.Fluent" -- smart software that translates text between English and 11 other languages. IBM employees use it to instantaneously ...
Researchers develop prototype to detect fake websites
(PhysOrg.com) -- Do you go online to pay bills, shop, transfer funds, sign up for classes, send email or instant messages or search for medical information? If so, then this pertains to you.
Emoticons may signal better customer service
Online customer service agents who use emoticons and who are fast typists may have a better chance of putting smiles on their customers' faces during business-related text chats, according to researchers.
Meet the new old thing—mobile messaging
When it comes to online communication, the big thing these days is mobile messaging.
Facebook launches mobile messaging app
Facebook launched a mobile messaging application Tuesday for Apple's iPhone and Android devices.
China's Alibaba to launch mobile operating system
China's leading e-commerce company Alibaba said Friday it will launch a mobile operating system, joining industry giants Google and Apple in providing software for smartphones.
Microsoft takes Office into the 'cloud' (Update)
Microsoft took its Office software into the Internet "cloud" on Tuesday, moving the suite of popular business tools online amid budding competition from Google's Web-based products.
Viewdle lets Android smartphones recognize friends
Northern California startup Viewdle on Wednesday released software that lets Android-powered smartphones recognize people's faces.


text:
If Luxury Designers Created Everyday Items
Why You Should Talk About Your Ex on a First Date
What Happens When You Miss a House or Car Payment?
10 Steps to Asking for the Raise You Desire
Halle Berry Just Dropped Major Surgery News
Simple Fixes For Bad Spending Habits
4 How-To Tips to Get Your Child Into Modeling
Dating Advice: Six Tips for Meeting Someone Special in 2015
#1 Predictor of Diabetic Amputation
6 Edgy Pieces to Instantly Update Your Style
Our 5 Favorite Celeb BFFs
Techniques to Make Your Groceries Last Longer
Getting Old Pays Off: Wonderful Discounts for Seniors
Learn From The Stars: How Long Should Your Engagement Be?
Eat Smart: Save Dollars While Dining Out
10 Ways to Become More Likeable in Business
Dinner Date Ideas to Turn Up the Heat
Watch Ellen Shut Down Bethenny Frankel's Ignorant Comments
Brad Pitt & Angelina Jolie: When is it Time to Seek Help?
5 Mistakes People Make When Working From Home
32 Ridiculously Cute Queer Women Couples
5 Things You Should Never Pay Full Price For
3 Tips to Help Graduates Land Employment
Items That Are Safe to Splurge On
The Real Cost of Cats and Dogs
BBQ on a Budget: 10 Things for the Perfect Cookout
Is Getting Hitched Irrelevant These Days?
Which Major Company Just Announced Their Pro LGBTQ?
Perfecting The Glam Pixie Cut


text:
Art F City
Posts tagged as:
Earlier today, Pussy Riot's Nadya Tolonnikova and fellow activist Katya Nenasheva were detained in Moscow for a public performance in solidarity with Russia's female prisoners.
A photo from the Tumblr ourpublicprivates next to a photo from a New York Times profile on Mike D's townhouse.
Image via SodaHead
Postcard from the original "Congo Village" exhibition. Courtesy the Art Newspaper.
Good morning. Bryant Park's ice rink closes this weekend, but we know it's still winter—snow starts falling on Sunday.
Brave the cold just a little longer, for we have so much art to see this week. Talks abound, from B. Wurtz on the history of sculpture to Winkleman Gallery's panel on African-Americans in Soviet culture. We have openings, like a feminist sound art retrospective at CUNY and Greenpoint's winter open studios night. Round out Sunday with a Genesis Breyer P-Orridge film-screening and book launch at PS1 and we'll call it a week. Just grin and bear it.
← Previous Entries
Advertise on AFC with Nectar Ads
WordPress Admin


text:
Marriage and the Family (Concise Edition): Biblical Essentials
- Occasion▼▲
- Audience▼▲
- Binding▼▲
- Features▼▲
- Format▼▲
- Language▼▲
- Media Type▼▲
- Series▼▲
- Guides & Workbooks▼▲
- Author / Artist▼▲
- Publisher▼▲
- Top Rated▼▲
- Price▼▲
- Discount▼▲
Product Description
Product Information
|Format: Paperback
Number of Pages: 192
Vendor: Crossway
Publication Date: 2012
|Dimensions: 8.25 X 5.50 (inches)
Availability: In Stock
Related Products
- eBOOK
Marriage and the Family: Biblical Essentials - eBookAndreas J. Kostenberger, David W. JonesCrossway / 2012 / ePub$7.99 Retail:
$9.99Save 20% ($2.00)Availability: In StockCBD Stock No: WW28971EB
No Ordinary Marriage: Together for God's GloryTim SavageCrossway / 2012 / Trade Paperback$11.99 Retail:5 Stars Out Of 5 1 Reviews
$14.99Save 20% ($3.00)Availability: In StockCBD Stock No: WW530332
God, Marriage, and FamilyAndreas Kostenberger, David JonesCrossway / 2010 / Trade Paperback$15.99 Retail:5 Stars Out Of 5 2 Reviews
$22.99Save 30% ($7.00)Availability: In StockCBD Stock No: WW503641
The Case Against Gay Marriage - Word Document [Download]Christianity Today InternationalChristianity Today / 2009 / Word Document$4.95Availability: In StockCBD Stock No: WW1123DF
Publisher's Description
During a time of cultural ferment and crisis with regard to marriage and the family, this book provides a timely solution, speaking directly to current issues and explaining the Bibles teaching on marriage and family.
Author Bio
Andreas J. Köstenberger (PhD, Trinity Evangelical Divinity School) is senior research professor of New Testament and biblical theology at Southeastern Baptist Theological Seminary in Wake Forest, North Carolina. He is a prolific author, distinguished evangelical scholar, and editor of the Journal of the Evangelical Theological Society. His books include The Heresy of Orthodoxy, God, Marriage, and Family, The Final Days of Jesus (with Justin Taylor), and God's Design for Man and Woman (with Margaret Köstenberger). Dr. Köstenberger and his wife have four children.
David W. Jones serves as Associate Professor of Christian Ethics and Coordinator of Th.M. and Thesis Studies at Southeastern Baptist Theological Seminary. He is the author of Reforming the Morality of Usury, the co-author of God, Marriage, and Family, and the co-author of Health, Wealth, & Happiness. Dr. Jones has also authored more than a dozen articles that have appeared in various academic publications and is a frequent speaker at churches, ministries, and Christian conferences. Dr. Jones currently resides in the Raleigh/Durham area of North Carolina with his wife and four children.
Product Reviews
Ask Christianbook
Ask Christianbook
Find Related Products
- Books >> Family >> Marriage & Divorce >> Marriage
- Family >> Marriage & Divorce >> Marriage
- Start A New Search


text:
Doctor insights on:
Pain In Lower Abdomen Back And Legs
Dr I have severe pain & burning sensation while urinating..feels to urinate frequently..also have pain in lower abdomen back sides and leg joints.help?
Urinary tract infect: You have urinary tract infection & need antibiotics.If you are not allergic,take bactrim DS 1 tablet twice daily for 7 days.In India you can get it in the pharmacy. need to take plenty of fluids.coconut water is very good.If your symptoms do not disappear,see a doctor. ...Read moreGet help from a doctor now ›
Lower Abdomen (Definition)
The lower abdomen is the area below the umbilicus(belly button) from one side of the ...Read more
Pain in lower abdomen, lower back and legs. Pain so bad I can't stop moving legs. Also, running a fever of 103. Very lightheaded when standing. ?
Go to the ER: You need to be evaluated and treated. Fever usually is due to underlying infenction and usually urinary tract infection is frequent to see in females but still can be due to other diseases. Again go to ER since simple testing can help to elucidate your diagnosis. Lightheaded probably you are dehydrated due to the fever. ...Read moreGet help from a doctor now ›
Hello, I'm a 25 year old experiencing pain to lower right abdomen, back, right leg. What could be causing this pain.?
Sciatica versus...: Causes of recurrent abdominal discomfort as described may be identified by first addressing signs/symptoms so as to localize the organ involved: in women: vaginal discharge or bleeding, alteration in periods, pregnancy risk? Fever, nausea, vomiting, altered stool pattern, blood with stool, tenderness, distension? Painful urination, blood in urine? Recent trauma, herniation? Stressors? Other risks? ...Read moreGet help from a doctor now ›
Ectopic removed 4 months back period delayed by 5 days, pregnancy test negative, pain in lower abdomen and lower back and legs, tiredness ?
Pain: Because you've had a prior ectopic, I would suggest a blood pregnancy test thru your providers office. In addition since ectopics are increased with a history of pelvic infection, it might be a good idea for further office evaluation. This could also be that you didn't ovulate this cycle, but with your history its better to be safe and see your doctor/gyn ...Read moreGet help from a doctor now ›
Iud for 2 yrs. For 1st time bleed for 6 days drk brown. Felt heviness in area till period date then another 7days pain in abdomen lower back, leg.Why?
Mirena : If you have a Progesterone iud like Mirena then no periods occur in about 50% of users. An occasional menstrual cycle should not be a surprised. Brown just indicates old blood. If you are concerned or if it continues then schedule a check up. ...Read moreGet help from a doctor now ›
Gas, bloated, increased waist size, swollen abdomen, pain= lower abdomen, back & leg, constipation, frequent urination & pain in sex. Overian cancer?
Your a bit young: Ovarian cancer is a possibility, however not likely do to your age. With that said, this does require a work up and you need to be seen by a doctor asap. ...Read moreGet help from a doctor now ›
Abnormal periods, several PT, neg. Pain in right lower abdomen, radiates to back. Leg pain. Loss of appitite. Wieght loss. Uncomfortable bowel movemnt?
Need pelvic exam: You could have a problem with your ovary so you should have a complete GYN exam. It is also possible to have a colon or kidney problem causing pain in the right lower abdomen. ...Read moreGet help from a doctor now ›
Lower back and lower abdominal pain that radiates down legs. Low left ab sharp pain (like something's there) and goes down leg. What could it be?
Pelvic pain ? : This sounds like something is compressing on your sacral nerves internally, or perhaps chronic nerve damage from the previous Caesarean section surgery. I suggest you see both an OB and pain specialist to pinpoint what this could be ...Read moreGet help from a doctor now ›
Its been 2 weeks of my IUI I have been getting crampings lower abdominal pain back pain and leg pain early morning nausea is it a good sign?
Might be ...: Time to get a blood pregnancy test: your symptoms can all occur in early pregnancy. If you're not pregnant get checked our for a urine infection, or a pelvic infection, which is rare after an iui. ...Read moreGet help from a doctor now ›
I have a blood clot in.right leg. Lower back pain on.right side, sciatica on right and lower abdominal pain with chills when I utinate?
Symptoms: I don't see a precise question. The abdominal pain and chills on urination sound like a urinary tract infection. You shoule be on a 'blood thinner' for the blood clot and a repeat ultrasound should be done in a week or so.Other pain sounds unrelated. ...Read moreGet help from a doctor now ›
- Talk to a doctor live online for free
- Will a lower back injury cause pain in the abdomen and groin area
- Dull pain in lower right abdomen and back
- Pain in lower left abdomen and left leg
- Ask a doctor a question free online
- Blood in urine discomfort in lower abdomen and back pain
- Can hyperthyroidism cause pain in lower left abdomen and back?
- Lower back pain and pressure in lower abdomen during pregnancy
- Pain in lower right abdomen and leg
- Pain in lower right abdomen and back and leg


text:
You are always welcome here at ringtone download service Audiko.net, where it's possible to use killer ringtones for your ringer. Today we have a ringtone of "Single tone" by Samsung as well as 35079 other ringtones by Samsung. "Single tone" is one of the best tracks from the "Samsung" album that was issued by Samsung at their label together with other 144 tracks. You can listen to all 4 Samsung – "Single tone" ringtone variations available here and download it for free directly to your smart phone. You can also listen to other 13 albums produced by Samsung for all time. "Single tone" is referred to , and you can download a huge amount of ringtones absolutely for free. And finally, we have collected lyrics for this track and you can view it here as well. So feel free to browse, listen, download ringtones at Audiko.net. Make your phone sound cool!
Samsung Single tone Ringtone
Albums by Samsung
Top ringtones by Samsung
New ringtones
- Juan Magan - Si No Te Quisiera ft. Belinda Lapiz Conciente (Vi
- Mindbenders - Groovy Kind Of Love
- Your - wife
- hello - joe
- Izaya-kun - Izaya-kun
- Andrea Bocelli & Giorgia - Vivo per lei
- RTTWLR - RTTWLR - Best Minimal Techno 2015 VOLUME THREE
- ard adz - Tell me Why @Ardadz
- Robin S. - Show Me Love - Marimba Ringtone
- Ñàòè Êàçàíîâà - Ñ÷àñòüå Åñòü


text:
Thornville woman flown to Columbus hospital from Heath crash
1:21 AM, Jul. 11, 2013
Email this article
Thornville woman flown to Columbus hospital from Heath crash
A 25-year old Thornville woman was taken by medical helicopter to the Wexner Medical Center at Ohio State University after a one-vehicle crash Wednesday morning on Thornwood Drive.
A link to this page will be included in your message.
View the last seven days
- Yesterday, Jul. 05
- Saturday, Jul. 04
- Friday, Jul. 03
- Thursday, Jul. 02
- Wednesday, Jul. 01
- Tuesday, Jun. 30
- Monday, Jun. 29
See our paid archives for news older than a week.
Things To Do
MORE Events | Submit an Event
Real Deals
Flip, shop and save on specials from your favorite retailers in central Ohio.
Most Commented
sign up for home delivery today


text:
Drinking Beer Through Your Ear
Drinking Beer Through Your Ear
SoBe Apologizes For 'Help Me' Message
Unlock your personal NFL Now stream by signing in to NFL.com
Broken News Daily
Have you ever gone swimming and gotten water in your ear? So annoying! Now, have you ever tried to drink beer through your ear? So weird! One woman allegedly tried this at the Czech Beer Festival and the resulting video is an odd thing of beauty. She uses a bendy straw and everything. But is it real or fake? Gotta be fake...right?
SoBe, a juice and water brand owned by PepsiCo, likes to include funny messages under their bottle caps, like, "Marry Me" and "That's What She Said." Unfortunately, one of their new messages, " Help Me Trapped In SoBe Factory," has tricked people into thinking it's real, and now, they're apologizing for the mistake.
A driver was so distracted by his GPS that he accidentally jumped the Flagler Memorial Bridge in Palm Beach, Florida. Luckily, the driver and his passenger were uninjured, but the same can't be said about the bridge. It was shut down for five hours for repairs. The driver was cited for reckless driving, while the GPS wasn't cited at all, because inanimate objects don't have driver's licenses.
By day, Dinesh Upadhyaya is a teacher in Mumbai, but by night, he becomes the YouTube superhero, "Maximouth", with the power to shove a ton of ANYTHING in his mouth. Maximouth currently holds 48 world records for shoving weird stuff in his mouth, including: 14 glass test tubes, 224 playing cards, 79 grapes, and 6 ping pong balls, and now, 1,001 straws!
A theater full of families fled the scene this weekend at The Danbarry Cinema in Middletown, Ohio when the projectionist accidentally showed the first reel of the horror movie Insidious 3 instead of the family film Inside Out. The unnamed manager at the cinemas immediately refunded everybody their money, and then upgraded everyone to a 3D showing of the Pixar movie. But one parent still isn't happy about the incident.
A man in Idaho has answered the question none of us ever had: would Nerf darts stick to your eyes? Charles Tietjen posted the video to Reddit with the title "Nerf Gun To The Eye" with the following description: "Don't try this. I press it on very lightly and I have contacts on underneath." Which is all well and good, but still doesn't explain WHY he's doing it.
Turn On Private Browsing Mode Now, Because You Don't Want Anyone To Catch You Watching This
Did 'SYTYCD' Outburst Send Dancer Packing?
Benjamin Booker covers Patsy Cline
Admit It: You Still Have These 4 Childhood Fears
How to make True Detective season 2 more fun: forget season 1
When You're In Line Behind An Indecisive Person
Community Episode 1: Ladders
Community Episode 2: Lawnmower Maintenance and Postnatal Care
Community Episode 3: Basic Crisis Room Decorum
Community Episode 4: Queer Studies and Advanced Waxing
Community Episode 5: Laws of Robotics and Party Rights
Community Episode 6: Basic Email Security
Sin City Saints Episode 1: The Fool Monty
Sin City Saints Episode 2: Smoke and Mirrors
Sin City Saints Episode 3: Gone Catfishing
Sin City Saints Episode 4: Mrs. Wu's Tang
Sin City Saints Episode 5: A Basket Full of Rainbows
Sin City Saints Episode 6: You Booze, You Lose


text:
Swimming pools
Swimming, aqua aerobics, toddler fun and more
There are two swimming pools at Burntwood Leisure Centre.
The main pool is 25 metre and has six lanes, making it ideal for competitive or leisurely swimming. We offer ladies only and adult only sessions, as well as fun sessions for children, swimming lessons, aqua aerobics classes, pool parties and various water-based clubs.
The small pool is a 13x7 metre shallow learner pool. With poolside seating areas, it's perfect for children learning to swim and for families to bring little ones.
If you're thinking of bringing children to swim at Burntwood Leisure please check out our child admission policy.
Lane swimming - Lane ropes are put in place on Mondays, Tuesdays, Wednesdays and Fridays between 12 and 1.30pm.
Swimming lessons - We run swimming lessons for all ages and abilities. To find out what's on offer take a look at our coaching courses section.
- For opening times see the swimming pool timetable
More information
Call Burntwood Leisure Centre on 01543 308810


text:
OBH has just launched a new website called Mother's Connection, which is intended to publicize the availability of addiction treatment for women who are pregnant. We hope the information here will be useful to you.
There are two intended audiences for the content here—one of course is women who are pregnant and considering treatment for addiction issues (as well as their loved ones who may be concerned about them), and the other is professionals working in the addiction treatment field who are looking for resources and information about treatment for women. Please check it out!
The OBH contact for this project is Karen Mooney, who can be reached at 303-866-7492 or email@example.com.
July 23, 2015 8:30a-12p (Registration begins at 8:00am)
Double Tree by Hilton, Denver-Westminster
Click here for more information.
The Office of Behavioral Health has re-posted the Emergency Mental Illness Report & Application (M-1) form to appropriately reflect C.R.S. 27-65-105. The word "imminent" has been changed back from "substantial". Though the definition of "danger to self and others" has expanded to include "substantial" (please click here for further information), "imminent" still remains as a part of the legislation and process.
Working towards Recovery: Implementing an Integrated Approach
"Using Supported Employment as a mode of therapy to expedite your client's road to recovery"
Presented by:
Gary R. Bond, Ph.D.
Professor of Psychiatry
Dartmouth Psychiatric Research Center
June 25, 2015
Click here for more details.
On May 16, 2013, Governor John Hickenlooper signed into law HB13-1296, creating the Civil Commitment Statute Review Task Force under C.R.S. §27-60-102.
Pursuant to C.R.S. §27-60-102 (3), the Civil Commitment Statute Review Task Force studied the definition of "danger to self or others" as set forth in section C.R.S. §27-65-102 (4.5) and, considering the civil liberties and public safety concerns of that definition, ratified the definition by a majority vote.
C.R.S. § 27-65-105, the section that governs mental health emergency procedure, continues to read "imminent danger to others or to himself or herself…"
"Danger to self or others" has been further defined to read:
a) "With respect to an individual, that the individual poses a substantial risk of physical harm
to himself or herself as manifested by evidence of recent threats of or attempts at suicide or
serious bodily harm to himself or herself; or"
b) "With respect to other persons, that the individual poses a substantial risk of physical harm
to another person or persons, as manifested by evidence of recent homicidal or other violent
behavior by the person in question, or by evidence that others are placed in reasonable fear of
violent behavior and serious physical harm to them, as evidenced by a recent overt act,
attempt, or threat to doserious physical harm by the person in question."
Additionally, the Civil Commitment Statute Review Task Force informally considered the definition and application of the term "imminent" in C.R.S. § 27-65-105. The plain language meaning of "imminent" should be applied, and can be found here. In section 105, the term "imminent" applies to the proximity in time of the dangerousness. More specifically, the term "imminent" applies to a determination of whether the danger to others or himself or herself is current; it does not apply to how soon in time a specific dangerous act may be undertaken.
Click here for the Colorado Revised Statutes, C.R.S. § 27-65-101 - 131
Click here for more detailed information regarding C.R.S. §27-65-102 (4.5).
Transition Age Youth with Behavioral Health Challenges: Current Status and Future Directions
An Informational Report and Recommendations to Improve Outcomes for Colorado's Transition Age Youth and Their Families.
The Office of Behavioral Health (OBH) announces a Request for Applications for Law Enforcement Assistance Funds (LEAF) prevention programs related to impaired driving. The funds are designated for fiscal year 2014-2015 which begins on July 1, 2014. Please review the documents and be aware of important deadlines as well as the OBH contact to answer any questions.
**All dates and times are subject to change. Please continue to check back for updated dates and times.
Any questions regarding the training can be referred to Anh Le, email@example.com.
OBH Rules Presentation: Integrated Behavioral Health Rules Slide Presentation
The Office of Behavioral Health Rules effective 11/1/13 can be found on the Secretary of State's website through the following link: Code of Colorado Regulations - CDHS/OBH Behavioral Health Rules and Regulations
The crosswalk of the former Volume #'s of Behavioral Health rules to their corresponding section in Volume 21, 2 CCR 502-1 can be found here: Where former Rules have been Integrated into 2 CCR 502-1, Volume 21
A new statewide effort has been launched in April called "Speak Now" to get parents to talk to their teens about the dangers of underage drinking. The campaign, created by the Colorado Department of Human Services, Office of Behavioral Health, provides parents with the resources they need to start a conversation with their teen and discuss the issue of teen alcohol consumption before unpleasant behaviors develop.
The Speak Now campaign encourages parents through its campaign website (www.speaknowcolorado.org) to have prompt and continued conversations with their kids about the dangers of teen drinking. The interactive website helps parents start a conversation by sending a personal text to their teen directly from the site, and also provides a "how to start a conversation" video that includes testimonials from other Colorado parents and local law enforcement. Downloadable resources address the latest Colorado underage drinking laws, statewide statistics, and effective ways to speak about alcohol and drugs. The site also links to community resources throughout Colorado. Much of the website's content is also available in Spanish at www.hableahoracolorado.org.
We are working to improve Colorado's Impaired Driver treatment and management system by promoting quality communication and strong collaborations. We want to invite treatment providers, probation officers, parole officers, and anyone else who may be interested to join us at one of the listed training sessions.
This year there are six sessions scheduled around the State. Please pass this link on to all agency staff and personnel. Just click on the link below and complete the registration form. Registration links are also available on the OBH website and on the TMS bulletin Board. If there are problems form or questions, please contact Webster Hendricks at 303-866-7499 or firstname.lastname@example.com.
Click here to register.
We hope to see you there.
In an effort to provide support to counselors and agencies providing DUI services, OBH has contracted with Anjali Nandi to provide some training to counselors who are currently providing DUI Level II education and therapy. There are 4 trainings left this fiscal year. There will be some additional trainings scheduled in the next fiscal year.
Different than basic group counseling training, this is an enhanced group skills training that provides counselors with practical ideas, exercises and strategies to use in their DUI groups. The training includes a focus on:
The next training is in:
Click here for additional information and registration details. Space is limited, sign up now.
The Office of Behavioral Health (OBH) proudly announces its 12th training for stakeholders in Colorado's Impaired Driver services arena. These training sessions are part of OBH's continuing efforts to improve the quality of Education and Treatment services provided to Impaired Drivers throughout Colorado. Past sessions have been rated beneficial to providers by the providers themselves.
So mark your calendars and join us as we share critical information and exchange ideas about changes and new expectations for defining, assessing, educating, and treating impaired driving in Colorado. click on link to view Dates and Times
This training is for counselors who have been facilitating DUI groups for at least one year and would like to renew their skills and walk away with practical ideas, exercises and strategies to use in group.
click here for more information and to download the application
(Please share this information with other staff)
LEGISLATIVE UPDATE: to access copies of all bills go to the General Assembly website www.leg.state.co.us
UPDATE: Regional Impaired Driver Treatment Training
This year's trainings have been a huge success with 340 registered to date. Unfortunately, Cortez was cancelled due to low numbers-sorry Cortez, maybe next time. The Westminster training had to be closed since we reached capacity. There is one training left in Grand Junction on June 24th. The registration link is on the TMS message board and the OBH website, "DUI Services" page. For copies of PowerPoints go to the OBH website www.colorado.gov/cdhs/dbh "Latest News" page.
Group Facilitation Skills Training – DUI counselors who have attended this enhanced group skills training have found it quite valuable. There is one training left this fiscal year in Steamboat Springs on June 22nd. TO REGISTER - EMAIL firstname.lastname@example.com. Look for a new training schedule this fall.


text:
Thanks for redeeming.{{else}}
Success! Thanks for repurchasing.{{/if}} {{else}} {{#if Expired}}
Increase my visibility!{{else}} {{#if IsMultiPack}}
{{#if HasMultiPack}} You have {{MultiPackCount}} top spot(s) left. Now loading you into the search listings... {{else}} You have used all top spots. Now loading you into the search listings... {{/if}}{{else}}
We are loading you into the search listing pages...{{/if}} {{/if}} {{/if}} {{/if}}
{{Current}} just saw you!{{/if}} {{#if LastTopSpotPurchaseIsMulti }} {{#if HasAnyTopSpot}}
{{#if HasFreeTopSpot }} {{ UnclaimedTopSpotFree }} Free {{/if}} {{#if HasPaidTopSpot }} {{#if HasFreeTopSpot }} & {{/if}} {{ MultiPackCount }} {{/if}} Top Spot{{#if Plural}}s{{/if}} Left{{else}}
0 Top Spot{{#if Plural}}s{{/if}} Left{{/if}} {{else}} {{#if HasFreeTopSpot }}
{{ UnclaimedTopSpotFree }} Top Spot{{#if Plural}}s{{/if}} Left{{/if}} {{/if}} {{else}} {{#if HasResults}}
{{Current}} see you now!{{else}} {{/if}} {{/if}}
You can now invite anyone to meet at your favorite Starbucks.
Limited-time feature
27 year old man | Burlington, VT, USA | Seeking women 20-26 within 100 miles of Fort Lauderdale, FL
Life is Great
I love yoga, working out, swimming and sports in general. I know what i want from this life. I am calm person. Some say that i am very responsible, honest and motivated. Some say that i am crazy. I love to read motivational type of books, visit seminars and everything that is related to personal grows. I rarely go in bars, i don't like smoke in there. But i love going out to see movies and to eat some great food. Laying on the beach and to travel. I like honest, friendly, simple people. I hate drama. I am a good man and i am looking for a girl with good personality and soul. On first meeting we can go to have some sushi or have a cup of coffee of tea.
Book club , Camping , Coffee and conversation , Business networking , Dining out , Movies/Videos , Music and concerts , Playing sports , Religion/Spiritual
Martial arts, Running, Swimming, VolleyBall, Walking / Hiking, Weights / Machines, Yoga
I exercise 5 or more times per week.
I like Cats, Dogs
Middle of the Road
Sushi, Yoga, Gym, Work Out, Swimming pool, Beach, My Business, Camping, Coffee or Tea, Dining out, Movies/Videos, Museums and art, Music and concerts, Pedal Boarding, Longboad, Italian Food, Self Development,
"Ready, Fire, Aim", "Unfair Advantage" "Blue ocean strategy"
Z{{Cta}} {{#if HasMoreInfo}} ?{{CtaSecondary}} {{/if}}
|What he is looking for
|5'7" (170cms)
|3'0" (91cms) to 8'11" (271cms)
|Body type:
|Athletic and toned
|No preference
|No preference
|Dark brown
|No preference
|No Way
|No Way, Occasionally, Yes, but trying to quit
|Never, Social Drinker
|Self-Employed / Entrepreneur
|No preference
|I'll tell you later
|No preference
|Never Married
|Never Married, Widow / Widower, Currently Separated, Divorced
|Have kids:
|Yes, and they sometimes live at home, No, Yes, and they live away from home, Yes, and they live at home
|Wants kids:
|Definitely, Someday, Not sure
|White / Caucasian
|No preference
White Russian=)))
|Christian / Catholic
|No preference
|English, Russian
|I'll tell you later
|No preference


text:
Updated 11/26/2013
While markets in former East Berlin districts are perfect for unearthing both trash and treasures, the antique market on Strasse des 17. Juni is at the high end of the spectrum. Open on weekends, the Berliner Trödelmarkt und Kunstmarkt is home to one of the city's more curated selections, with vintage and high-end secondhand jewelry, housewares, silverware, books, and toys. The flea market stands are nearer the Tiergarten S-bahn station, while handicrafts begin past the Charlottenburg gates.
Strasse des 17. Juni, Berlin, Berlin, 10623, Germany
Website: www.berliner-troedelmarkt.de
Shopping Details:
Updated 11/26/2013
No Thanks


text:
They feel bad, so they found you these other deals to make up for it.
Select Local Merchants
Sacramento Youth SymphonyRead MoreDuring the show, junior virtuosos will play classic holiday tunes to connect with their community through service and steward holiday cheer. The library space can accommodate at least 400 community members for the concert, which will culminate in a finale conducted by a young audience member. The symphony still needs additional funding to cover the costs of transporting instruments, renting out the venue, and producing the concert.3443 Ramona AveSacramento, CA US
Kevin HartRead MoreHershey Theatre The Hershey Theatre, conceived in 1933 by noted philanthropist and chocolatier Milton S. Hershey, stands as an opulent tribute to the performing arts. Taking architectural cues from Saint Mark's Basilica in Venice, the foyer's towering arches gleam with golden paint and crystal chandeliers. The blue-and-gold mosaic that leads to the main seating area is the masterwork of two German artists who spent two years on its construction. Once inside the theater, audiences might think they've stepped onto the streets of Venice thanks to the atmospheric ceiling, stonework facades, and gondoliers paddling them to their seats. ####Bethel Woods Center for the Arts Music has permeated the 800 manicured acres where the Bethel Woods Center for the Arts has stood since 1969, when farmer Max Yasgur agreed to let love, peace, and harmony grow wild at the very first Woodstock festival. These days, the renowned outdoor venue and cultural center continues to attract the biggest acts in music to its pavilion stage. The open-air design ensures ample ventilation on the natural sloping lawn, and a roof protects up to 15,000 fans from inclement weather and the prying eyes of Cessna pilots.1 Sports Pkwy.Sacramento, CA US
Live NationRead MoreMore than half a century ago, three partners raised a vibrant, multicolored tent on an underdeveloped industrial site and established the Westbury Music Fair. It followed its first production, The King and I, with a decade of top-name talent and Broadway musicals. Then, recognizing its place on the theater scene was permanent, it planted its roots as a fully enclosed theater-in-the-round. Expanding its repertoire to match its new digs, the theater showcased performers such as The Who, Bruce Springsteen, and Julie Andrews. Today, past a lounge blazing in purple and red lights, guests find that same circular stage hosting equally great musical acts, musical theater, and competitive musical chairs.248 W Fremont StStockton, CA US
California SymphonyRead MoreThe California Symphony has treated the tunefully inclined to artful performances of both new music and classical classics for nearly a quarter of a century. Audiences for the March 6 concert, "In the Spotlight," will witness the skilled batonery of guest conductor George Cleve as he leads the world-premiere performance of Bay Area composer Cindy Cox's most recent work. With a unique voice noted for its tunings, harmonies, and textural colorations, Cox's piece will showcase regional orchestral musicians, such as flutist Monica Daniel-Barker, clarinetist Jerome Simas, and violist Marcel Gemperli. The evening will also include selections from Chaminade's Flute Concertino, Bruch's Concerto for Clarinet and Viola, and Dvo??k's Symphony no. 7, generally considered the luckiest of all Dvo??k's symphonies.1601 Civic DrWalnut Creek, CA US
Modesto Symphony OrchestraRead MoreWhen the Modesto Symphony Orchestra played their first concert in 1931, the town had 17,000 residents?making it the smallest settlement with its own symphony orchestra in the nation. But even as their city has grown around them, the orchestra's members have retained their timeless commitment to fine music. The group continues to perform seasons that blend soul-stirring classics with toe-tapping pops pieces. The Modesto Symphony Youth Orchestra also adds their freshly sprouted strings to the mix, either during their own concerts or guest appearances with the ensemble.1000 I St.Modesto, CA US
Berkeley SymphonyRead More1969: British maestro Adrian Boult's prot?g? Thomas Rarick debuts the Berkeley Promenade Orchestra?which, in true '60s spirit, performs wearing casual clothes in unconventional settings while being conducted entirely by good vibes. 1978: Kent Nagano takes the reins as music director, heralding such changes as programming focusing on rarely heard 20th-century scores, a switch to formal attire, and a name change. 1984: The orchestra joins forces with Frank Zappa for a critically acclaimed concert featuring elaborate stage sets and life-size puppets. 2003: The orchestra gets a comfortable pullout sofa and therefore its first composer-in-residence: Naomi Sekiya, whose Sinfonia delle Ombre for two guitars and orchestra debuts later that year. 2009: Joana Carneiro becomes the third music director in the orchestra's 40-year history, forging relationships with prominent Bay Area composers such as John Adams, Gabriela Lena Frank, and Paul Dresher.101 Zellerbach Hall, Ste. 4800Berkeley, CA US


text:
|Home | About | Journals | Submit | Contact Us | Français
Orally delivered replicating adenovirus (Ad) vaccines have been used for decades to prevent adenovirus serotype 4 and 7 respiratory illness in military recruits, demonstrating exemplary safety and high efficacy. That experience suggests that oral administration of live recombinant Ads (rAds) holds promise for immunization against other infectious diseases, including those that have been refractory to traditional vaccination methods. Live rAds can express intact antigens from free-standing transgenes during replication in infected cells. Alternatively, antigenic epitopes can be displayed on the rAd capsid itself, allowing presentation of the epitope to the immune system both prior to and during replication of the virus. Such capsid-display rAds offer a novel vaccine approach that could be used either independently of or in combination with transgene expression strategies to provide a new tool in the search for protection from infectious disease.
Oral delivery of immunogens to the gut is regarded as the "Holy Grail" for vaccinologists [1]. The intestine is the largest lymphoid organ and gut-associated immune cells represent up to 90% of immunocompetent cells [2]. Oral immunization offers immunological and logistical advantages including stimulation of mucosal immune responses preferentially at the site of entry for many infectious agents and ability to elicit strong systemic immunity. Oral immunization is cost effective and offers improved patient compliance due to the ease of vaccine administration, freedom from needles and from the requirement for trained medical personnel. All three oral vaccines licensed for use in the US [3] contain live virus. Live-virus vaccines add to the inherent advantages of oral immunization the ability to immunize with small (and hence less expensive) doses, and induction of a breadth of immune responses similar to those induced by natural infection. These characteristics would facilitate routine immunization and response to epidemics or pandemics [4] and make live oral immunization attractive in resource-poor regions, where economy and logistical tractability are critically important.
Licensed oral adenovirus (Ad) serotype 4 and 7 vaccines provide a model for use of live recombinant adenoviruses (rAds) for oral immunization. Since the 1970's, live oral Ad vaccines have been used by the United States military to prevent acute respiratory disease caused by Ad4 and Ad7 [5]. These vaccines contain lyophilized live, wild type (WT) virus incorporated into enteric tablets that protect the virus against the low pH of the stomach. After oral administration of the tablets, live virus is released into the intestine where asymptomatic replication occurs. In a single dose, the vaccines generate an immune response that was over 95% effective in preventing Ad4- and Ad7-induced respiratory illness in a clinical trial involving more than 40,000 soldiers [6–9]. The historical success of Ad military vaccines suggests great potential for recombinant vaccines using the oral replicating Ad platform.
rAds have been used to deliver vaccine antigens in over 90 pre-clinical and clinical trials [10, 11]. The rationales for use of rAd vaccines include genome stability and ease of manipulation, natural tropism for mucosal inductive sites including the gut and upper respiratory tract and ability to elicit vigorous humoral and cellular immune responses. rAds infect a broad spectrum of cells, including dendritic cells, allowing for efficient antigen presentation and can therefore also prime a robust cell-mediated response [12, 13]. However, most rAd vaccine candidates are replication defective and not intended for oral administration. Here, we review work on replicating rAd vaccines that may provide a route to effective oral immunization.
Most current rAd vaccine candidates are transgene expression vectors, commonly engineered to express a foreign gene inserted into early region 1 (E1) or, occasionally, early region 4 (E4) of the genome [14]. E1 and E4 are essential for viral replication, and most such rAds are replication-defective [15–17]. Extensive experience with defective recombinants in humans and animal models has shown promise in several cases [18].
Replication-competent transgene vectors can be constructed by careful choice of the site of transgene insertion but relatively few have been extensively investigated. Study of replicating rAd vaccines is complicated by the requirement for a host that supports viral replication if vaccines are to be evaluated under conditions that mimic their intended use in humans. Mice do not support human adenovirus replication. However, golden hamsters, cotton rats, dogs, pigs, monkeys (see below), and chimpanzees all support replication of some human Ads, providing systems that might be exploited to test replicating vaccines [19–24]. Cotton rats and hamsters have found use in characterization of replicating oncolytic adenoviruses [19, 25], and dogs have been used in evaluation of live rAd vaccines [21]. In practice, however, well-developed immunological reagents, perceived similarity of primate and human immune responses, and availability of suitable challenges to assess efficacy have restricted most studies of replication-competent rAds in permissive hosts to primates (chimpanzees or monkeys), or to human volunteers.
In early studies, replication-competent rAd7 and rAd4 expressing the hepatitis B virus surface antigen (HBsAg) were used to immunize (rAd7 HBsAg) and then boost (rAd4 HBsAg) two Ad4, Ad7-seronegative chimpanzees (rAd7/rAd4 HBsAg) by the oral route [23]. After primary vaccinations, both chimpanzees shed vaccine virus for 6–7 weeks and developed Ad7 antibodies, suggesting successful Ad7 replication in the chimpanzee gut. One developed transient seropositivity for HBsAg after the first inoculation; both developed modest titers after the second. A third chimpanzee immunized with WT Ad7 and then rAd4 HBsAg (WTAd7/rAd4 HBsAg) developed no HBsAg antibodies. Both rAd7/rAd4 HBsAg chimpanzees were protected from acute clinical disease but were not protected from infection as evident by development of antibodies against the HBV core protein in response to HBV challenge. The animal that did not seroconvert (WTAd7/rAd4 HBsAg), along with an unimmunized control, became clinically infected with HBV [23]. Three human volunteers in a small phase I vaccine trial immunized with the rAd7 HBsAg vaccine exhibited no adverse effects and shed virus between days 4 and 13 post vaccination with no evidence of person-to-person spread. Although all subjects had a significant increase in Ad7 antibodies, none made antibodies to HBsAg [26]. Protection from disease, if not infection, in chimpanzees, despite lack of seroconversion in humans, suggests potential value in using oral enteric vaccination with rAd to induce humoral immune responses to foreign pathogens.
Most animal studies of replicating rAds have been conducted in macaques. WT Ad2 and Ad5 do not replicate in monkeys, and these experiments therefore require use of an Ad5 host range mutation (hr404), located in the 72k DNA binding protein, that permits replication in monkey cells and macaques [24, 27]. A transgene-type rAd5 hr404 (rAd5hr) virus expressing the env and rev genes from SIV (Ad5hr-SIVenv/rev) was able to replicate in vivo in rhesus macaques [28]. Priming orally and intranasally, followed by intratracheal immunization 12 weeks later with Ad5hr-SIVenv/rev, generated proliferating T cells to Env and strong serum neutralizing anti-Env antibodies. Mucosal secretions also contained Env-specific IgG and IgA antibodies. Although this vaccine did not induce sterilizing immunity, it conferred acute-phase protection following intravaginal challenge with SIV [28]. Partial protection of reboosted and rechallenged transiently viremic macaques was associated with both cellular and humoral immune responses [29]. To broaden rAd-induced immunity to SIV, additional rhesus macaques were immunized simultaneously with replicating constructs expressing SIV env, rev and gag genes through oral and intranasal administration [30]. Specific T-cell responses were generated against all SIV gene products and there was a persistent response to Gag evident for more than 10 weeks post-immunization. Interestingly, immunization primed CD8+ T cells for a persistent and potent response to both dominant and subdominant epitopes [30, 31]. Intrarectal challenge with SIV demonstrated that the vaccine did not induce sterile immunity but acute viral replication was suppressed. Cellular immunity to SIV Gag and Env, along with nasal and vaginal Env-specific IgG antibodies, correlated with a significant reduction of acute phase viremia [32]. Immunized groups exhibited significant protection, with 39% of macaques having either no viremia, cleared viremia or controlled viremia at the threshold of detection 40 weeks post-challenge.
In these studies, only 35% of macaques exhibiting rAd shedding [30], suggesting that the protocol used, bicarbonate neutralization of the stomach prior to virus delivery, might not preserve rAd infectivity. Use of enteric-coated capsules for virus administration resulted in shedding virus in stool samples of 100% of immunized macaques [33] emphasizing the importance of an optimal oral delivery method.
Recently, phase I clinical trial data has been presented for a transgene-type replication-competent rAd4 vaccine (rAd4-H5-Vtn) expressing influenza H5 hemagglutinin (HA) [34]. This virus, which induced protective immune responses in a nonpermissive mouse model [35], contains an insertion of the H5 HA gene in place of part of E3. 166 healthy volunteers received vaccine dosages ranging from 107 to 1011 recombinant virus particles (VP) [34]. Each cohort received three rAd vaccinations orally and an intramuscular boost with inactivated H5N1 vaccine. Administration of the rAd was associated with mild headache, abdominal pain, nasal congestion and diarrhea. There was no confirmed transmission of the rAd4-H5-Vtn virus to household contacts. Pre-existing antibody to Ad4 was associated with a lower immune response to the vaccine, but this effect was overcome in the high-dose cohorts of 1010 and 1011 VP. In mice, this recombinant elicits good humoral Ad4 and HA responses but a low cell-mediated response [35]. In humans, the vaccine induced a significant level of Ad4 seroconversion and HA-specific cellular immune responses in 70% of volunteers receiving 1011 VP [34]. However, HA-specific antibody responses assessed by hemagglutination-inhibition (HAI) were minimal at all doses tested, with seroconversion in 4% to 19% of vaccinated volunteers. Plasma IgA ELISA titers mirrored HAI, although IgG ELISA responses indicated 50% seroconversion in the 1011 VP cohort. The H5 HA antigen is an intrinsically poor immunogen [36], however following boost of the inactivated H5N1 vaccine, 80% to 100% of volunteers seroconverted and 80% to 89% demonstrated antibody titers high enough to be considered protective in the 1010 and 1011 VP cohorts, respectively [34]. This indicates that although the Ad4-H5-Vtn vaccine can induce a cellular response, it is only capable of priming an HA-specific antibody response. The cellular immune response and replication of the vaccine as assessed by Ad4 seroconversion or PCR positive rectal swabs, primarily occurred after the first dose, suggesting that only one oral dose may be necessary to induce a cellular response and prime an antibody response.
The doses of Ad4-H5-Vtn required to induce vector immune responses are 100-fold (or more) greater than that in the Ad4 vaccine (105 – 107 TCID50 [5]). rAd4-H5-Vtn lacks E3, which functions in evading the host immune response [37] and may contribute to the vigor or duration of replication, and thus to the immunogenicity of the, WT vaccines. That possibility has not been experimentally addressed.
Numerous clinical trials of replicating oncolytic rAds have been conducted. In general, these studies do not include analyses of immune responses. Where vector responses have been measured they are efficiently induced [38, 39], but there are no reports of responses to transgene products.
Despite the efficacy of the oral Ad4 and Ad7 vaccines and efficient induction of antibodies against the vector, oral rAd vectors induce only modest antibody responses to transgene products in both replicating and non-replicating forms [23, 40] (Berg and Ketner, unpublished). However, a second rAd antigen expression method may offer a more potent approach to induction of humoral immunity. In capsid-display recombinants, segments of foreign antigens are incorporated into one of the capsid proteins such that they are displayed on the surface of the virus particle. Capsid-incorporated antigens are available for binding by surface antibody on B cells and can be processed by the exogenous (MHC class II) pathway. Thus, capsid display recombinants can be immunogenic without intracellular antigen expression, including in systems that do not support virus replication. Replication in a permissive host would further allow persistent antigen presentation via both the exogenous and the endogenous (MHC class I) pathways, with the potential of inducing both humoral and cellular responses. Capsid-display vectors are extremely immunogenic in mice [41–43] and therefore may offer greater efficacy in inducing humoral responses in permissive systems than do transgene rAds.
Several capsid proteins can display foreign epitopes, including hexon, fiber, penton base and pIX (Table 1, Figure 1A, and below). Currently, immunogenicity data is available only in mice, and conclusions therefore have been drawn only in the absence of viral replication.
The ~960 amino acid Ad hexon protein is the most abundant of the capsid proteins, present in 720 copies per particle [44]. Analysis of hexon amino acid sequences from different serotypes revealed 9 hypervariable regions (HVRs) that diverge in sequence and length among serotypes [45]. Crystal structures of Ad2 and Ad5 hexon show that HVRs reside in two loops that form the surface-exposed portion of hexon. HVR 1–6 are located within the DEI loop and HVR 7–9 lie within the FGI loop (Figure 1 B and D) [45, 46]. These HVRs contain serotype-specific epitopes that are primary targets of neutralizing antibodies (nAb) [47].
X-ray crystallography suggests that HVRs 2, 3, 5, 6 and 7 are unordered and protrude from the capsid surface. Virus containing insertions of His6 peptides with flanking spacers into those HVRs are viable, with normal virion thermostability and infectivity [48]. His6 in HVR2 or 5 is capable of binding tightly to the His6 antibody, suggesting that the peptide is exposed on the virion when incorporated into these regions [48]. Assessed with epitopes of increasing size, HVR5 was found to accommodate a maximum of 65 amino acids, while the maximum length accommodated in HVR2 was 33 amino acids [49]. Modifications in HVR1 or 5 reduced susceptibility to neutralization by preexisting immunity (PEI) to the Ad vector [41, 50]. Substituting all the HVR loops in Ad5 with those derived from Ad43, a serotype with a low prevalence, produced a vector capable of escaping neutralization with anti-Ad5 sera from mouse, rabbit and humans [51] and that was still highly immunogenic in the presence of PEI to the WT virus.
The first capsid display recombinants incorporated 8 amino acids of the poliovirus type 3 VP1 capsid protein into regions now recognized as HVR1/2. Antiserum raised against the rAd recognized the poliovirus capsid itself [52]. Worgall et al. incorporated an immunodominant peptide from the outer membrane protein F (OprF) of Pseudomonas aeruginosa into HVR5 [43, 53]. Immunization with this rAd induced IgG1 and IgG2a antibody subtypes, elicited epitope-specific CD4+ and CD8+ T cell responses, and was capable of protecting 60–80% of mice from a lethal pulmonary challenge with three different P. aeruginosa strains. Efficacy was increased with subsequent boosts [43, 53]. In contrast, a B-cell epitope from Bacillus anthracis protective antigen (PA), a subunit of the lethal toxin, incorporated into HVR5, induced non-neutralizing antibodies and failed to protect against a challenge with lethal toxin [54]. The discordant results from these studies may reflect differential antibody titers or differing properties of the selected epitopes.
Subsequently, Shiratsuchi et al., inserted a B cell epitope from the circumsporozoite protein (CSP) of the murine malaria parasite Plasmodium yoelii into hexon HVR1 or 5 in a recombinant that also expressed CSP as a transgene [41]. The HVR1 recombinant induced high titer antibodies even in mice pre-immunized with WT Ad, suggesting that alteration of HVR1 allowed for evasion of neutralizing Ad antibodies. An rAd incorporating a B-cell epitope from P. falciparum CSP in HVR1 induced high-titer antibodies in mice that recognized parasites expressing the P. falciparum CSP and neutralized sporozoites bearing the P. falciparum CSP gene in vitro [55].
The location of epitopes inserted in hexon is an important determinant of immunological properties [49]. rAds that displayed an epitope from the VP1 capsid protein of Enterovirus 71 in HVRs 1, 2, or 7 were viable and protected neonatal mice from lethal challenge through passive immunization and maternally-acquired antibodies [56]. However, antibody isotype depended on the location of the epitope insertion: insertions into HVR1 induced mostly IgG2a antibodies (Th1) while an HVR7 insertion predominantly produced IgG1 antibodies (Th2), demonstrating that insertion sites on hexon are not immunologically equivalent [56]. Similarly, insertion of the conserved extracellular domain of matrix protein 2 (M2e) of influenza A virus into variable region 1 (VR1) or VR4 of hexon of the chimpanzee-origin adenovirus SAd-V25 (AdC68), only the VR1 recombinant provided partial protection from a lethal influenza challenge [57]. Capsid display recombinants induced more robust responses than a transgene type recombinant expressing an M2e fusion protein, supporting the hypothesis that antibody responses are best induced by antigen displayed in a repetitive and structured fashion to allow for cross-linkage of the B cell receptors.
Recent studies of rAds with modifications in two hexon HVRs have demonstrated the potential for single recombinants to elicit simultaneous antibody responses against two distinct epitopes [58]. 'Multivalent' capsid display recombinants offer potential for broadening immune responses or inducing responses to genetically variable pathogens. However, recombinants with different combinations of modified HVRs induced strikingly different responses, indicating that the design of effective multivalent hexon-modified rAds may not be straightforward.
The penton base and fiber form the penton complex present at the 12 vertices of the capsid (Figure 1A). Each penton base monomer (~570 residues) contains an Arg-Gly-Asp (RGD) integrin-binding motif located within a flexible loop at the capsid surface [59]. An influenza A virus HA epitope inserted into the RGD loop of penton base was accessible to anti-HA antibodies, confirming surface location [60]. However, anti-HA antibodies were not detected in mice immunized with a penton base recombinant containing HA inserted into the RGD loop [60]. The insertion decreased infectivity for DC's, potentially by interfering with integrin binding, which is involved in virion internalization.
Fibers are homotrimers of the fiber protein (polypeptide IV) that protrude from the 12 vertices of the Ad virion and are responsible for attachment to the host cell (Figure 1A). The fiber protein has 3 domains: an N-terminal domain that attaches to the penton base, a central shaft with repeating motifs, and a C-terminal globular knob responsible for virus attachment to the host cell (Figure 1E). Ad5 fiber contains 582 amino acids and is 35–40 nM in length, but fiber length varies among serotypes due to differing numbers of repeats in the fiber shaft.
The crystal structure of the fiber knob reveals that the HI loop (Figure 1C and 1E) does not contribute to intramolecular interactions within the knob, consists mostly of hydrophilic amino acid residues, is exposed on the surface of the knob and is not involved in the formation of cell-binding sites [61]. A FLAG epitope inserted into the HI loop was also accessible to anti-FLAG antibodies, confirming that the HI loop is exposed [62]. Therefore, the HI loop is seen as particularly suitable for manipulation and most modifications initially were made at this location [60, 63]. More recently, a series of rAds with insertions of the P. aeruginosa OprF Epi8 epitope in fiber loops CD, DE, FG, HI and at the C terminus [64] have been examined for effects of insertions on viral growth in vitro and for immunogenicity. Incorporation of Epi8 into the FG and HI loops had little effect on viral growth whereas insertion into the CD and DE loops or at the C terminus strongly reduced infectivity. FG and HI loop insertions also elicited the strongest humoral and cell-mediated immune responses and were partially protective against challenge [64].
Fiber is a target for neutralizing antibodies and substitutions can contribute to evasion of PEI. For example, modification of the HI loop circumvented nAb present in ascites fluid from ovarian cancer patients [65]. Consistent with this, FG and HI loop recombinants were more effective at inducing antibody and protection in the presence of PEI than was a transgene-type recombinant expressing all of OprF [64]. The ability to manipulate fiber at multiple sites to allow for the efficacy in the presence of PEI makes fiber insertions a promising modification for capsid-display vaccines.
Fiber modifications intended to redirect or ablate virus binding to specific cellular receptors have also been explored [43, 66–68]. However, immunogenicity generally is not addressed in those studies.
pIX (approximately 140 amino acids) is present in about 240 copies per virion. Trimers of pIX contribute to stability of the virus particle [69, 70]. The C-terminus of pIX is exposed on the surface of the virion and has been used as a substrate on which to attach large polypeptides including fluorescent proteins, fully functional enzymes and foreign antigens in viable rAds [71–75]. pIX fusions containing the envelope protein gp70 of the Friend murine leukemia virus (FV) [75] and the Yersinia pestis V and F1 capsular antigens [42] induced high-titer antibodies. The ability of pIX to accommodate very large proteins makes it an attractive site for display of conformational epitopes.
The immunogenicity of influenza A virus HA epitopes inserted into various Ad capsid proteins has been compared [60]. Insertion sites included hexon HVR5, the RGD loop of penton base, the HI loop of the fiber knob and the C terminus of pIX. All HA insertions were located on the virion surface, however, an anti-HA antibody demonstrated strongest binding to HA incorporated into hexon. Infection of A549 cells and DCs showed that HA incorporation into hexon interferes minimally with virus entry in vitro, whereas incorporation into fiber knob, pIX and penton base partially reduced the intracellular Ad genome copy numbers following infection. The humoral immune response was strongest against the hexon insertion when immunizing with the same number of particles but fiber was the most immunogenic when controlling for the number of HA copies per virion [60]. A comparison of an ovalbumin (OVA) epitope inserted into the fiber HI loop or hexon HVR5 indicated that fiber insertions were better detected in native virions and triggered a more dramatic increase in anti-OVA antibody responses upon re-administration [63].
Antibodies to many Ad serotypes are prevalent in the human population. PEI to the vaccine serotype can interfere with a robust immune response against the foreign antigen even in non-replicating rAds [23, 76], although mucosally administered replication-defective rAd vaccines have elicited transgene-specific antibodies despite the presence of PEI, and homologous serotype boosts can be effective [32, 77, 78]. Importantly, if capable of suppressing the growth of viable rAds, PEI might mitigate the inherent advantage of vaccine vector replication after administration of a low dose [79], and live rAds thus may be more sensitive to PEI than their defective counterparts. PEI can be addressed by use of uncommon human adenovirus serotypes or viruses from other species [80, 81] [82] as vectors. Additionally, as noted above, modifications to both hexon and fiber have been shown to reduce susceptibility to PEI [41, 50, 51] and properly-designed capsid display rAds therefore may be inherently resistant to PEI. Limited experience with replicating rAds has provided some data on the effects of PEI [34], but this topic must be more thoroughly addressed.
Concerns have been expressed over the safety of replicating vaccines due to the possibility of inducing disease in the immunocompromised and to the possibility of unintentional spread to contacts. Systemic adenovirus infections can be fatal in people who are profoundly immunocompromised, for example, in the course of bone marrow transplantation [83, 84]. Further, Ad is commonly present in AIDS-related deaths, although it is not generally believed that it was the cause [85, 86]. Clearly, live rAds cannot be administered to the severely immunodeficient. However, unwitting administration of the military vaccine to a small number of recruits with early HIV infection produced no observed ill effects, nor did the concurrent HIV infection prolong shedding, suggesting a small margin of safety in that population [87]. Transmission of the oral military Ad vaccine did occur, but required intimate contact, as it was not observed among recruits in the barracks [88, 89], and no confirmed transmission of the rAd4-H5-Vtn virus to contacts was observed in its recent clinical trial [34]. This aspect of use of live vaccines, rAd or others, must be carefully investigated.
Replication-competent transgene or capsid display rAds delivered orally to the gut mucosa offer an unconventional immunization approach. Transgene rAds have been shown to induce a robust cellular-mediated immune response, and capsid-display rAds promise to induce strong humoral responses. Critically, transgene and capsid display designs possess complementary immunological characteristics and can be combined in single rAds [41], and such hybrid rAds offer a potential route to greater potency than either approach alone. Multiple-antigen hybrid rAds, in particular, may be capable of increasing the breadth of immune responses to pathogens with a high mutation rate, such as influenza A, or a complex biology, such as malaria. Continued innovation in vaccine research is critical in order to control diseases such as HIV, influenza and malaria that have proven refractory to conventional immunization strategies, and replicating rAds have earned their place among the novel strategies worthy of exploration.
This work was funded by NIH grant 1R01AI079132, the Johns Hopkins Malaria Research Institute, the Marjorie Gilbert Foundation, the Eliasberg Foundation and C.D. was funded through the Johns Hopkins Sommer Scholars. I would also like to thank Dr. Kasey Karen and Laura Gelston for their thoughtful insight and helpful review of this article.
Conflict of Interest The authors have no competing financial interests to declare.
Author Contributions C.D. wrote the paper and performed research on the topic. A.P. and G.K. contributed to the conception and revising of the article.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


text:
Originally written on The Sports Fan Journal | Last updated 11/28/12
The last time a grassroots movement was launched through a TSFJ channel, it was in 2010 when I proclaimed that Michael Vick should be the 2010 NFL Most Valuable Player. The award ended up going to Sir Thomas Brady, with Vick coming in second and earning the NFL Comeback Player of the Year Award. So [...]The post Rasheed Wallace For Starter In 2013 NBA All-Star Game: A Grassroots Movement appeared first on The Sports Fan Journal.
Comments are closed.
What do you think?To leave a comment, you can:
NBA News
Delivered to your inbox
You'll also receive Yardbarker's daily Top 10, featuring the best sports stories from around the web. Customize your newsletter to get articles on your favorite sports and teams. And the best part? It's free!
Follow us on Twitter
|Best of Yardbarker
|NFL News
|MLB News
Today's Best Stuff
For Bloggers
Join the Yardbarker Network for more promotion, traffic, and money.
Company Info
What is Yardbarker?
Yardbarker is the largest network of sports blogs and pro athlete blogs on the web. This site is the hub of the Yardbarker Network, where our editors and algorithms curate the best sports content from our network and beyond.
|© 2015 Yardbarker, Inc. All rights reserved. Use of this website (including any and all parts and components) constitutes your acceptance of these Terms of Use and Privacy Policy. (What's New?)


text:
I been smokin' in my pictures since Myspace
from Wiz Khalifa – Mary 3x Lyrics on Genius
Wiz has been smoking and taking pictures of him and doobies since the times when Myspace was popular. And still does it!
To help improve the quality of the lyrics, visit Wiz Khalifa – Mary 3x Lyrics and leave a suggestion at the bottom of the page


text:
Ali Fedotowsky: Emily Maynard 'Deserves to Find Love' on 'The Bachelorette'
- Photo: ABC/Promotional1 of 17
- Photo: Sara Jaye Weiss/StarTraks2 of 17
- Photo: ALBERT MICHAEL/StarTraks3 of 17
- Photo: MAB/Splash News4 of 17
- Photo: Splash News/Splash News5 of 17
- Photo: Splash News/Splash News6 of 17
- Photo: Promotional7 of 17
- Photo: Brabus/Pacific Coast News8 of 17
- Photo: Matt Symons/PacificCoastNews.com9 of 17
- Photo: London Entertainment/Splash News10 of 17
- Photo: Kaminski/Splash News11 of 17
- Photo: London Ent/Splash News12 of 17
- Photo: Jen Lowery/Splash News13 of 17
- Photo: Dan Steinberg/R-STEINBERG14 of 17
- Photo: JD3/WENN15 of 17
- Photo: Al Powers/PowersImagery.com/.16 of 17
- Prev
Having already gone through the "Bachelorette" experience, Ali Fedotowsky knows just what new leading lady Emily Maynard is up against -- and Fedotowsky says she is just right for the gig.
"Emily is amazing! She's such a sweetheart," Fedotowsky -- who recently split from her 2010 "Bachelorette" love match Roberto Martinez -- told Us Weekly at our annual Hot Hollywood bash Wednesday at Greystone Manor in West Hollywood, Calif. "If anyone deserves to find love, it's her."
PHOTOS: Take a look back at Emily's time on The Bachelor
Though fans were first introduced to single mom Maynard, 26, on Brad Womack's season of The Bachelor when she fell for the clean-cut winemaker, Fedotowsky hints Maynard's spinoff season may be a little different.
PHOTOS: See what Bachelor and Bachelorette alums are up to now
"Emily told me she likes guys with tattoos, so we'll see what kind of guys she has on this season," Fedotowsky, 27, says of Maynard. "It should be interesting. I'm psyched."
Filming her season in Charlotte, N.C., where she lives with her 6-year-old daughter Ricki, Maynard enjoyed her show's first one-on-one date March 16.
VIDEO: Emily's daughter bonds with Brad on 'The Bachelor'
Dining at Italian eatery Osso with a contestant identified by show insiders as 31-year-old Ryan Bowers, Maynard later danced the night away with the Atlanta-based gym owner at a Gloriana concert.
"She looked happy, like she was having a nice time," an eyewitness told Us after their date. Still, the witness says, "Emily didn't kiss Ryan at the end of the song. She just gave him a hug and a kiss on the cheek."
Tell Us: Do you think Emily will find love as this season's new "Bachelorette?"
This article originally appeared on Usmagazine.com: Ali Fedotowsky: Emily Maynard "Deserves to Find Love" on "The Bachelorette."
Twitter Hookup for Jennifer Love Hewitt and 'Bachelorette' Reject?
Get out the vote
- button.LOL
- button.AWW
- button.OMG
- button.HOT
Most Watched on Wonderwall
Naked Set
Channing Tatum, Joe Manganiello and co-stars dish on being naked and wearing thongs on the set of "Magic Mike XXL" with Wonderwall.com's Kirby Kristen.Watch Video »
Shirtless Studs
Check out Val Chmerkovskiy, Ian Somerhalder and more shirtless stars on Instagram on today's Celebs Gone Social.Watch Video »
Jealous Spouses?
Channing Tatum, Jada Pinkett Smith and Stephen "tWitch" Boss dish on what their spouses really think of their steamy "Magic Mike XXL" roles.Watch Video »
Wax On
Joe Manganiello, Matt Bomer and co-stars dish on the horrors of waxing and spray tanning for their roles in "Magic Mike XXL."Watch Video »
Get all the scoop on "The Bachelorette" on Replay hosted by Wonderwall's Kirby Kristen.Watch Video »
Sans Makeup!
From Kate Hudson to Tyra Banks, check out these gorgeous stars sans makeup!Watch Video »
Like us on Facebook?
UP NEXThuge weight loss
From Elle
From Crowd Ignite


text:
With 1.7 million freelancers, we'll match you with the perfect talent.
The client has made the following changes to the job.
Job awarded.
Client prefers freelancers from:
You are still able to submit a proposal for this job.
The client prefers freelancers from
a different location.
We are looking for someone well versed in WordPress, more specifically plugin integration and customization. This work is for a site selling services through appointments. The project involves integrating/linking multiple plugins together.
This site primarily uses a form plugin (Gravity Forms), an appointment plugin (Appointments Plus), and a membership and commerce plugin (S2 Members). This part of the project focuses primarily on integrating the appointment and the membership plugin.
Add parameters on Admin side:
* Options to select multiple zipcodes where service provider is providing service.
* Add new provider rating/review drop down field (range 1-5)
User side:
* On appointment calendar, time calendar will show available time based on the following criteria:
* First, providers who are giving service on respective zipcode will be filtered first. If there are multiple providers available from that zipcode, then,
* Second, check provider ratings/review and select provider wi...
Sign in or Register to see more


text:
Are you smarter than your computer? What about a robot? Explore the science of artificial intelligence.
"Either you stand up and be counted or you stand out and be counted out."
About StumbleDNA StumbleDNA
Hasan's Interests
Advertising is everywhere. Learn the tricks of the marketing trade, from billboards to commercials.
Before there was Farmville, there was agriculture. Explore food production, sustainable farming and more.
Stay up to date on AIDS and HIV research, prevention, treatment and awareness.
Independent and edgy, get a different spin from alternative news that's far from mainstream.
Last Tuesday might feel like ancient history, but the Greeks and Romans knew better. Check it out.
From baby animals to wild creatures to exotic pets, discover cute pictures and more about animals.
From Disney to Flash, the art of animation has brought our favorite cartoons to the screen.
From ancient Greek to modern designs, explore the architecture that has defined countless landscapes.
Flex your creativity by exploring performing arts, literature, music, visual arts and more.
Bucks. Moolah. Dough. Whatever you call it, money matters, and so do banking, lending and investing.
We all need a little pampering sometimes. Explore makeup trends, hairstyles, skincare and more.
Think ordinary is boring? Explore the weird, the strange, the obscure, and the downright freaky.
Learn about brain disorders and the symptoms of neurological, psychological and nervous system diseases.
Let's make a deal. Explore the world of business, from small business management to profit margins.
Learn about symptoms, prevention and treatment for breast, lung, skin and other types of cancer.
What's your five-year plan? Figure it out with career planning tests, interview advice, resume tips and more.
Saving up for a Porsche? Either way, learn about cars, technologies, stunts and more here.
Fascinated by the lives of the rich and famous? Don't miss the latest celebrity news and gossip.
Can't go a day without your cell phone? Learn about mobile plans, networks, providers and models.


text:
- Product Information
Product Description
It is time for turkey and time to decorate your table for a Thanksgiving party. Our 15" honeycomb tissue turkey centerpiece is sold by the piece. Please order in increments of 1 piece.
- Questions & Answers
- Reviews
Customer Reviews
- These are great! Review by Caroline P.
I ordered a few of these for our family's Thanksgiving dinner, and they are just the greatest!
(Posted on 11/9/10)
Write Your Own Review
Minnie Mouse Birthday Party Ideas
Her birthday party will be a huge hit with a Minnie Mouse theme! Use these decorating ideas to help your put together the most adorable Minnie Mouse party.
1950s Sock Hop Party Ideas
Invite friends over for a rockin' good time when you throw a fifties theme party! Use these party tips to assist you in putting together the best sock hop anyone's ever seen.
Throw a Beach Party with these Helpful Beach Party Ideas
Plan a get-together on the beach, or throw a beach-themed bash in your home, using these fun beach party tips!


text:
Until yesterday, I never even knew that Meat Week existed. And I call myself a carnivore. But Meat Week is very real. That's why the domain name is meatweekisreal.com. The annual celebration of meat runs from January 31 to February 6 and, just like Fight Club, has spread under the radar to 15 cities in six years.
Founders Chris Cantey and Erni Walker decided that Meat Week "would be a holiday during which BBQ was eaten every night of the week." And so the status quo in Kansas City is slowly steamrolling into a national celebration. I think it's time we got involved.
We were built for Meat Week. It's a holiday based on barbecue consumption that encourages overeating of meat. The celebration is focused on a different barbecue joint for seven consecutive nights, with the eighth night being a BYOBBQ (Bring Your Own Barbecue) party. Participants get to vote for the best sauce and rubs, as well as document the experience with photos and videos. We could even improve on the formula, working our way from pork cheeks to pork butt in an homage to the idea of eating from the snout to the tail. Although, if we started and ended with burnt ends, I don't think anybody would blame us.
I know there are those of you who will say Kansas City doesn't need a fictional holiday to prove we are inhospitable to vegetarians. Every week is meat week. We have our lab results to confirm our love of barbecue. But would it be so wrong to bury the cleaver for a week and celebrate eight wonders of Kansas City barbecue?
Meat Week may have begun in Tallahassee, Florida, but I believe it can be perfected in Kansas City. We've got 51 weeks and five days to prepare for 2012. Hold up a rib if you're in.
[Image via Flickr: Mike Licht]