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Job Description
Vice President, Quality Assurance Dublin
Our client is a fast growing highly profitable multinational biopharmaceutical company with an exciting pipeline of drug compounds at an advanced stage in research.
- The VP Quality Assurance will proactively develop, lead and drive the execution of the quality assurance strategy across commercial & clinical manufacturing activities as well as commercial affiliate activities by overseeing organizational and programmatic elements of the company's corporate quality control, quality assurance and quality compliance functions.
- The position holder will serve as a key and active member of the Technical Operations leadership team and interact with the team and other management teams to ensure business objectives are aligned and that the company is performing to operational objectives.
- Coach, mentor and lead highly dynamic team members to help achieve the requirements of this position as well as the individual career goals of team members. Develop and champion an organizational culture that promotes behaviours that lead to superior business performance and organisational excellence.
- Ensure that the company's product quality and reliability meets or exceeds customer's expectations. Creates an organizational commitment to customer service.
Key Responsibilities
- Lead the company's quality assurance program to provide appropriate oversight of and commercial & clinical manufacturing activities.
- Liaise with R&D QA in relation to pre-clinical, clinical, pharmacovigilance operations as they pertain to commercial affiliates
- Work with VP R&D QA to ensure that the appropriate level of service is provided in relation to the management of the QA systems. Develop and maintain a service level agreement to codify the QA systems service to R&D.
- Develop and execute quality by design and quality assurance strategy for new product development.
- Develop quality assurance plans and systems to ensure commercial manufacturing, process development programs and commercial affiliates remain compliant with all applicable regulations and guidelines.
- Keep abreast of competitive quality control and assurance practices and utilize this knowledge during on-going development and adjustment of company plans.
- Support Regulatory Affairs to develop and maintain strong internal and external relationships with regulatory bodies and authorities.
- Effectively create and champion quality process enhancement initiatives to maintain an environment of continuous improvement throughout the organization
- Develop, implement, manage and oversee GXP quality systems to support commercial manufacturing, process development and commercial affiliate activities across the entire company.
- Ensure an effective and compliant vendor qualification program is in place for suppliers
- Ensure that cGMP requirements, quality standards and policies are recognised, understood and maintained across the company
- Analyses regulatory authorities' programmes and activities in areas relevant to bio/pharmaceutical products and advises management of potential and actual actions that could adversely affect the business, present quality exposures, or represent opportunities to be pursued.
- Ensures a GXP compliant documentation control system is maintained by managing the Global Quality Management system and associated employees.
- Work across all disciplines to ensure that the company maintains a state of readiness for GMP inspections by regulatory agencies. Ensures all employees comply with all applicable company and governmental (EPA, OSHA, FDA, etc.) regulations, policies and guidelines.
- Provide oversight for Quality Control activities performed by contract testing labs and contract manufacturing companies.
- Achieve financial objectives by preparing the quality assurance budget, scheduling expenditures; analysing variances and initiating corrective actions
- Maintain professional and technical knowledge by attending educational workshops; reviewing professional publications; establishing personal networks and participating in professional societies.
- Travels to locations in order to facilitate/coordinate activities, resolve issues, etc.
Person Spec
- BSc in life sciences. MSc or PhD preferred.
- 15+ years in pharmaceutical industry, including a minimum of 10 years in a senior leadership position within the bio/pharmaceutical industry
- Experience in strategic planning and collaboration with executive and key operational groups
- Progressive and proven track record of leadership and managing quality with global responsibility across multiple functions
- Extensive experience in cGXP and other regulatory compliance requirements
- Excellent organizational, verbal, communication and presentation skills
- Ability to effectively lead and participate on multi-disciplinary teams
- Ability to work independently with minimal direction
- Ability to develop and manage a high-performance team focused on accountability and meeting/exceeding expectations.
- Ability to lead, influence, create and work within a multi-functional environment
- Assertive, proven manager with a strong results orientation and sense of urgency
- Knowledgeable of FDA/EMEA regulatory requirements applicable to biologics and pharmaceuticals. Ability to apply cGXP regulations and other FDA and international guidelines to all aspects of the position. Proven success in managing in a global organization
Key Competencies Required
- Leading the Organization: Develops/communicates a compelling vision and sense of purpose for the function/organization; works collaboratively to formulate long-range and mid-term strategies; demonstrates courage in advancing new, innovative ideas; champions change initiatives to enhance organizational performance.
- Collaboration: Works with others and builds effective relationships to accomplish common goals and objectives. Shares information, ideas and solutions with others. Recognises when compromise is necessary while working towards consensus with a focus on outcomes which reflect the collective need.
- Influence and Impact: Develops effective influence strategies based on an understanding of the motivations and needs of others; effectively represents one's own perspective and communicates in a manner that generates support and commitment for proposals/recommendations to enhance the organization's performance.
- Integrity: Displays honesty, truthfulness, trustworthy, principled actions and leadership, business ethics and compliance. Demonstrates consistency between words and actions. Direct and honest in communication and feedback. Honours commitments to others. Handles confidential and sensitive information appropriately.
- Pursuit of Excellence: Continually improves and adds value. Is committed to high quality and standards. Is proactive in addressing issues that might cause problems or processes needing improvement.
- Innovation: Approaches problems with curiosity and open-mindedness. Takes educated risks. Is willing to explore new ideas and methods. Is willing to embrace and lead change. Is passionate about quality.
- Leadership responsibilities are fulfilled through:
- Excellent interpersonal skills
- Quality management skills: problem solving, statistical thinking, design of experiments, etc.
- Relationship skills: negotiation skills, presentation skills, able to read the corporate culture, listening skills, harvests people's energy, manages team members.
- Superior time management skills
- Attention to detail without losing sight of the big picture
- Keeps up to date with technical and managerial developments in the industry
- Adaptability and flexibility.
- Ability to travel globally up to 30%, as needed.
Cv to firstname.lastname@example.com 01 2302400 www.rftgroup.ie


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All good things come to an end...
The squeak of a swing in use, the pitter patter of tiny feet and the tinkling of children's laughter surrounded me. Red, pink and white balloons hung from the room like garlands and paper hearts adorned the walls.
It was my daughter's first birthday party.
The theme was Valentine's Day and cheesy love songs wafted through the speakers whilst children played pin the heart on the cupid and hunted for hidden hearts amongst the playground. We were blessed with an abundance of sunshine, so the hall we had hired and decorated held only a few guests with the majority of them enjoying the surrounding park lands. I spent months planning and preparing, but on the day the little one decided to sleep during my decoration time, so I gave instructions to my husband and hoped for the best as I stayed at home with my sleeping beauty. I have to say, although it didn't turn out exactly as I had envisioned, he did a spectacular job bringing her birthday to life.
We had a whopping 70 guests (the husband assured me that most people wouldn't come, only two were unable to make it), so needless to say I was rather busy attending to everyone, organising games and ensuring there was enough food, all with a 10kg toddler on my hip (as I expected, Miss V was a little overwhelmed by all the people and only wanted to be held by mummy). Whilst it was wonderful seeing everyone, next year will definitely be a more intimate affair. I didn't take any photos of the day myself, but luckily I have a few snap-happy friends who did, so I'll share a few with you.
The children's dessert table included:
- red apples
- fresh strawberries
- home made strawberry and apple juice
- coconut and mixed berry yoghurt
- gingerbread men
- mini vanilla cupcakes
- and the birthday cake which was a strawberry and white chocolate mud swirl
Valentine's favourite part of the day was when daddy pushed her on the swing. And of course later at home when she got to rip open all of those gifts :).
This year has brought a lot of change and new experiences for me. And I must admit, that before my daughter came along, I ignorantly assumed that I could just 'fit her in' to my life without having to change much. Boy, was my head up in the clouds. As it turns out, young kids aren't very fond of fine dining or long days at the beach or large events etc. What they do want is PLENTY of time with mummy and daddy to play and explore. Watching mummy typing on her laptop is not something Miss V endorses and with only 1-2 hours a day of alone time, after the housework is done and lunch is eaten, I am lucky to have enough time crumbs left to do one yoga pose or read a few pages of a book.
And thus it is with a feeling of sadness that I have decided to say goodbye for now to my Greedy Gourmand. There are so many items on my 'to-do' list that I just can't justify spending the rather long time it takes to blog one entry, even if it's only once per month. Especially as I have decided to try to home school Miss V myself for the first 6 years of her life, and as with anything I do, I want to give it my everything and make it as enriching and fun for her as possible. Needless to say, my plate will certainly be full.
I don't want to say 'Goodbye for good' as who knows what the future holds as I do very much hope to return one day.
But for now, I wish all my treasured readers days filled with fine weather, fantastic company and most of all, fabulous food.

subset: commoncrawl


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The Dye Club at Barefoot Resort
Pete Dye has maintained his reputation of combining breathtaking views and infamous pitfalls in this North Myrtle Beach masterpiece. The Barefoot Dye course is semi-private is both memorable and challenging. Rated #10 in "Myrtle Beach top 50 courses" by Golf Digest and also "Places to Play, 2004." Pete Dye combines native grass, Bentgrass greens, and dramatic visual effects in this par 73, 7,343-yard layout.


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338 Laws of Biblical Leadership
When you think of great leaders in the Bible, who do you think of? Perhaps David, Solomon, Moses, and Jesus? However, there are many more great leaders from who we can learn valuable lessons. This course will look closely at Biblical characters, their history, their methodology, and their practical activity in leadership. You will see how they relate to the Lord in wonderful and difficult times and then be able to apply that to your life.
Qualifies for the Church Leadership Certificate.
Main Campus Schedule
- Spring II - Mondays, 6:00 pm - Nehru Grant


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I really like shooting sunset engagement photos in Chicago because I have a chance to experiment and always try to make the bustling city look intimate – as if no one else is here but the couple. This is exactly what I did with Anthony and Beth while we explored the Chicago river bridges and Olive Park.
Being a Chicago engagement photographer means I have to look for the best like possible in many different scenarios. It was pretty easy here because the sun had set behind the skyline by the time we started. Perfect. Beth and Anthony were totally awesome to work with. We captured some amazing photos while exploring and chatting about their future. It was a blast!
Here's a sneak peek at their photos!


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Home Office
|Printable version
Joint action between the UK and France on migrant pressure
The Home Secretary met French Interior Minister Bernard Cazeneuve to reaffirm their joint commitment to tackle illegal migration.
Both Ministers attended a UK/France government meeting recently (Tuesday 28 July) on illegal migrants making the journey across the Mediterranean to get to Europe.
They discussed the European Agenda on Migration and wider diplomatic collaboration to resolve the migration challenge in the Mediterranean, which is contributing to the situation in Calais and Coquelles.
France and the UK reaffirmed the determination of both countries to enhance practical co-operation ahead of the EU-Africa summit on migration in November, and expressed their regret at the recent loss of life amongst migrants trying to cross the Channel.
The joint action between our countries will include work on development and diplomacy in source and transit countries, action against organised immigration crime and the need to ensure an effective returns programme for illegal migrants.
Tackling illegal migration and its causes upstream
What has been happening in the Mediterranean in recent months is an unacceptable and tragic reminder of the huge risks migrants take when they attempt the perilous journey to reach Europe.
In this context, the EU is fully engaged on this important issue, addressing it at the level of the European Council in April and June 2015.The UK and France are playing a full part in dealing with the immediate situation to prevent further loss of life at sea.
Both countries agree that it is important to stabilise countries from which migrants are coming, and to target and stop the callous criminals who lie behind this vile trade in human beings. Only by doing that can we find a long-term solution to the problem.
Until we do this, numbers will continue to grow, criminals will get richer and public confidence will be undermined.To support this, the UK and France are playing a leading role in pushing for action through the EU and the UN to tackle the root causes of illegal immigration and the organised trafficking gangs behind it. Considerable progress has already been made through better intelligence sharing and increased collaboration between law enforcement agencies.
The UK and France are committed to working together to pursue and disrupt the organised crime groups profiting from the people smuggling trade in source and transit countries in North, East and West Africa.
Therefore, the UK and France welcomed the decision to launch the EU CSDP mission at the Foreign Affairs Council in June reinforcing the EU's determination to combat smuggling of migrants.The UK and France are committed to enriching the intelligence picture, developing a shared strategic analysis of the problems. We need to ensure that all possible information and intelligence, including from migrant debriefing, is shared across Europe though the JOT MARE analysis centre in Europol so that we can develop operational intelligence to target the criminals. To assist, the UK and France are both posting intelligence and law enforcement specialists in the analysis centre.
With Europol and EU partners, the UK and France have supported the establishment of the EU Regional Taskforce in Sicily, but there is still more to be done across Europe at transit points. Following the "hotspot approach" put forward by the Commission, migrants should be systematically identified on arrival; for those that do not need international protection, return should be effectively enforced. Upstream work is equally important and our two countries have plans for closer engagement with source countries, so we can support intelligence gathering and investigations at source.
The UK and France agree it is vital we deal with the continuous migration of people from countries of origin. Both countries have agreed to work together on returning migrants to their countries of origin, particularly in West Africa. In Niger, a support centre for migrants is expected to open by the end of the year under the auspices of the International Organization for Migration. To reach these goals, the Valletta conference will be of utmost importance; the EU must set an ambitious and concrete agenda combining development issues, capacity building and an improvement in the short term of the cooperation of these countries in the field of readmission.
The UK Government has announced a new range of programmes to address the root causes of the migrant crisis. This includes aid initiatives totalling £217 million in Africa, to help approximately 2.5 million refugees and vulnerable people in the countries that the majority of migrants are travelling from or through. An additional £100 million in aid will help those displaced as a result of the Syria crisis.
With more than €3 billion a year in development assistance to Africa, France contributes to addressing the root causes of migration. Countries of origin and transit in West Africa are among those countries who receive the most, including to reinforce their capacities and to help them with the management of migration and refugees. Both countries agreed to coordinate their efforts in this field and push for ambitious EU aid programmes to develop the skills and improve the lives of those in source countries, aiming to improve standards of living and reduce drivers for migration.
The Port of Calais and the Channel Tunnel
The UK and France continue to work together on implementing the Joint Declaration of September 2014, which included £12 million financed by the United Kingdom, to address the current migrant situation in Nord Pas de Calais, alongside a further £1.4 million (2m Euros) towards the secure waiting area for lorries at Calais (announced by the Home Secretary on 14 July).
As the Home Secretary described in the UK Parliament on 14 July, it was also confirmed recently that the UK has agreed to additional funding of up to £7 million towards increasing security at the Channel Tunnel railhead at Coquelles.
The French government has deployed significant police reinforcements in Calais to maintain law and order and ensure the security of goods and people. In addition, France has an active programme of humanitarian support for migrants aiming especially at encouraging their access to international protection. France is already contributing 10 million Euros a year to cover the costs of humanitarian support for migrants in Calais, and expects that significant additional money will need to be spent in achieving the conditions that are needed.
Both sides agree to strengthen cooperation in identifying and providing help for victims of human trafficking and prosecuting smugglers involved in this. France and the UK intend to continue their communication campaigns in order to inform migrants about possibilities of seeking asylum in France and the realities of life for illegal migrants in the UK.
This work to improve security at the site has already started with deployment of the security fences used at the NATO summit – and permanent fencing too. This will protect the train platforms where migrants are attempting to board waiting and slow moving trains destined for the UK. And the first UK contribution of extra fencing at the Channel Tunnel will be completed this week.
The French Interior Minister welcomed the Home Secretary's recent announcement that the UK Government will support the Port of Calais to create a secure waiting area for UK-bound lorries within the Port. The new secure waiting area is being progressed and we have reached an agreement with the Port to provide secure waiting for a number of lorries with immediate effect. The secure waiting area, coupled with the additional fencing at Calais port, will enable 230 vehicles to wait safely when queues occur. The two Ministers also discussed the continuing law enforcement focus in the Calais region, to prevent illegal migration and avoid further loss of life on the railway line.
The two Ministers are particularly pleased with the progress achieved in the recent meeting and will be expecting regular reports from officials on taking forward the different strands of work agreed. They agreed that there should be a further UK/France government dialogue in Paris before the end of the year, alongside continuing daily operational collaboration.
Latest News from
Home Office
Over 500 criminals and immigration offenders removed30/09/2022 16:12:00
Foreign criminals removed in September had received combined prison sentences of more than 337 years.
Our 'effective delivery' principle in action: Updating a scientific e-licensing service29/09/2022 11:10:00
Blog posted by: Ben Stevens, Product Lead, Enablers, 29 September 2022 – Categories: DDaT Strategy, Delivery.
New support for victims of county lines exploitation26/09/2022 11:10:00
Hundreds more victims expected to be helped through funding of support services to 2025.
New crackdown on fraud and money laundering to protect UK economy22/09/2022 15:34:00
Wide ranging reforms designed to bear down on kleptocrats, organised criminals and terrorists abusing the UK's open economy have been introduced to Parliament today.
Foreign criminals and illegal entrants to the UK removed to Albania05/09/2022 15:20:00
Offenders removed had received combined prison sentences of more than 87 years.
Independent review on departure of Metropolitan Police Commissioner published05/09/2022 10:20:00
Sir Tom Winsor's review into the circumstances of Dame Cressida Dick's departure has been published.
Brave, inspirational and selfless acts recognised with new Home Secretary commendation02/09/2022 11:10:00
Award for outstanding contributions in the field of home affairs by civil servants, members of police and fire services and members of the public.
Community support funding announced for people of Liverpool30/08/2022 10:20:00
Home Secretary made the announcement on a visit to Liverpool.


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The 10 benefits of green hydrogen in logistics
The decarbonization of the planet is one of the objectives, which…
On May 11, 2022
The decarbonization of the planet is one of the objectives, which…
On May 11, 2022
The thought-provoking factor, in achieving a five-star delivery…
On May 4, 2022
No matter which activity you are in, we have the logistics solutions you need to optimize your supply chain.
We work with you to develop and effectively implement smart logistics solutions.
At FM Logistic, we are driven by our collective entrepreneurial spirit and our shared passion for making supply chains more sustainable.
Joining FM Logistic means joining a company where we believe that everyone can be a driving force in making supply chains more sustainable and building better tomorrows.See our jobs offers
At FM Logistic, we are 27,500 people who believe that supply chains
have the power to create positive impacts for people and the planet.
Fully independent, we activate our beliefs in 14 countries across Europe, Asia and Latin America.Contact us


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Township meetings are the1st and 3rd Tuesday at 7:00 p.m. (Nov.
through Apr.), 8:00 p.m. (May through Oct.) at Township Office.
Township Office : 04266 County Road 12, 419-636-0823 (Phone, Fax,
Zoning Inspector: Todd Burkholder
Zoning Office: 04266 County Road 12, 419-636-5522
Center Township is a zoned township, permits required, fee
Drive culverts require a permit, no fee.
Township Trustees
A. Grube
04477 County Road 12
Bryan, OH 43506
Jeffrey K. Burkholder
02919 County Road 12-50
Fiscal Officer
Todd Burkholder
11264 County Road C-60
Ryan W. Muehlfeld
04569 County Road 12
The recycle trailer is located at the Center Township
Complex on County Road 12 the second full weekend of every month. Acceptable items are as
follows; clear and brown glass bottles and jars only, plastic
bottles #1 and #2, newspapers, steel cans, aluminum cans. "NO
TRASH OR GARBAGE PLEASE." Unacceptable items are taken to the
landfill at a charge to the program. There is a site for leaf and
grass compost. There is a separate compost area for
brush and small branches. Old compost can be taken free of
Cemetery lots are available in Brown, Williams Center
and Yackee Cemeteries. Contact the Fiscal Officer for information.
A large rentable room is available for meetings,
dinners, parties, etc. Contact Fiscal Officer for information.
In the best interest of residents and families of
Center Township, whenever changing addresses or obtaining a new address,
please contact the Williams County Communications Agency at 419-636-8497
with your updated information. This is very important to the
emergency services (Sheriff, Fire and EMS) of Williams County to a
faster response time to you.


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On this week's episode of the Real Life Podcast, the boys gather to talk all things Oilers, recap last week's trip to Calgary, figure out the best and worst of the week, and a reminisce about the first 10 years of Oilersnation.
To start off the episode, Wanye wishes Baggedmilk a happy birthday and grills him for not ageing a day since they've met. Did he make a pact with Satan? All signs point to yes. From there, Baggedmilk and the Squire recap the Nation Road Trip to Calgary and tell the story of how they ended up with the Saddledome's shovel. After a short detour comprised of Drake and Scott Stapp talk, the guys introduce a new podcast segment where they go over the best and worst Oilers moments from the week that was. Lastly, Wanye and the Squire recount the early days of Oilersnation, the struggles that went along with launching the site, and talk about this weekend's 10th Anniversary Party that's going down at the Pint Downtown.
Listen to Real Life on Soundcloud here, on iTunes here and on Google Play.
- Episode 66: McPoints, Vegas, and Fearless Predictions
- Episode 65: Vodka, Talkin' Business, and the Oilers Death March
- Episode 64: Technical Difficulties, Klefbom's abs, and the Year of Nuge
- Episode 63: Uffe Bodin and former Oilers in Sweden
- Episode 62: Trade Deadline and Secure Phone Lines
- Episode 61: "That's how Blockbuster screwed themselves"


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Integrins are αβ heterodimeric adhesion receptors that relay signals bidirectionally across the plasma membrane between the extracellular matrix and cell-surface ligands, and cytoskeletal and signalling effectors. The physical and chemical signals that are controlled by integrins are essential for intercellular communication and underpin all aspects of metazoan existence. To mediate such diverse functions, integrins exhibit structural diversity, flexibility and dynamism. Conformational changes, as opposed to surface expression or clustering, are central to the regulation of receptor function. In recent years, there has been intense interest in determining the three-dimensional structure of integrins, and analysing the shape changes that underpin the interconversion between functional states. Considering the central importance of the integrin signalling nexus, it is perhaps no surprise that obtaining this information has been difficult, and the answers gained so far have been complicated. In this Commentary, we pose some of the key remaining questions that surround integrin structure-function relationships and review the evidence that supports the current models.
It is now almost 20 years since it was first demonstrated that the ligand-binding activity of integrins is regulated by conformational changes (Frelinger et al., 1990), and more than a decade since integrins were fully recognised as allosteric proteins (Mould, 1996). Integrins are known to adopt three major conformational states: `inactive' (low affinity), `primed' or `active' (high affinity), and ligand occupied. Major advances in our understanding of these states have taken place in the past decade, including the determination of the first crystal structures of integrin dimers (Xiong et al., 2001; Xiong et al., 2002; Xiao et al., 2004) (Fig. 1), but controversy remains. Specifically, there has been much debate concerning the precise nature of each conformational state and the key shape changes that distinguish their formation. In the `switchblade' model (Beglova et al., 2002; Takagi et al., 2002; Shimaoka et al., 2002; Nishida et al., 2006), the three states correspond to conformations that are bent, extended and extended with an open headpiece. Broadly speaking, this model is currently the most widely accepted paradigm, but there is also evidence that integrins can bind ligand in a bent (or partially unbent) conformation (Arnaout et al., 2007).
Integrins are αβ heterodimers (Fig. 1), and their priming or activation from the inside out is thought to be initiated by separation of the two subunits at their cytoplasmic and transmembrane regions (Kim et al., 2003; Luo et al., 2004; Vinogradova et al., 2002), which then leads to unbending of the ligand-binding headpiece and conformational changes that increase ligand-binding affinity (Luo and Springer, 2006; Takagi and Springer, 2002). Inside-out integrin activation can be controlled by talin (Tadokoro et al., 2003), and crystal and nuclear magnetic resonance (NMR) structures of the complex comprising talin and the integrin β-subunit cytoplasmic domain have been solved (McCleverty et al., 2007; Wegener et al., 2007). There is also evidence that outside-in activation upon ligand binding stabilises an extended integrin conformer, which again leads to prolonged separation of the α- and β-subunit receptor legs, transmembrane regions and cytoplasmic domains (Luo and Springer, 2006).
Although the existence of conformational changes is incontrovertible, it is important to determine whether these changes are all-or-nothing responses or whether functional intermediate forms exist. Owing to a relative paucity of structural information, we do not have detailed insights into the structure-function relationship of different integrin dimers, and we do not know whether these vary between dimers. We also have limited information about the subcellular distribution of integrin conformations. Finally, because integrin activity and therefore function can be modulated in a variety of ways, including by ligand, divalent cations, reducing agents, monoclonal antibodies, the interaction of intracellular proteins (including talin), and engineered mutations, it is important to determine whether different agonists induce specific shape changes that result in different signalling responses. In this Commentary, we focus on the importance of transmembrane-leg separation and the bending and extension of integrins, pose some of the key remaining questions surrounding integrin structure-function relationships, and review the supporting evidence for the current models.
How do cytoplasmic factors control integrin conformation?
Binding of integrin β-subunit cytoplasmic domains to talin is a key convergence point for signals that regulate integrin activation (Tadokoro et al., 2003). It has been proposed that contact between the talin phosphotyrosine-binding (PTB) domain and the membrane-proximal region of the cytoplasmic domain is crucial for activation (Wegener et al., 2007). It has also been shown that Dok1 negatively regulates integrin activation (Oxley et al., 2008). The Dok1 PTB domain binds exclusively to the central NPLY motif of the β3 integrin cytoplasmic domain (Oxley et al., 2008), competes with talin for this site, but does not cause activation as it does not bind the membrane-proximal region. It has also been reported recently that kindlin-2 promotes integrin activation in a similar manner to that of talin (Shi et al., 2007b), and that kindlin-2 and talin share a common aspartic acid residue in the tyrosine-binding pocket. These reports imply that tyrosine phosphorylation may be a common mechanism for regulating inside-out signalling in integrins.
Most analyses of talin-integrin binding have used the isolated talin PTB domain, and it has been shown that the intact talin protein is a much less potent integrin activator. Recent structural studies, in combination with biochemical and mutational approaches, have provided an explanation for this discrepancy (Goksoy et al., 2008). The talin FERM domain, via its PTB domain, has been found to interact with the talin rod domain to restrain the molecule in an inactive conformation. The talin mutation M139A disrupts this PTB-rod interaction, but not the interaction of PTB with integrin, and therefore constitutively activates the platelet integrin αIIbβ3. Thus, in the closed state, the integrin membrane-proximal binding site of the talin head domain is masked by the rod domain. Following receipt of intracellular stimuli, talin undergoes a conformational change so that its PTB domain can then bind to the integrin membrane-proximal region. This, in turn, leads to separation of the integrin αβ cytoplasmic domain and inside-out activation. One possibility is that phosphatidylinositol (4,5)-bisphosphate (PIP2) binding serves as the trigger for the conformational change in talin. Using nuclear magnetic resonance (NMR), PIP2 has been shown to disrupt the inhibitory PTB-rod interaction (Goksoy et al., 2008). Taken together, these two studies (Goksoy et al., 2008; Oxley et al., 2008), along with other earlier structural studies (Garcia-Alvarez et al., 2003; Vinogradova et al., 2002; Wegener et al., 2007), have now provided the field with a clearer view of how conformational changes occur during talin-mediated integrin activation.
How are shape changes propagated across the plasma membrane?
Two recent papers that describe the three-dimensional structure of the integrin αIIb and β3-transmembrane segments have provided insights into how signals are transduced via the integrin transmembrane regions (Lau et al., 2008a; Lau et al., 2008b). These structures show that upon activation, the αβ extracellular domains connect to the transmembrane domains at different crossing angles. The structure of the αIIb transmembrane segment is characterised by a linear α-helix between I966 and K989, followed by a reversal of the backbone for residues F992-F993. This structure packs the two phenylalanine residues against the αIIb transmembrane helix and orientates the residues towards the lipid core of the membrane. Alanine substitution of either of these two residues leads to receptor activation (Hughes et al., 1996), implying that these residues are required for maintaining the inactive state. The authors conclude that the unusual G991-F993 motif of αIIb, which is almost completely conserved in integrin α-subunits, is a key element in the transduction of signals across the plasma membrane. Although the mechanism of inside-out signalling is now somewhat clearer, there are still a number of questions that remain to be answered concerning conformational states of the integrin extracellular domains.
Is bent integrin inactive?
In the crystal structure of integrin αVβ3, the bend in the integrin is at 135°, an obtuse angle (Fig. 1B). When αVβ3 and αIIbβ3 are engineered to be locked in this extreme conformation, they are unable to bind ligand, even though they are expressed on the cell surface (Takagi et al., 2002). In addition, negatively stained images of soluble αVβ3, αLβ2 and αXβ2 integrins show predominantly bent structures under conditions in which ligand binding is low, that is in which the C-termini are clasped, or when samples are prepared in Ca2+-containing buffer (Nishida et al., 2006; Takagi et al., 2002). However, electron microscopy (EM) images obtained under these conditions show that molecules exhibit varying degrees of bending, from 135° to almost right-angled forms. If this case were extrapolated to a cellular environment, the ligand-binding pocket might be positioned away from the cell membrane and available to bind ligand. This would produce a primed integrin that was not fully extended. Such a `breathing' movement has already been proposed as a mechanism for the conversion of bent to extended integrin (Beglova et al., 2002; Takagi et al., 2002), and would also allow stimulatory monoclonal antibodies to bind and exert their effect. In this context, modelling data combined with experimental hydrodynamic analyses of β3 integrins in solution (Rocco et al., 2008) suggest that a 20° head-tail unbending of αVβ3 integrin is necessary to achieve a good fit with the experimental transmission EM (TEM) and crystallographic data (Adair et al., 2005; Xiong et al., 2001).
There is also the question as to whether all integrin dimers are bent when inactive. Rotary shadowed images of integrin α5β1 with clasped C-termini reveal only extended conformers (Takagi et al., 2001) and, although the resolution of the images may not have been high enough to reveal bent conformers, this indicates that inactive integrin might not necessarily be bent. Furthermore, a cryo-EM reconstruction of unstimulated αIIbβ3 integrin indicated a partially extended, z-shaped conformation (Adair and Yeager, 2002) and, in the multi-resolution study mentioned above (Rocco et al., 2008), the same integrin was modelled to be fully extended at rest. Both structural and biochemical data indicate that inactive integrin adopts a more compact shape. However, the images of the very bent conformer were obtained with the extracellular domain in isolation, and the contribution of the transmembrane and cytoplasmic regions to the physiological conformation, as well as possible interaction of the integrin legs with other cell-surface receptors, remains poorly understood.
Is activated integrin extended?
Although current models of integrin function suggest that conversion to a high-affinity receptor requires extension, there is ample evidence to suggest that ligand-bound integrin can adopt a bent conformation. Crystallised αVβ3 integrin can bind a cyclic RGD-sequence-containing peptide while in the bent conformation (Xiong et al., 2002), and TEM images also show bent αVβ3 in complex with a fragment of fibronectin (Adair et al., 2005).
Further evidence has been gained from fluorescence resonance energy transfer (FRET) experiments using either integrin α4β1 (Chigaev et al., 2003; Chigaev et al., 2007) or αIIbβ3 (Coutinho et al., 2007). With α4β1, FRET between fluorescently tagged LDV-sequence-containing peptide, a ligand for α4β1, and labelled cell membrane was measured in the presence of various agonists. Mn2+ induces a 5 nm movement of the integrin away from the membrane and stimulation by chemokines produces a smaller 2.5 nm change. A fully extended integrin would require a 10 nm movement, therefore, the results not only provide evidence that an active or ligand-bound integrin does not need to straighten completely, but that different stimuli can induce apparently different conformations and that the degree of unbending of the receptor correlates with its activity. In addition, although the phorbol ester PMA was shown to activate α4β1, no accompanying extension of the receptor was detected (Chigaev et al., 2007). This finding might be explained by the effects of PMA on receptor clustering or trafficking.
One study measured changes in FRET between antibodies directed against the head-piece and leg regions of αIIbβ3 on platelets (Coutinho et al., 2007). On resting platelets, a separation of 7.0-7.5 nm between the headpiece and membrane was measured, which only slightly increased upon activation with ADP or thrombin receptor-activating peptide (TRAP), again suggesting that activated integrin can still be bent. Cryoelectron tomographic studies also indicate that αIIbβ3 remains the same height in reconstituted membranes after activation by Mn2+ (Ye et al., 2008).
Experiments investigating competition between a panel of antibodies directed against the calf2 domain and the βA domain (Fig. 1) of the same integrin also suggest that different agonists induce specific conformations (Calzada et al., 2002). On resting platelets, antibodies that bind to the βA domain cross-compete with those that recognise the calf2 domain of the α-subunit, suggesting a bent conformation. Surprisingly, activation using ADP or TRAP induces a conformational change that was interpreted as a closing of the bent conformation, in agreement with the FRET data above. Conversely, stimulation with arachidonic acid induces a different conformational change involving an opening of the αβ interface, which is consistent with extension of the integrin.
It is well known that different integrins within the same family differ in their response to agonists. Integrin αXβ2 is harder to activate than other β2 integrins (Lu et al., 2001), αIIbβ3 is more resistant to the effects of Mn2+ than αVβ3 (Kamata et al., 2005), and there is a differential response of β1 integrins to both Mn2+ and ligand as measured by the exposure of epitopes on the β-subunit (Bazzoni et al., 1998). How these differences relate to structure has not been resolved, but it is clear that the same agonist can have diverse influences on integrin function. It is also important to point out that the energy barrier between different conformational states is likely to vary for different integrins – for example, it has been shown that interactions between leg domains are stronger for αIIbβ3 than for αVβ3, which may help to explain why the default state of αIIbβ3 integrin on platelets is completely inactive, whereas αVβ3 integrin is constitutively active on many cell types (Kamata et al., 2005).
Recent structural data using two constructs of the integrin β2 subunit have revealed a possible level of complexity to the straightening of the receptor. A construct comprising the plexin, semaphorin and integrin (PSI) domain, the hybrid domain and epidermal growth factor (EGF)-like repeats 1 and 2 crystallised in a bent conformation; however, following the addition of EGF-3, they adopt an extended form. The differences in the two structures showed that rather than a simple unbending in one plane, the transition involves a twisting of EGF-2 relative to EGF-1, a change of angle of a disulphide bond, and disordering of an α-helix (Shi et al., 2007a). As most EM images of integrins show very poor resolution of the lower β-subunit leg, it seems likely that this region is extremely flexible and can adopt a variety of positions relative to the α-subunit, which remains fixed and stable. Electron tomographic analysis of αIIbβ3 integrin also shows the β3 lower leg in many different conformations (Iwasaki et al., 2005), and this raises the possibility that a twisting of the β-subunit around the stable α-subunit could yield intermediate conformers that are agonist-specific. Indeed, such a twisting could reveal activating epitopes in the β-subunit leg without the receptor necessarily fully extending.
In summary, upon activation, integrins certainly undergo a conformational change that involves unbending of the receptor. However, evidence is beginning to emerge that the degree of extension is both agonist- and integrin-specific. In addition, active integrin might not be necessarily fully extended. This would also suggest that a rapid conversion from the bent to extended conformation does not occur and that intermediate forms are functionally relevant. In addition, most of the current structural data are restricted to β2 and β3 integrins, the activation of which, by necessity, must be precisely controlled, and it remains to be seen whether this information can be extrapolated to β1 integrins on adherent cells.
How far does the hybrid domain move?
Although opinion on receptor extension is still varied, there is general agreement that ligand binding is accompanied by an outwards movement of the β-hybrid domain, that this represents the key conformational change in the switch from inactive to active integrin, and that this is a clear indicator of receptor affinity (Rocco et al., 2008; Takagi et al., 2003; Xiao et al., 2004). However, the extent of this swing-out is unclear, with reports varying from 10° to 80° (Adair and Yeager, 2002; Mould et al., 2003b; Xiao et al., 2004). This variation could be interpreted as evidence for intermediate conformations, particularly as the α7 helix in both the αA and βA domains has been shown to have a degree of elasticity (Jin et al., 2004; Shimaoka et al., 2003; Yang et al., 2004). However, it might also relate to the nature of the material used, because the smaller the integrin fragment – and therefore the lower the constraint imposed upon the hybrid domain – the larger the reported movement.
Molecular dynamics modelling has predicted that the hybrid domain of integrin αVβ3 swings open about 20° when the leg-region constraints are lifted (Puklin-Faucher et al., 2006), and that this also involves an inward movement of the α1 helix as previously shown (Mould et al., 2003a). These changes might be enough to induce alterations in receptor affinity, and were suggested to represent outside-in integrin priming (Puklin-Faucher et al., 2006). Further molecular dynamics analysis revealed that conversion to the state in which the hybrid domain was fully extended (an 80° movement) required the application of force to overcome the energy barrier needed for this change to occur. Thus, there is evidence to suggest that different positions of the hybrid domain relative to the βA domain are physiologically relevant. These findings also raise the question of whether full extension of an integrin with a concomitant full outward movement of the hybrid domain is only achieved once the cell is under tension, and thus represents a post-ligand-binding event. In addition, this Commentary highlights that we might have to be more precise in what we term `active' integrin, because it seems likely that different agonists have wide-ranging effects that are integrin-specific and what `activates' one receptor may not apply to all receptors.
How are conformational changes coupled?
The pathway of conformational change from the interior of the cell to the ligand-binding site of the integrin (a long-range distance of more than 20 nm) is a poorly researched topic, but it probably underpins cellular control of integrin activity. A major restraint that holds integrins in an inactive state appears to be the interaction between α- and β-cytoplasmic domains. As mentioned above, disruption of these interactions through the binding of proteins such as talin is proposed to be the first step in the pathway (Han et al., 2006). Consistent with this proposal, mutations that disrupt the interactions between the cytoplasmic domains lead to constitutively active integrins, whereas locking the legs of the integrin together prevents activation. A weakening of the interactions between the leg regions of the α- and β-subunits allows unbending of the receptor.
In the bent state, interactions between the hybrid domain and the leg domains prevent the outward swing of the hybrid domain, but this constraint is removed in the extended state and the hybrid domain is free to move. It should be noted that extension does not by itself cause increased affinity, although extension of the integrin on the cell surface is likely to result in increased capture efficiency of ligands (Chigaev et al., 2007). Instead, conformational changes in the head are the key determinant of ligand-binding activity, specifically the conformation of the βA domain, which, in turn, is determined by the position of the hybrid domain. Thus, a swing-out of the hybrid domain away from the α-subunit pulls downwards on the α7 helix of the βA domain and favours the upward movement of the α1 helix (Xiao et al., 2004). The motion of these two helices shifts the βA domain from a low-affinity into a high-affinity conformation (Mould et al., 2003a). Mutations that favour a downward shift of the α7 helix (Cheng et al., 2007; Hato et al., 2006; Mould et al., 2003a) also result in a high-affinity state.
How does force affect integrin activation?
Normally, receptor-ligand bonds are weakened by applied force because the receptor and ligand are pulled apart (these types of bonds are known as slip bonds). By contrast, catch bonds are interactions that are strengthened by tensile force. The nature of these interactions can be explained by allostery: force promotes the formation of a higher-affinity conformation (Thomas et al., 2008). Recently, the adhesion molecule P-selectin has been proposed to form catch bonds with its ligand sialyl-Lewis-X because force promotes an unbending of the molecule that leads to enhanced carbohydrate recognition (Phan et al., 2006; Thomas, 2006). Is there evidence that integrin-ligand interactions are enhanced by force? First, it has been shown that that moderate shear forces can activate leukocyte integrins (Astrof et al., 2006). Second, molecular dynamics predicts that applying tensile force to the integrin-ligand interface pulls on the α1 helix and leads to an opening of the hybrid-domain hinge – this opening would reinforce the bond by stabilising the active conformation of the βA domain (Puklin-Faucher et al., 2006).
Until recently, integrin catch bonds have not been observed directly, however, our atomic force spectroscopy experiments have shown that the lifetimes of α5β1-integrin-fibronectin interactions are increased by forces in the range of 20-40 pN (F. Kong, A. J. Garcia, A.P.M., M.J.H. and C. Zhu, unpublished data). This ability of integrin-ligand bonds to strengthen with force might be of importance, not only for leukocyte trafficking, but also for the migration of many cell types.
We previously proposed that multiple intermediate conformations of integrins exist, based on flexible joints and hinges in the receptor, particularly at the knees and the interface of the hybrid and βA domains (Mould and Humphries, 2004). Experimental evidence is now emerging suggesting that a spectrum of conformations is possible, with variations in the extent of unbending and hybrid-domain swing-out, which might be both integrin- and agonist-specific. We propose that the information discussed in this Commentary is integrated into a five-component model that provides a scenario that takes into account much of the current biochemical and structural data, and also highlights a possible conformational distinction between inside-out and outside-in signalling (Fig. 2). The dynamic equilibrium that exists between active and inactive integrin challenges our ability to investigate the validity of proposed intermediate forms, but these problems are gradually being overcome to provide new insights into integrin structure-function relationships. In the future, it will be of great importance to obtain crystal structures of additional integrin conformations and of integrins that are bound to macromolecular ligands.
The work in the authors' laboratory that contributed to this Commentary was supported by grants from the Wellcome Trust (to M.J.H.). Deposited in PMC for release after 6 months.


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January 1943. "New York. Sixteen-year-old boy who is in the naval reserve on Mulberry Street." Along with a trove of telephone graffiti that looks as old as he is. Photo by Marjory Collins for the Office of War Information. View full size.
I don't know how old this list is, but this number was still a payphone at some point, probably at the Post Office at 8th Avenue and 31st Street in New York - right across the street from (then and now) Penn Station and (now) Madison Square Garden. See http://www.payphone-project.com/numbers/usa/NY/NEW_YORK/212-962-8354.htm... . Looking at a higher-level page at Payphone Project, the upper reaches of 962, from about line 8000 on up, were populated with a plurality of pay phones.
Per the BLS inflation calculator, that nickel from 1943 would be worth about 67 cents in 2013, or about 13.4 cents a minute. That's pretty high for a modern postpaid (contract) cell phone, but not that far off from what some prepaid cell phones cost. But you would have to supply your own wall to write on.
The pay phone is actually manufactured by the the Gray Telephone Pay Station Company although they were sold through Western Electric as well as other distributors.
I've read that the reason for those alphanumeric codes, such as WOrth 2-9970, is that Bell System engineers did not believe people could easily memorize a seven-digit number. Their research indicated that five digits was the limit, so they created mnemonics such as this to fill in the rest and allow the required quantity of exchange subscribers, while enabling memorization of a few numbers.
It's well-known that Bell employed the most brilliant engineers, and in hindsight, the irony is that they were both wrong and right. Most people nowadays can't memorize a seven-digit phone number, because we don't need to. The computers in our pockets, which we refer to somewhat quaintly as phones, do it for us. But those of us who grew up before cell phones learned to do it, from necessity.
In 1989-1990, I worked for a rental car company, moving surplus cars to locations where they were needed. At the destination, I had to write the car's seven-digit inventory number on a ticket. It would be most efficient to write it while walking to the office, instead of while standing over the windshield, but I found I couldn't memorize the number in its given nn-nnn-nn format. But if I mentally converted it to nnn-nnnn (just like a phone number) I had no problem memorizing seven digits for a minute or two.
You too can own an old style Western Electric pay phone like our young sailor friend is using (sans dust and spider webs). Current bidding on Ebay stands at $1,136.
Perhaps this is just an unusually old payphone, but it's interesting that in 1943 there are still instructions on how to dial the central office/exchange name (here, WOrth) directly instead of relaying that information orally to an operator.
This telephone number on the sailor's pay telephone is an example of when exchange names were in their heyday in New York City. I always enjoy Shorpy photos when the 'phone numbers include a combination of letters and numbers. As I grew up our numbers included WHitehall, AMherst and CAstle. I still use CAstle to this day. Some U.S. cities, notably Seattle and Philadelphia, continued the use of office names well into the 1970s. You could always tell a person's neighbourhood by the exchange name. Here is a full list of New York City exchange names. Note also the cost is five minutes for a nickel.


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KRASNAYA POLYANA, Russia — Carina Vogt of Germany has never won a World Cup event. She now owns women's ski jumping's first-ever Olympic gold medal.
The 22-year-old Vogt performed when it counted Tuesday at the Sochi Games, scoring 247.4 points on the normal hill at the Rus-Ski Gorki Jumping Center.
Daniela Iraschko-Stolz of Austria took silver and Coline Mattell of France earned bronze.
Sara Takanashi of Japan, the World Cup leader in the sport and heavy favorite heading into the Sochi Games, was a disappointing fourth.
Vogt, who has four second-place finishes in World Cup events this year, had been quiet in training runs, allowing Takanashi and Iraschko-Stolz to take much of the hype as they dueled for supremacy.
"I can't find the right words," Vogt said. "I'm just speechless because training yesterday was not so good. Now I've improved today. I've not won a World Cup till now. It's unbelievable."
Iraschko-Stolz said she had to battle some anxious moments before her silver medal-winning performance.
"It was difficult to jump today because of nerves, difficult to overcome it," Iraschko-Stolz said.
In 2011, the International Olympic Committee agreed to allow the women to compete at Sochi — 90 years after men did at the inaugural Winter Games in 1924.
Japan had been counting on Takanashi, 17, to end an Olympic gold medal drought. The country's last gold came at the 2006 Turin Games when Shizuka Arakawa won the ladies singles in figure skating.
"I couldn't jump the way I wanted to on both attempts." Takanashi said. "I came here wanting to do my best. I'm incredibly disappointed."
Sarah Hendrickson, the 19-year-old defending world champion from Park City, Utah, finished 21st of 30 starters, clearly still affected by right knee surgery she underwent in August. Although she showed improved form Tuesday, she plans to take the rest of the season off.
Hendrickson says she wasn't surprised to see Takanashi off the podium.
"It's a crazy world the Olympics," she said. "It shows she is a human being. I wish I could tell her she is still an amazing athlete and that she has many good years to come."
Hendrickson, because she has no ranking from being off the World Cup circuit with her injury, was the first jumper in the Olympic final.
"It's an amazing feeling to be the first one to jump in the first women's ski jumping competition at the Olympics," she said. "My performance was not the best, but I kind of expected it."
Two other Americans from Park City competed — Jessica Jerome was 10th and former world champion Lindsey Van 15th.


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HONOLULU, July 12, 2011 /PRNewswire via COMTEX/ --
For the third time in eight months, Hawaiian Airlines began service to a new destination in Asia today with the inauguration of daily service between Honolulu and Osaka, Japan.
(Photo: http://photos.prnewswire.com/prnh/20110712/LA34417)
(Logo: http://photos.prnewswire.com/prnh/20040827/LAF044LOGO)
To celebrate the launch of its new route, Hawaiian treated today's inaugural flight passengers to performances of Hawaiian music, hula and a Japanese cultural dance honoring Osaka's beauty. Passengers also received fresh flower lei and participated in a traditional Hawaiian blessing before boarding the aircraft.
"Demand for our services in Japan has returned to pre-tsunami levels, and we are grateful for the enthusiastic response we are receiving from the people of Osaka. This new daily service reflects our confidence in the Japan market and in the important Kansai region in particular," said Mark Dunkerley, Hawaiian's president and CEO.
Hawaiian's daily, nonstop service from Osaka adds approximately 100,000 new air seats annually to Hawaii from Japan, the state's second-largest market for visitors, and continues an expansion into Asia that is helping to boost Hawaii's visitor industry and economy. Hawaiian introduced service to Tokyo's Haneda Airport in November 2010 and Seoul's Incheon International Airport in January 2011.
"Congratulations to Hawaiian Airlines on its launch of direct service between Honolulu and Osaka's Kansai International Airport," said Mike McCartney, president and CEO of the Hawai'i Tourism Authority (HTA). "The new direct flight from Western Japan follows two other milestone flights into the Asia market for Hawaiian Airlines, from Honolulu to Haneda, Japan and Incheon, South Korea.
"The HTA estimates the Osaka route will generate up to $120 million in visitor spending and $18 million in tax revenue annually. Together, all three routes will provide up to $350 million in visitor spending and $38 million in tax revenue annually for Hawaii's tourism economy," said McCartney.
Hawaiian's new service to Osaka offers travelers in the region an authentic Hawaii travel experience. Its award-winning "Hawaii Starts Here" inflight service program showcases Hawaii's culture, people and tradition of hospitality. At the same time, it also offers new pan-Asian cuisine, Japanese entertainment options, and onboard products designed for the enjoyment of Japanese travelers.
With approximately three million residents, Osaka is a major economic and commercial center and comprises the largest segment of the Keihanshin Area, which also includes Kyoto and Kobe, and is Japan's second-most populous area with more than 18 million residents.
In addition, Osaka's Kansai International Airport is a regional hub giving Hawaiian the capability to attract a broader range of customers from Asia via convenient flight connections from other cities in Japan, China and Asia, as well as same-day ground connections from several major cities in Japan.
Hawaiian's Flight #449 will depart Honolulu International Airport daily at 2:20 p.m. and arrive at Kansai International Airport at 6:00 p.m. the next day. Return Flight #450 will depart Osaka daily at 9:30 p.m. and arrive in Honolulu at 10:50 a.m. the same day. (Osaka is 19 hours ahead of Honolulu and the flight crosses the International Dateline.)
Hawaiian will initially operate the Honolulu-Osaka flights with its 264-seat Boeing 767-300ER aircraft, before introducing its new 294-seat Airbus A330-200 aircraft on the route.
Tickets for the Osaka flights can be purchased online at Hawaiian's Japanese-language website, www.HawaiianAirlines.co.jp, and its English-language website, www.HawaiianAirlines.com, or by phone via its sales office in Japan at 03-5405-8761 and toll-free in the U.S. through its reservations center at 1-800-367-5320.
About Hawaiian Airlines
Hawaiian has led all U.S. carriers in on-time performance for each of the past seven years (2004-2010) as reported by the U.S. Department of Transportation. In addition, consumer surveys by Conde Nast Traveler, Travel + Leisure and Zagat have all ranked Hawaiian the top domestic airline offering flights to Hawaii. Hawaiian was also the nation's highest-ranked carrier for service quality and performance in the prestigious Airline Quality Rating (AQR) study for 2008 and 2009.
Now in its 82nd year of continuous service in Hawaii, Hawaiian is the largest provider of passenger air service to Hawaii from the state's primary visitor markets on the U.S. mainland. Hawaiian offers nonstop service to Hawaii from more U.S. gateway cities (10) than any other airline, as well as service to South Korea, Japan, the Philippines, Australia, American Samoa, and Tahiti. Hawaiian also provides approximately 150 daily jet flights between the Hawaiian Islands.
Hawaiian Airlines, Inc. is a subsidiary of Hawaiian Holdings, Inc. (NASDAQ: HA). Additional information is available at HawaiianAirlines.com.
SOURCE Hawaiian Airlines


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Last week, I shared my story and passion for discipling unchurched women. I won't rehash it here, but will simply say God has repeatedly planted our family in places with hard soil – places where it is difficult for the gospel to take root.
But regardless of where you live – whether it's the Bible belt or beyond – the condition of the fields in which our churches are seeking to sow and grow the gospel are rapidly changing.
Western culture is becoming increasingly unchurched – comprised of individuals who aren't affiliated with any church.
Consider these stats from the Barna Research Group concerning American adults. In 2014, it found that 45 percent of Americans were unchurched. That figure is up from 33 percent in 2003 and 30 percent in the 1990s. So, the number of unchurched individuals in America is increasing and this trend is only gaining momentum as we shift farther and farther from our nation's Judeo-Christian roots.
Specifically, women are a key component of this cultural shift away from church or Christianity at large. Ten years ago, more men were unchurched than women. Today, the gender gap has closed from 20 points to 8 points.
In fact, Barna says a large number of unchurched women are actually "de-churched." The majority of unchurched women (85%) haven't attended church in 6 months or more.
So, it's not simply that these women are unreached – that they haven't heard the gospel or been exposed to it – but somewhere along the way they decided church wasn't for them and unplugged altogether.
Unchurched women are not a monolithic group. Depending on where they live and what they do, they will look differently. But as I've traveled speaking and working with different women's ministries, I've discovered that unchurched women commonly share many, if not all, of these four markers:
(1) No Church Home
Lacking a church home means more than simply not attending church, it also includes the concept of lacking a church background. Unchurched women are very often from families who have remained unchurched for generations. Their home life offers them little to no support for spiritual realities and often they have few to no life examples that model healthy relationships or wise living.
How this impacts discipleship: Because the chances are high that unchurched women are from broken homes, believers from an unchurched background will need help grounding their identity in Christ rather than their roles, successes, failures, works, affiliations, acclamations, preferences, or personalities.
Additionally, they will need help finding their place in the church, understanding how the body of Christ operates, and what constitutes heathy and fruitful living. They will need to be challenged to count the cost of Christian service. They will need to taught kingdom realities and what part their lives play in bringing that kingdom to bear through the church.
(2) No Bible Knowledge
Unchurched women have neither studied the Bible nor read it at any length for themselves. Even more likely, they do not own their own copy of the Bible.
I met a 70-year-old woman, who despite growing up in a non-evangelical church, never owned a Bible. She was bright and funny and full of life, but lacked any sort of Bible knowledge. When she first opened the Scriptures, she couldn't find Genesis 1:1. For this reason, when she started studying the Bible, she had to learn how the Bible was put together, not simply what it said.
The seismic transition from paper to the digital world makes this loss an even greater reality. Many individuals simply use their phone or google to look up information. If pressed to look up a Bible verse, they will have no framework for the unity of the Scriptures or the underlying story it presents.
How this impacts discipleship: Discipleship, then, cannot consist solely of best-selling Bible studies. It must include more than what the Bible says about certain topics, specifically how to view the Bible, how to read the Bible, why the Bible is trustworthy and important, and how the different parts of the Bible fit together.
Churches will need to go back to the basics and explain the gospel and its implications for daily living as if they are speaking to someone who doesn't share their heart language. The biggest discipleship obstacle you'll find when facing biblical illiteracy is the assumption that a disciple understands what they are learning.
(3) No Biblical Worldview
Another hurdle churches will face in discipling unchurched women is their lack of a shared worldview. Instead of a biblical worldview, unchurched women will possess one of the following worldviews (or a synthesis of them).
–universalism (all religions lead to God)
–secularism (life devoid of God)
–pantheism (God is in all things)
–humanism (man is God)
–relativism (man can determine truth apart from God)
–traditionalism (man can earn his or her way back to God)
How this impacts discipleship: Individuals who lack a biblical worldview will have a loose understanding of creation and sin. Discipleship, then, cannot begin with the story of the cross; it must begin where Scripture begins and explain how sin came to be and the full range of consequences sin brings. Churches will need to disciple according to the entire story of the Bible (creation, fall, redemption, and restoration) to shape a disciple's worldview around the Bible.
Probably the biggest change churches or women's ministries can make right now in how they disciple unchurched women is to throw out all those to-do lists that comprise most discipleship material (go to church, title, pray, read your Bible, etc.). Those activities are important, but they place emphasis on the fruit of salvation (behavior) before a new plant has firmly taken root (heart transformation because of Christ).
Instead, churches must help guide believers as they filter their current beliefs through the prism of the Scriptures, allowing the Spirit to convict their hearts, prompting true and lasting heart change. True discipleship seeks to bring the gospel to bear on a person's total life. This is particularly true for women who come to Christ from a legalistic or tradition-based religion. This doesn't mean we set aside obedience – far from it! It simply means we are careful not to neglect the gospel in lieu of works.
(4) No Gospel Exposure
Because these women lack a church home, a church background, Bible knowledge, and a biblical worldview, they will also very likely lack gospel exposure.
Even if a woman grew up in a non-evangelical tradition and knows about Christ, her understanding of the gospel very likely will prove incomplete. She might have heard the good news and rejected it on multiple occasions. If she is from a pluralistic religion, she will consider Jesus to be a good teacher among many religious figures. If she is from a secular background, she will have been taught that parts of Christ's story are myths (such as his virgin birth and resurrection).
How this impacts discipleship: Lack of gospel exposure will most certainly mean unchurched women will be surrounded by layers of strongholds and sin, perhaps even generational sin since she is very likely to come from an unchurched family. Discipleship structures will need to address the reality of the spiritual battle ahead of these women when they commit their lives to Christ. They will need to learn how to bring the gospel to bear on each area of darkness in their lives and how the gospel frees them to live in Christ.
Discipling unchurched women starts with the gospel and continues as they are increasingly rooted in its truth.
Traditionally, discipleship emphasizes the bearing of fruit – the transformation into the image of Christ. Spiritual fruit, then, is the evidence that God is changing us into the healthy creation we were intended to be from the very beginning through his Spirit.
However, discipling unchurched women looks differently from those who have grown up in the nutrient-rich soil of a churched culture. Discipling unchurched women is first and foremost, a root-building ministry. When we disciple unchurched women, we must first ensure they are firmly rooted to the church and the gospel. If we do not adequately address the roots of their faith, their fruit will be short-lived. After their first initial growth spurt, the heat of life will scorch them and they will wither away.
If you are a women's ministry leader, very soon you will have to consider how your church or ministry team can best engage unchurched women with the gospel. Next week, we will look at the root-building discipleship process for these women so they might remain securely anchored in the hope of the gospel. I hope you'll join me!


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In thinking about my maternal grandmother's funeral card for our current case study, how would you best cite it as a source? Consider that:
- You are writing about this in an email to another researcher.
- You obtained the scanned image of the original in my possession.
- I am Frances' granddaughter, Pat (Player) Richley-Erickson.
Be sure to answer the following:
- How would you describe it?
- What can you tell about Frances from the information provided?
- What is missing?
- Which additional records might this lead you to review?
Write to Ol' Myrt, and give me your suggestions. This time, the randomly-awarded prize is 4 (count 'em four!) 512MG flash drives courtesy of our friends at Ages-Online.com. Send replies to firstname.lastname@example.com .
If I work this right, I might get some assistance in my research. [Very big grin!]
Myrt :)
Your friend in genealogy.


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What Is Respite Care? Is It The Right Choice For My Situation?
Respite Care is temporary care provided in the home or in a facility for a person that is handicapped or recovering from illness, surgery or a fall. Respite Care is designed to provide relief to the primary caregiver.
Respite Care provides much needed relief for family members, often an overwhelmed spouse. Family members caring for a loved one often neglect their own health and well being.


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He was in me and said I can't believe this happened because of facebook. MOOD KILLER.
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So, is this what the poke button is used for because I still can't figure that shit out.
Guess their relationship's Facebook status just changed, lol
XXX just went from "in a relationship" to "single"
Your first mistake was talking during sex
Note to self don't talk about anything but sex when I be fuckin!
Cd xxx. V. C. C. Cccqq
@ maskedman... that's hilarious!
Haha big fail on his art lmao
Facebook is very handy for picking up unsatisfied wives;) BUT, you definitely don't say that shit while you're balls deep. You save that shit till after she's swallowed or she's wiping her face off;)
hahaha that shit blows.
Kip drordy
Fuck yeah !
Facebook.....some jacked up sh*t
Awkward. Guys who don't know what to say should just shut up and hump else completely ruin everything
I can't believe it's not butter
Lol 3:03 and 3:48
But... That's something that's best said shortly after the sex that was somehow caused by facebook. Duh.
Love it hate facebook
Shut up and take it...
so wats a guy gotta do too "get in you"
As long as the meat is in the cumhole it's not important.


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David D. Kirkpatrick teases more out of the fact that someone will fill out a questionnaire than would be possible if he were at a paper that worked seven days a week. (He's not, he's at the New York Times.) From his "Nominee Gets First Chance to Counter Critics:"
Strategists close to the White House, who requested anonymity for fear of reprisal, say they hope that Ms. Miers can use open-ended questions about subjects like "judicial activism" to lay out her approach to constitutional issues and to placate her conservative critics without providing ammunition to potential liberal opponents.
Her answers could play a role in helping the White House and its allies recast the debate over her selection in terms of "judicial restraint" that prevailed during the confirmation of Chief Justice John G. Roberts Jr.
Billie notes Glen Justice's "As Scrutiny Grew, DeLay Continued to Raise Money:"
Representative Tom DeLay continued to raise hundreds of thousands of dollars in the three months before his indictment in September despite facing legal scrutiny and political pressure over his ties to lobbyists, his foreign travel and his political tactics.
Mr. DeLay, a Texas Republican who has been charged in a campaign finance case in his home state, raised about $920,000 for his campaign from July 1 to Sept. 30, according to reports filed with the Federal Election Commission. His total for the year is about $2.3 million, and he had about $1.2 million remaining on hand.
He was charged with conspiracy Sept. 28 and with money laundering several days later. Mr. DeLay has vowed to fight the charges, which he says are a political ploy by a Democratic prosecutor; until the case is resolved, he has stepped aside as House majority leader.
I'll note this from the article:
Some say fellow lawmakers will want to distance themselves from Mr. DeLay, while others say that his defense will resonate with loyalists and draw more money.
That's also known as "we just don't know." And one wonders how and why it made in the article.
Ericka e-mails to note that "truth comes out in bits and pieces" and steers us to David E. Sanger's "Administration's Tone Signals a Longer, Broader Iraq Conflict:"
For most of the 30 months since American-led forces ousted Saddam Hussein, the Bush administration has argued that as democracy took hold in Iraq, the insurgency would lose steam because Al Qaeda and the opponents of the country's interim government had nothing to offer Iraqis or the people of the Middle East.
Over time, President Bush told troops at Fort Bragg, N.C., this spring, "the terrorists will lose their sponsors, lose their recruits, and lose their hopes for turning that region into a base for attacks on America and our allies around the world."
But inside the administration, that belief provides less solace than it once did. Senior officials say the intelligence reports flowing over their desks in recent months argue that even if democratic institutions take hold, the insurgency may strengthen. And that possibility has created a quandary for an administration that desperately wants to equate democracy-building with winning the war, but so far has not been able to match the two.
The resistance's strength is noted, but are we something else? A trial balloon to justify changing course? I'm not referring to bringing the troops home. I'm talking about a trial balloon to justify being more open about what the government has been doing all along?
Rachel e-mails to note Katrina vanden Heuvel's "Innocent Voices" (Editor's Cut, The Nation):
When Oscar Torres saw a Venezuelan band perform the song "Casas de carton" ("cardboard houses") in 2001, he knew that he wanted to "write something about the song" that he remembered so well from his childhood days growing up in war-torn and impoverished El Salvador. Soon after, Torres started working on a screenplay that ultimately served as the basis for the film Innocent Voices which will begin playing in 11 US cities on October 14.
The film has received critical acclaim after being released in Latin America and shown at this year's Amnesty International Film Festival. It deserves a wide audience in the United States. Directed by the talented Mexican filmmaker Luis Mandoki, Innocent Voices tells the story of Torres' embattled youth. The narrative is exquisitely told through the eyes of an 11-year-old boy named Chava whose character is based on Torres' boyhood. (Chava, appropriately, is a nickname for "Salvador.") Innocent Voices depicts the horror of war and its impact on children caught in the middle of El Salvador's civil strife in the 1980s.
There are no "good guys" in this conflict (though it's fair to say that the government paramilitary militias are definitely the "worse guys.") The film shows the government's soldiers hunting down and conscripting all 12-year-old boys in the village to serve in the military. But the bullets of the rebel-led Farabundo Marti National Liberation Front (FMLN) kill children just as effectively as the guns of the right-wing government's forces. And then there are the US soldiers who train and arm the government's military and who come across as depraved and without remorse.
Zach e-mails to note Robert Parry's "Bush's Latest Iraq War Lies" (Consortium News):
With his earlier war rationales shattered, George W. Bush now says the Iraq War must be continued indefinitely because of the presence of foreign Islamic fighters -- even though they are estimated to represent only a tiny fraction of the Iraqi insurgency and might well quit the struggle if U.S. troops were to leave Iraq.
In an Oct. 6 speech aimed at rallying U.S. public support for the Iraq War, Bush painted a harrowing picture of the consequences that would follow an American withdrawal. Bush warned of "a radical Islamic empire that spans from Spain to Indonesia" and the strategic isolation of the United States.
Bush's alarmist vision, however, clashes with both recent intelligence assessments on the significance of foreign fighters to the Iraq War and fears expressed in an intercepted letter purportedly written by al-Qaeda's second-in-command Ayman Zawahiri to al-Qaeda's chief in Iraq, Abu Musab Zarqawi.
The "Zawahiri letter" cautions that an American withdrawal might prompt the "mujahedeen" in Iraq to "lay down their weapons, and silence the fighting zeal." To avert this military collapse, the letter calls for selling these foreign fighters on a broader vision of an Islamic "caliphate" in the Middle East, although nothing nearly as expansive as the global empire that Bush depicted.
But the "Zawahiri letter" indicates that even this more modest "caliphate" is just an "idea" that he mentioned "only to stress … that the mujahedeen must not have their mission end with the expulsion of the Americans from Iraq."
In other words, assuming U.S. intelligence is correct that the letter was written by Zawahiri, al-Qaeda sees promoting the dream of an unlikely "caliphate" as a needed sales pitch to keep the jihadists from simply returning to their everyday lives once the Americans depart Iraq.
Exaggerated Threat
Bush also appears to be exaggerating the significance of the foreign fighters.
Though their spectacular suicide bombings have garnered headlines and killed hundreds of Iraqis, recent intelligence assessments put the size of this foreign jihadist force at only a few thousand, or around 5 percent of the overall Iraqi insurgency.
Zach sends more from Consortium and we'll note it in later entries. There's a third entry that I feel needs to be done because Ava had prepared a report for it that got killed due to running out of time. I asked if she wanted to write something on it and she said no, she just wants to move on with the week. (Members will grasp the why of that.) It was an important topic and she worked hard on it. If I had her notes, I'd attempt to reconstruct it. I don't, so I'll just note it via excerpts.
But it's an issue the community cares about and it needs to be noted.
Lastly, via BuzzFlash, Susan found Lorna Tychostup's "Weapons of Mass Deception: An Interview with Danny Schechter" (Chronogram):
Lorna Tychostup: Weapons of Mass Deception begins by discussing the difference between "journalism" and "coverage." Can you explain the difference?
Danny Schechter: Coverage can be pointing the camera at something, at a press conference, at a bomb going off, at a bunch of tanks rolling down the road and you can report on what you are watching and seeing. Journalism attempts to put information in context. It attempts to add a dimension of reporting so that you find out what else is going on, what is the back story to it, offer some assessment, analysis, context, etc. And that is what is often lacking.
LT: How would you define journalism?
DS: Journalism is an effort to report on news, on the news of the day. It is an effort to try to explain what is going on, to find out what is going on, first of all. Check the accuracy of the claims by government agencies and the like, and also to offer some perspective. Different countries have different styles of journalism, but ours tends to be a news story with the five W's and an H--who, what, where, when, why, and how. That is [our] classical approach to journalism--an effort by the press, which has been given a First Amendment protection to serve the public interest--to be a check on power. Not only tell us what is going on, not only to inform us, but also to bring out information that other people want hidden.
LT: What is "independent" journalism? How does it fit into the definition?
DS: We are living in an age of corporate domination of big media. Larger and larger companies controlling the information system—publishing, television, radio, print; often companies that are not really primarily committed to journalism but they are in the media business. They are into advertising, entertainment, and other forms of communication. Reporting is a small part of it. Sometimes their [business] priorities take priority over their journalistic interests.
LT: Independent journalism, how does it fit into this?
DS: In corporate hierarchies and structures, reporters report to their bosses. Priorities often are set at the top of a hierarchy. Independent journalists, can be but not always are, separate from those structures, initiate their own stories, work as freelancers, or work for publications that are not dominated by big media cartels. For example, the New Yorker is a corporate publication. It is owned by Condé Nast but has a reputation for independent writing. So journalists like Seymour Hersh appear in the New Yorker and they are a lot more critical in their outlook--which is another characteristic of independent journalists--than journalists who work for big corporate organizations. When you work in a big structure, you tend to conform to what is expected of you and the priorities. If someone says, "OK, we are going to spend 80 percent of our resources covering entertainment and only 5 percent of our resources covering the world, if you want to work in that organization, that is what you do. Journalists don't initiate a lot of their own stories. They're assigned to cover stories. They're told how much time they have, and how to do it. There are certain templates of coverage. That is why there is so much similarity in coverage, why it all sort of looks alike.
For an example of independent journalism, watch Democracy Now! today (or listen, or read the transcripts).
The e-mail address for this site is firstname.lastname@example.com.
the new york times
katrina vanden heuvel
robert parry
danny schechter
harriet miers


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Color is something we can't escape. It's all around us, from our neighborhoods and the people in them, to the food we eat, color is a part of our everyday lives. When it comes to fashion it's not just the outfit that makes us feel like we look our best, it's also the color. We all have a color that makes our skin pop, eyes glow and bodies look like pow, and we try to wear it every chance we get. Whether it's a mini skirt and flirty top, or a pair of our favorite sky high heels, we try our best to incorporate our signature color into each outfit because we know it helps show off our best assets.
Your signature color can not only boost your outfit's wow factor, but your confidence as well. Knowing that the color you have makes you look good, makes you feel good as well and we all know that confidence is sexy! Actress Lisa Raye McCoy is famous for her signature white wardrobe and says that she loves it because the crisp, clean color makes her "feel like an angel." Having a signature color also helps you showcase your personality, giving people a sense of who you are through your clothing and the range of fun outfit possibilities can be endless!
Do you have a signature color? What does your color say about you?
– Danielle Pointdujour


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Sri Lanka High Commission also known as Sri Lankan Embassy is referred an ambassador and group of people, who were sent to India, for representing and advancing the interests of their country with Indian Government. Apart from the basic role of promoting social, professionals, cultural and educational exchanges between the two countries, the commission is focused towards helping the Sri Lankan local businessman to set their market in the the city, where it is located. The commission is currently helping a large number of Garments, Tea, Stationery, Spices and Coconut Oil business holders in making their presence in the capital- Delhi and various other parts of India. Further, as the nerve center for a nation's diplomatic affairs within the borders of another nation, the embassy works towards maintaining healthy relationships between two countries.
Contact Us
27, Kautilya Marg, Chanakyapuri, New Delhi, Delhi, 110021, India
Phone :+918037261209


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RELs work in partnership with states and districts to 1) conduct original high quality research, 2) provide training, coaching, and technical support, and 3) disseminate high quality research findings about how to support college students and students transitioning to college. A selected list of resources developed by the REL Program appears below.
Archived Webinars
For more resources in ERIC on the topic of Postsecondary, click here.
For more resources in the What Works Clearinghouse on the topic of Postsecondary, click here.


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Description: Online Kitchen Ware Shop.
Website: Chefs Catalog
Coupon Code: Link – Use Coupon
Expiry: 12/31/2009
Details: Wusthof Gourmet 3-in. Paring Knife – Compact paring knife is well-suited for cleaning, paring, peeling, and slicing and mincing small fruits and vegetables and making intricate garnishes. Handmade in Germany since 1814, Wusthof cutlery is prized by the world's top chefs for restaurant and home cooking. The Gourmet line features a precision-stamped blade of high-carbon stainless-steel that sharpens easily and holds its edge. Compression rivets securely attach the high-impact handle to the full tang for superior balance and maneuverability. 3″ blade. So buy this Wusthof Gourmet 3-in. Paring Knife from chefscatalog.com and Save 63%.
Use it on your own Luck.