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Round trip flights to Oakland from Nanaimo
When you're looking to find round trip flights to Oakland from Nanaimo, WestJet is your reliable resource. You'll be pleased to discover that our aircraft fly to over 150 destinations in North America, Central America, the Caribbean and Europe, including Oakland International Airport. But we don't just offer great flights to fantastic destinations; we also deliver a caring and considerate air travel experience, one that includes safety, comfort and reasonable prices. You can count on us for reputable service offered at an impressive value.
Your trip to the Bright Side of the Bay begins with WestJet
Airport Details: To OAK, Oakland International Airport From YCD, Nanaimo Airport
Often called the "Bright Side of the Bay" for its bright, sunny skies and pleasantly moderate climate, Oakland is an alluring destination for all kinds of visitors. The Oakland Museum of California serves as the perfect jumping-off point for those seeking heritage and history; in fact, this renowned institution is home to almost 2 million objects and artefacts that reveal all about California's spectacular past. For a change of pace, the Pacific Pinball Museum in nearby Alameda offers a unique history to explore and get hands-on with. Visitors can learn more about this fun pastime and take advantage of all-you-can-play pinball on 100 machines (included with the price of admission). Nearby Grizzly Peak provides nature lovers with a welcome distraction from the bustle of the big city — and arguably the finest views of the bay.
Don't wait any longer. Book WestJet round trip flights now and you'll be all set to fly to culturally rich, ethnically diverse Oakland with ease. Whether you're gearing up to enjoy coveted attractions like Jack London Square, the Chabot Space and Science Center and Lake Merritt or you're just taking a business trip, you can get there with WestJet. Fly to Oakland from Nanaimo with WestJet and enjoy the journey along the way.
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Which Schools Offer Dental Programs in San Diego, CA?
Learn about dental programs in the San Diego, CA, area. Get information about degrees available and admission and program requirements to make an informed decision about your education. Schools offering Dental Assisting degrees can also be found in these popular choices.
Undergraduate and graduate level degree programs are available in the dental field from several institutions in the San Diego, CA, area. Get important program and school information below.
There are a variety of dental programs in the San Diego area; career options range from dental assistant to dental hygienist to dentist. Regardless of level, these programs combine classroom and clinical training, and they also prepare graduates for professional licensing or certification exams. Dental assisting certificate programs may require background checks and fingerprinting; associate's degree programs in dental hygiene may require prerequisite math and science coursework; and postbaccalaureate dentistry programs may require completion of a relevant undergraduate curriculum and professional observation. Read on to learn more about your dental program options below.
Dental Certificate Programs in the San Diego Area
The dental assisting certificate program at San Diego Mesa College offers instruction in areas such as chair-side assisting, equipment operation and instrument sterilization, as well as business management in a clinical setting. In addition to the Certificate of Achievement, upon completion of the program you are granted a performance certificate indicating your capacity to utilize dental X-ray equipment in California. You can also expect to receive preparation for state and national dental assisting exams, should you want to become licensed or practice in another state upon graduation.
Program Name: Certificate of Achievement in Dental Assisting
Program Length: 2 semesters
Tuition and Fees: $1,144 per year for CA residents; $7,024 per year for non-residents (2018-2019)
Prerequisites: Dental communications course (offered summers only)
Requirements: Background check and fingerprinting for entry into clinical practicum portion of program
Palomar College is located about 30 miles north of San Diego in San Marcos, which has a population of about 80,000. In Palomar's dental assisting certificate program, you are required to achieve at least a C in every course, and your hands-on clinical performance are relevant in your grade administration. This program offers coursework in topics such as managing a practice, radiography and preventative dentistry, as well as written composition and communications.
Program Name: Registered Dental Assisting Certificate
Prerequisites: Completion of required English course and two specified dental courses
Requirements: Attendance at program orientation, very good vision and hearing, CPR certification, at least 18 years of age
School Type: 2-year public, 23,917 students (all undergraduate)
Dental Associate Degree Programs in the San Diego Area
San Diego Mesa College also offers an associate degree in dental assisting. The AS in Dental Assisting program comprises all the requirements of the certificate program, plus additional elective and general education units for a total of 60 units (the required amount to acquire an associate degree). In both programs, you are required to undergo hands-on clinical classes that include upholding the safety and ethics codes of the facility where you're practicing.
Program Name: Associate in Science in Dental Assisting
Program Length: 2 years, full-time
While Southwestern College's main campus is located in Chula Vista, the dental hygiene program takes place in National City, which is about five miles south of San Diego along the California coast. This program begins each fall and includes instruction in infection control, dental health in a community context, periodontics and control of pain. You'll also have the opportunity to perform professional dental services (under the supervision of dentists or registered dental hygienists) for the public at the school's Dental Hygiene Clinic.
Program Name: Associate of Science in Dental Hygiene
Prerequisites: Completion of specified courses in chemistry, biology, communications, English, social sciences and health; grade point average of at least 2.70 in science courses
Requirements: CPR certification; proof of immunizations for rubeola and rubella, hepatitis B, varicella; screening for tuberculosis; physical exam
Dentistry Program Close to the San Diego Region
Loma Linda University is the nearest school to the San Diego area where you can earn a DDS, the degree required to obtain licensure to practice as a dentist. The school is located in Loma Linda, which is approximately 100 miles north of San Diego. While a baccalaureate degree is not required for admission to the dental program, candidates who have one are given preference in admissions decisions. In addition to the required coursework in the subjects listed above, the dental school recommends taking courses in subjects such as mathematics, histology, microbiology and art, among others. Loma Linda's dentistry program includes ample opportunities for you to practice providing direct dental care to patients.
Program Name: Doctor of Dental Surgery (DDS)
Specialization Areas: Maxillofacial and oral surgery, orthodontics, endodontics, periodontics, pediatric dentistry, oral pathology, prosthodontics
Tuition and Fees: $34,012 per year (2018-2019)
Prerequisites: One year of academic and laboratory instruction in general chemistry, general physics, English literature and composition, biology (or zoology) and organic chemistry; one semester of biochemistry
Requirements: 144 units of college coursework with at least a C grade, written and verbal English capacities, at least 20 hours of professional dental observation, three reference letters
School Type: 4-year, private not-for-profit; 4,448 students (1,192 undergraduate)
Students near San Diego, CA, can choose from several institutions for their certificate or associate degree in the dental field, or can pursue their Doctor of Dental Surgery (DDS) at Loma Linda University.
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Russia vows 'promising' virus vaccines in September
BSS/AFP
30 July, 2020, 12:10 pm
Last modified: 30 July, 2020, 12:15 pm
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Russia, which has the world's fourth-largest coronavirus caseload, hopes to be the first country to produce a vaccine
File Photo: A woman holds a small bottle labbeled with a "Vaccine COVID-19" sticker and a medical syringe in this illustration taken April 10, 2020. Reuters/Dado Ruvic/Illustration
Russia said Wednesday that it plans to begin production of two "promising" coronavirus vaccines in September and October as Moscow races to develop a formula before Western countries.
At a meeting chaired by President Vladimir Putin, Deputy Prime Minister Tatyana Golikova singled out two vaccines under development by a research institute in Moscow and a lab in Siberia.
"Today (Wednesday)there are two vaccines that are the most promising," Golikova said.
Production of the first, which is being tested by the Moscow-based Gamaleya institute and the defence ministry, is set for September, Golikova said.
Another vaccine being developed by the Vektor State labratory near the Siberian city of Novosibirsk should be launched in October, she added.
Russia, which has the world's fourth-largest coronavirus caseload, hopes to be the first country to produce a vaccine.
Scientists in the West have raised concerns about the speed of development of Russian vaccines, suggesting that researchers might be cutting corners after coming under pressure from the authorities to deliver.
Russian President Vladimir Putin on Wednesday said it was important to achieve a finished product in a "careful and balanced way."
"One should be absolutely certain in a vaccine," he said.
Kirill Dmitriev, the head of Russia's sovereign wealth fund which is financing the Gamaleya trials, said the country hoped to be the first to approve a vaccine.
"It's a Sputnik moment," he told US broadcaster CNN, referring to the launch in 1957 of the world's first space satellite by Russia.
"Russia will have got there first," Dmitriev forecast.
Russia has reported more than 828,000 coronavirus cases and 13,600 deaths so far.
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St Marys, Georgia: Small Town with Big Connections
July 5, 2009 by Debi Lander
Cumberland Lady
Everyone's wired these days: my husband works from his laptop, my daughter texts from her cell phone–while listening to her i-pod, I use Facebook to stay current with my friends and my 89-year-old mother sends e-mail. Goodness! Sometimes we need to disconnect.
Nearby Cumberland Island is the place to escape, but you can't get there from here. No, you've got to go to St. Marys, because St Marys is the hub, the little town with big connections.
The National Park Service runs a ferry from the wharf of St Marys to Cumberland Island. The barrier island, whose domain name ought to be www.wilderness beach, lets you become the browser on her shores. Search for wild horses, shells, loggerhead turtles and historic mansions. On Cumberland, bikes are the high-speed mode of transportation.
You must obtain a permit to camp overnight, or else you'll have to return home. Some prefer to stay at the only hotel, the elegant Greyfield Inn. The lodge requires a two-night stay and provides guests with a private water taxi.
St Marys is just 20 minutes north of the Jacksonville airport making it easy to reach the quaint seaside village. I felt like I'd stepped back to pre-computer days when the pace was slower and somehow more personal.
In St Marys colorful cottages line tree-shaded streets, yards are nicely kept, and people ride around in golf carts, for heaven sakes. Meander her sidewalks and you'll find Market on the Square- the general store, the Riverside Cafe which serves breakfast all-day, a cigar company, bait shop, bookstore, gift shops and a saloon.
Pirate Welcome at Goodbread
Of course the most relaxing way to spend the day on Cumberland
is to plan a full weekend retreat. Spend a night in one of many St Marys B & B's, such as the Goodbread House, a Victorian style inn. Mardja, the proprietor, serves a scrumptious breakfast in time to catch the 9 AM ferry. But if you must, Goodbread's offers free WiFi!
Another connection to and from St Marys links with Fernandina. The new Cumberland Sound Ferry transports people while they listen to an ecosystem narrative and cross into beautiful Georgia low-country. Sometimes passengers get lucky and spot a submarine from Kings Bay Naval Base.
Save a day this summer and drive to St Mary, then access Cumberland Island. It is definitely the place to shut-down.
St. Marys Harbor
This article appeared in the July 2009 edition of The Mandarin Newsline.
www.stmaryswelcome.com St. Marys Welcome Center and Visitor Information
www.nps.gov/cuis/ Cumberland Island National Park
Filed Under: Travel Journal/Blog
Tagged: connections, Cumberland Island, Fernandina, ferry, Florida, Georgia, Jacksonville, National Park Service, small town, St Marys


The Ipcress File
This espionage thriller represents a landmark in spy movies introducing the sly, dry intelligence agent Harry Palmer. The story, centers on Palmer's investigation into British Intelligence security. He's soon enmeshed in a world of double-dealing, kidnap and murder and finds a traitor is operating at the heart of the secret service. Will the mysterious 'Ipcress File' reveal who the traitor is?
Director: Sidney J. Furie
Actors: Aubrey Richards, Frank Gatliff, Gordon Jackson, Guy Doleman, Michael Caine, Nigel Green, Sue Lloyd
November Criminals
Addison Schacht investigates the murder of his friend Kevin, with the help of Phoebe, and they discover the truth is darker than they ever imagined.
The new story follows the heroic efforts of the crypto-zoological agency Monarch as its members face off against a battery of god-sized monsters, including the mighty Godzilla, who collides with…
Genre: Action, Adventure, Drama, Science Fiction, Thriller
Running Scared
Two street-wise Chicago cops have to shake off some rust after returning from a Key West vacation to pursue a drug dealer that nearly killed them in the past.
Genre: Action, Comedy, Crime, Thriller
Among the lights and sounds of the city a predator roams night clubs and bars searching for victims for his sexually twisted fantasies. Even people with normal everyday jobs have…
Welcome to Rekall, the company that can turn your dreams into real memories. For a factory worker named Douglas Quaid, even though he's got a beautiful wife who he loves,…
Genre: Action, Adventure, Science Fiction, Thriller
Sue Ann is a loner who keeps to herself in her quiet Ohio town. One day, she is asked by Maggie, a new teenager in town, to buy some booze…
When a Harvard-educated CIA agent is killed during an operation, the secret agency recruits his twin brother.
Country: Czech Republic, USA
Genre: Action, Adventure, Comedy, Thriller
When a gruesome killer targets the staff of a Psychiatric facility, its up to ex-cop turned Private investigator David Evans to find the killer and put his own life back…
Ride the Pink Horse
In the border town of San Pablo, preparing for an annual 'Mexican Fiesta,' the tough, mysterious and laconic Gagin arrives. His mission is to find the equally mysterious Frank Hugo,…
When the White House (Secret Service Code: "Olympus") is captured by a terrorist mastermind and the President is kidnapped, disgraced former Presidential guard Mike Banning finds himself trapped within the…
Living Among Us
Vampires have just made themselves public! Now a group of documentarians have been granted access to spend some time with them and learn how they live and coexist with humans….
Genre: Fantasy, Horror, Science Fiction, Thriller
When someone murders his beloved cat, Clinton, an adult child, demands justice. Taking it upon himself to solve the case, he teams up with an unlikely ally, Greta, and the…
Genre: Comedy, Mystery, Thriller
Trailer: The Ipcress File


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Injured Acrobats Will Sue After Accident
Leave a Comment / Personal Injury / By Fox Law Staff
Seven Injured Acrobats Will Sue After Accident, Four Spoke At Press Conference
The seven injured acrobats will sue after accident that occurred last month. The acrobats who were injured in a horrifying accident during a circus performance in Providence will file a lawsuit seeking compensation for their injuries, their lawyers said Tuesday. Four of these circus acrobats injured during their hair-hanging stunt discussed publicly the accident that sent them plummeting to the ground. The women, who gave comments at a news conference arranged by their lawyers, were injured when a single carabiner clip snapped during their hair-hanging "human chandelier" act, part of the May 4th performance of the Ringling Bros and Barnun & Bailey Circus. With tears in their eyes, they talked about wanting to recover from their injuries, and for three of them to walk again. Some grieved the end of their circus careers. All of the victims put the greatest priority during the press conference on thanking people all over the world who have followed their recovery.
Viktoriya Medeiros, 34 years old | Injured Acrobats Will Sue After Accident
Viktoriya Medeiros, who was sitting in a wheelchair and wearing a neck brace during the press conference, designed the hair-hanging "human chandelier" act with her husband. She states that the women know they are lucky to be alive. She wore a neck brace and was in a wheelchair. She said she won't be able to perform the stunt ever again.
"I will not be able to go back and to make what I know to do best, what I love to do. It's my dreams," Medeiros said.
"We are all terribly injured. Some of us require many surgeries. We are learning to use our arms, hands and necks again (in) hours and hours of daily physical therapy. We are hoping we can heal enough that we can live our lives without this pain."
"Most of us cannot walk normal, yet. I hope that's going to happen one day."
Julissa Segrera, 20 years old | Injured Acrobats Will Sue After Accident
Julia Segrera, the only American who was involved in the accident, spoke from her wheelchair. She is also the youngest of those injured.
"My dream was to be a star performer and now my dream is to get up and walk."
"We are trying to come to terms with knowing we will never be the same. The girls hope that one day we will be healed enough so we can live our lives without this pain."
"Your prayers are still needed."
Dayana Costa, 26 years old | Injured Acrobats Will Sue After Accident
Dayana Costa's injuries required little steel rods to be placed in her lower arm and hand. They joined an external rod that held it altogether. She chocked back tears as she spoke, and was comforted by her friend as she discussed how difficult and scary the recovery has been.
"I am thankful to God and for many angels for giving me my life back and a chance to live my dreams. I believe the same God that saved me, my friends' life, is the same God that's going to give our victory."
"It's been a very painful recovery," Dayana Costa said through tears. "The doctors still don't know what's going to happen. Every day is really hard. Every day is something new."
Svitlana Balanicheva, 22 years old | Injured Acrobats Will Sue After Accident
Svitlana Balanicheva who is a native of Ukraine, talked about the pride she took from being a circus performer and how she adored entertaining families and especially children. Balanicheva, the only one of the four aerialists not in a wheelchair, thanked people for their love and support. She spoke for both herself and for 25-year-old Viktorila Liakhova, who remained in Providence, where she was having surgery Tuesday.
"To go through what we did is something we never dreamed of"
"We always like to entertain families. Now we have nightmares about it."
The Lawyers | Injured Acrobats Will Sue After Accident
Thomas K. Prindable and Michael S. Krzak, of Clifford Law Offices of Chicago, accompanied the aerialists. Krzak told reporters that the firm has set out to investigate the circus incident, identify any party with legal responsibility and target that party in a lawsuit.
"They want to make sure this never happens in another circus act again. These girls never would have gotten up on the human chandelier if they thought there was any chance of the human chandelier failing. The girls are in pretty bad shape. I think it's safe to say they're going to be here for a while. The most important thing for these girls is that they not be sent somewhere else. They need to heal together."
"We're going to do everything we can for these young ladies," said another lawyer, adding that it's possible the carabiner manufacturer could be the target of a lawsuit, but that his team has been prevented from reviewing the evidence so far by the federal Occupational Safety and Health Administration."
The women want to get to the "root cause" of the accident, as it affects a number of aerial acts. Investigators from the Occupational Safety and Health Administration are also probing the accident. The women's medical treatment is being covered through workers compensation. We wish these young women the best.
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Madonna takes on frightening world with new album 'Madame X'
Gun control, poverty and the marginalized, Madonna's new album "Madame X" sees the Queen of Pop wanting to "fight back" in what she sees as a frightening modern world.
In an interview with Reuters, Madonna also said she was horrified by moves to restrict LGTBQ and women's rights, namely in her native United States.
"If you're talking about the far right and the rights that are being taken away from, say the LGBTQ community or women's rights … obviously I am traumatized and horrified," Madonna said.
A longtime campaigner for the LGTBQ community and known for her charity work in Malawi, Madonna, 60, said she would keep fighting for those causes.
"There's still an enormous amount of poverty in Malawi and the rate of HIV has gone down considerably but it's not disappeared," she said. "(There are) all the problems that are recurring in America because of new legislation so I am going to have to keep fighting for the same things."
On her 14th studio album, Madonna addresses U.S. gun control laws and uses a snippet of a speech by school shooting survivor Emma Gonzalez in the rousing single "I Rise", a song she says aims to give a voice to marginalized people.
"Dark Ballet", a piano ballad infused with electronic pop, was inspired by Joan of Arc and references a world "up in flames", while in "Killers Who Are Partying" she sings about the poor, exploited children as well as a woman raped.
"It's pretty frightening, yes, it's pretty scary … There is stuff going on everywhere in the world," she said when asked how she felt about the state of the world.
"When you think about the amount of people who have died, been killed, have been wounded, whose lives have been changed irrevocably because of the lack of gun control in America, it's such a huge, huge problem.
"I care deeply about it so I couldn't not write about it," she said.
She also said she took issue with some U.S. states restricting abortion rights.
"These are crazy times because we fought really hard for a lot of these freedoms and now it seems like they are all systematically being taken away …It doesn't make me feel hopeless. It just makes me want to fight back."
CelebrityCultureMadame XMadonnaMusic


Christchurch United players reach final in Japan tournament
Christchurch United talents Seamus Gallagher and Nicholas Murphy have returned from Japan with incredible memories, new friendships and invaluable new experiences about what is required at the highest level.
The two Christchurch United players were invited to bolster the Wellington Phoenix Soccer School under-12 squad for a grueling two-week tour around Japan where they played 11 matches against some of Japan's leading professional football clubs.
Nicholas said he was grateful to have experienced "a-once-in-a-lifetime opportunity" on and off the pitch, as a footballer and as a young person.
The St Bedes student had been immensely impressed by the intensity his Japanese peers who come through one of the best youth development systems in the world.
"They were quick, disciplined and kept their hunger for the whole game," said Nicholas.
Seamus said he was inspired by playing against teams who operate at a professional level.
"It left me with the question of how do I close the gap between what I can do and how they play in Japan?" said the St Thomas student.
"I'm going to have to work ten times harder."
As the tour progressed, the Christchurch United players and their Phoenix team-mates proved that they could adjust to their new opponents and environments.
The rapid progress of the New Zealanders was no more evident than the last weekend when they reached the final of the high-profile Reysol tournament.
The Phoenix team beat five Japanese club sides, including a nail-biting penalty shoot-out against Funabashi FC in the semi-final, before the top Japanese professional club Kashiwa Reysol proved to be too strong in the final.
The narrow 2-0 defeat against the host team was still a massive step forward because the same opponent had inflicted a heavy 7-2 defeat on the touring Phoenix team only four days earlier.
Phoenix Soccer School Director Jo Dawkins said that the Christchurch United players had been a "fantastic" addition to the squad.
"Both on and off the field the boys became extremely valued members of our team. We look forward to keeping an eye on their development in Christchurch," said Dawkins.
Christchurch United Academy Director Colin Williamson said the club was immensely proud the players had performed so well and was looking forward to hearing the stories from Japan.
"It will be interesting to see how they will use these experiences. They went over with some of New Zealand's best talents, got some good results but were also well beaten by some clubs, so they have seen what it takes to compete with top international players," said Williamson.
"Hopefully these experiences will inspire them and hopefully they can share those experiences to inspire others in the club as well."
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Drugs, the permanent way
By Andy Extance2017-04-10T10:05:00+01:00
Exceptions to a long-held rule against chemically bonding to biological targets are powering new cancer medicines, finds Andy Extance
From its discovery in the late 1800s until the 1970s, the humble aspirin kept a secret hidden that would have unnerved medicinal chemists. Not only does its active component, acetylsalicylic acid, dock with cyclooxygenase enzymes COX-1 and COX-2 and stop them making the prostaglandin molecules behind inflammations – it bonds to them covalently and permanently. Such irreversibility has long made drug developers anxious, in part due to another medicine cabinet stalwart, paracetamol. Our bodies metabolise paracetamol, also known as acetaminophen, to make a highly reactive intermediate that covalently binds to liver proteins. This has been linked with toxicity, and fear of similar problems has driven an orthodoxy in drug discovery to avoid drugs that attach permanently.
Source: Nature Chemical Biology
Some inhibitors bond reversibly to their targets, but other are unable to free themselves afterwards
Today, that orthodoxy lies shattered. Several recent studies have shown that there are many covalent drugs, as they are known, despite the bias against them. For example, one study analysing 71 enzymes found around a quarter were covalently inhibited by approved drugs.1 In 2011, researchers estimated that 26 covalent drugs for which data were available accounted for over $33 billion (£26.4 billion) in annual worldwide sales.2 Consequently, drug developers have come to realise that covalent binding is more than just allowable – in some circumstances it's actually desirable. 'We're only now trying to design them rationally, rather than be limited to discovering them serendipitously,' admits Renato Bauer, a medicinal chemist at Eli Lilly in Indianapolis, US.
Over the past five years those efforts have already paid dividends, with five intentionally covalently bonding cancer drugs hitting the market. Yet much remains for scientists like Bauer to do, including bringing the approach to diseases that can't tolerate off-target effects like those that originally caused alarm.
Jamming the lock
If enzymes are locks and the molecules that bind with them are keys, covalent inhibitors effectively snap the key off in the lock. The permanent obstruction is an advantage, underscores David Goldstein, chief scientific officer at Principia Biopharma in San Francisco, US. Such molecules can turn off enzymes in one hit, at least until our cells resynthesize them, which can happen over a timescale of several hours to a few days. Therefore patients should need to take less of the drugs.
Enzyme-lifetime permanence, and the advantage covalent attachment has in competing with enzymes' normal partners, also means drug molecules might be designed so any excess leaves the body quicker. And while non-covalent drugs rely on binding site features that are usually similar in different enzyme family members, covalent attachment happens at reactive sites that are not always shared. Consequently, covalent inhibitor drugs could be more selective. Overall, these advantages could minimise patients' exposure to drugs, any side-effects they might cause, and also interactions that could lead to resistance.
'Principia was founded to expand upon that concept to create small molecule drugs that could achieve greater selectivity and longer target engagement than traditional non-covalent methodologies,' Goldstein explains. 'Such an approach was envisioned to realise drugs with both greater efficacy and tolerability.' And appropriately, the primary drug class scientists using this expectation-upending approach have focused on – kinase inhibitor cancer drugs – has itself upended expectations.
Not undruggable, but unpleasant
Kinases are enzymes vital to many biological processes, involved in processing ATP, the 'energy currency' molecule. Because humans have a 'kinome' of over 500 kinases with similar active sites in which drugs would bind, they were once seen as 'undruggable'. If a drug blocks one kinase type to stop cancer cell metabolism then it's likely to block others, with potentially serious adverse effects. Nevertheless, in 2001 tyrosine kinase inhibitor (TKI) imatinib (Glivec), was approved for chronic myelogenous leukaemia, a rare cancer. And today, for the improved survival chances various TKIs now on the market bring, cancer patients are prepared to accept their unpleasant downsides, which can include severe diarrhoea.
'Selective targeting of a small number of kinases remains one of the major challenges,' Goldstein says. 'This problem is particularly acute within the stomach and upper gastrointestinal (GI) tract where drug concentrations are often very high following an oral dose. At those concentrations, poorly selective TKIs can inhibit a significant fraction of the kinome expressed in the GI tract, leading to severe and often dose-limiting toxicities.'
By contrast, targeting cysteine amino acid residues through covalent binding enables TKIs to achieve 'unprecedented selectivity and potency', Goldstein asserts. Principia is using this approach in PRN1371, a TKI targeting the fibroblast growth factor receptor currently in phase I trials. Covalent drugs have also been used to inhibit epidermal growth factor receptor (EGFR) tyrosine kinases when they have mutated and made cancers resistant to non-covalent drugs.
It requires great precision to shape molecules so that they attach only to reactive sites on one enzyme type and avoid others. To achieve this, Pfizer has taken a detailed approach to using and studying covalent inhibitors, explains Adam Gilbert, the senior director of design and synthesis sciences at the company's Groton site in the US. 'We decided to pursue covalent inhibitors for targets/programmes where they would offer a distinct advantage over reversible inhibitors,' Gilbert explains. 'We also decided that understanding the reactivity of the covalent inhibitor electrophiles with biologically relevant nucleophiles would give us insight into covalent inhibitor design.'
Pfizer's studies include analysing the intrinsic reactivity of covalent inhibitor electrophiles with glutathione3 and N-acetyl-lysine4, to model cysteine and lysine amino acid nucleophiles they might target respectively. 'We subsequently used this data to inform the design of covalent inhibitors for a number of past and current programmes by using the least reactive electrophile to give us the potency and selectivity we desired,' Gilbert says.
With improving covalent kinase inhibitor selectivity the greatest challenge Pfizer initially faced, Gilbert adds, it joined forces with Ben Cravatt at the Scripps Research Institute in San Diego, US. Cravatt had been drawn to covalent inhibitors as a more rigorous tool for understanding how small molecules interact in biological systems. 'Because they remain permanently attached, you can inventory proteins using mass spectroscopy-based methods,' he explains. Among the details listed in such inventories are the exact locations where covalent attachments are happening.
Testing warheads
For example, Cravatt's team and Pfizer teams cultured cancer cells with covalent TKIs. Smashing the cells open and analysing fragments of the proteins inside identified 29 off-target proteins that inhibitors attached to.5 The study revealed specific TKI 'concentration windows' for selective target inhibition beyond which they reacted with off-target proteins, with toxic effects.
The results also showed covalent attachments are frequently not actually in the binding pocket 'keyhole' enzyme inhibitors normally target, Cravatt says. 'Every drug that I'm aware of today that's covalently targeting cysteine is actually targeting non-catalytic, bystander cysteines on the outside of the protein,' he says. 'They're reasonably selective, but most of their off-targets aren't kinases, they're other proteins that harbour functional cysteine residues.'
Afatanib
At Scripps' site in Florida, US, scientists are exploring whether in some instances covalent inhibition might work in reverse. Kate Carroll's group found that some cancer cells became resistant to Boehringer Ingelheim's covalent TKI afatinib (Giotrif) due to the oxidation of its target cysteine in EGFR. This happens because there are lots of reactive oxygen species in cancer cells, which can convert cysteine to its sulfenic acid (Cys-SOH), explains team member Vinayak Gupta.
Rather than a nucleophile like cysteine, the sulfenic acid is an electrophile, which may help explain other compounds' biological activity. 'The idea here is that there are "nucleophilic" compounds already "hidden" in current natural products such as curcumin and FDA-approved drugs such as [Pfizer's TKI] tofacitinib,' Gupta says.6 'It is a distinct possibility that there may be an underlying mechanism of action driven by these "hidden" nucleophiles targeting Cys-SOH in their biological targets.'
Tofacitinib
Consequently, Carroll, Gupta and their colleagues have sought to profile the molecules that could exploit this phenomenon. But initially, in contrast to the relatively broad range of electrophile inhibitors available, there was only one moderately reactive nucleophile available to detect Cys-SOH. The Scripps Florida team have therefore developed a library of potential covalent inhibitors. 'We now have nucleophilic warheads that react with Cys-SOH at biologically relevant rates, more than 200 times faster than the previous standard for Cys-SOH probes, both irreversibly and reversibly,' Gupta says.7 That's especially important as scientists seek to understand how to sort such arsenals, eliminating cruder blunderbusses and getting closer to the proverbial magic bullet.
Toxicity dumped?
Despite their advantages, covalent drugs have seldom been developed for diseases other than cancer, except in older drugs where the covalent effect was introduced accidentally. Outside of life-or-death diseases, the risk of adverse effects caused by irreversible modification from off-target nucleophiles has been deemed too great.
Highly reactive, poorly selective covalent binders, for example, 'could certainly cause toxicity issues' by raising protein molecular weights above the threshold where they trigger immune responses, says Gilbert. He and his Pfizer colleagues therefore treated human liver cells with radiolabelled covalent drugs in the lab to estimate the 'covalent binding burden' limit that might be allowable.8 'We found examples of safe covalent drugs which have been used for decades with a covalent binding burden of less than 10 mg/day,' Gilbert says. 'While one can't say if 10 mg/day is the magic binding burden limit for a safe agent, we believe the binding burden assay can be used to optimize covalent binders towards safer space.'
Source: PDB:4G5J
Afatinib covalently binds to the epidermal growth factor receptor (EGFR) tyrosine kinase – the covalent bond is highlighted
By working to ensure their drugs are selective enough, various companies are now able to put low dose covalent inhibitors into clinical trials. 'These compounds are showing good safety profiles,' Gilbert says. 'One can't rule out or predict idiosyncratic toxicity with these agents, but so far this well-designed new generation of covalent inhibitors shows similar toxicity profiles to reversible inhibitors.'
That might be acceptable when fighting cancer, but it still means covalent inhibitors are challenging to develop for chronic non-life-threatening diseases, Goldstein asserts. Consequently, Principia Biopharma is exploiting a concept pioneered by its co-founder, Jack Taunton of the University of California, San Francisco (UCSF). His team discovered that electrophiles like cyanoacrylamides could bond to cysteine residues covalently – but unlike other existing drugs, they do so reversibly.9
The consequence of any off-target binding with compounds like cyanoacrylamides should be transient, Goldstein explains. 'With reversible covalent inhibition, we have demonstrated that proteins regain their function when the inhibitor dissociates from its target, not permanently altering their structure and function,' he says. 'As such, the consequence of reversible covalent binding is not different from non-covalent small molecule drugs.'
Principia uses the approach to target Bruton's tyrosine kinase (BTK), a key element in human immune signalling pathways, involved in diseases like rheumatoid arthritis.10 Currently the company is running phase II trials in the rare and potentially life-threatening skin-blistering disease pemphigus vulgaris. 'In autoimmune disease, Principia's lead molecule, PRN1008 is a reversible covalent inhibitor that inhibits 100% of BTK initially after oral dosing,' Goldstein explains. 'It slowly comes off the target resulting in approximately 60-80% inhibition prior to the next dose despite high clearance of the compound. This profile achieves high efficacy combined with good tolerability and safety.'
Bound for success?
For medicinal chemists at Eli Lilly, Bauer says, interest in covalent inhibitors extends broadly – not only to electrophiles that react reversibly, but also to electrophiles for which little is currently known in drug discovery. Lilly also has a irreversible covalent BTK inhibitor in phase II trials for rheumatoid arthritis. It appears that conventional design of properties such as molecular shape can produce sufficient selectivity to avoid off-target binding in cases like this. 'Whether moderate electrophiles, such as acrylamides, are disposed to indiscriminate alkylation seems to depend more on the properties of the parent molecule rather than the simple fact that an electrophile is present,' Bauer explains.
Like any individual drug, covalent inhibitors still face high chances of failing to secure regulatory approval. Nevertheless, this new approach could have an even broader and fundamentally important impact. 'Covalent binding is also proving important in other areas of discovery, like in chemical biology approaches to understanding disease,' Bauer explains. 'For early stage projects, covalent inhibitors play additional roles, such as tool molecules to elucidate the effect of perturbing a biological pathway. Covalent inhibition is unique and complementary to many conventional approaches.'
Perhaps covalent inhibitors' greatest opportunity is exemplified by another non-kinase target that Bauer highlights. K-Ras(G12C) is a mutated GTPase protein, involved in cell signalling, which occurs in about 20% of lung cancers. However, it 'has historically been viewed as something that's very difficult to drug', cautions Cravatt. Yet by exploiting reactive cysteines, in 2013 Kevan Shokat's UCSF team found compounds that bind it.11 These covalent inhibitors exploit their ability to attach outside the conventional binding pocket 'keyhole', in a previously unknown site.
And Cravatt's team has found scope for emulating this sneaky lock-picking approach elsewhere. They have screened small electrophiles in cancer cells with the help of an extremely reactive iodoacetamide electrophile, which reacts with every available cysteine, unless blocked by another compound.12 The Scripps researchers then added isotopic tags to the iodoacetamide residues, which allowed them to quantify their relative abundance. 'You're assessing 50–100 enzymes, in a mechanistically related class,' Cravatt explains.
Their results indicate that – as in UCSF's K-Ras(G12C) work – covalent inhibitors often target 'totally different folds, totally different functions', Cravatt explains. He's now exploring this phenomenon more broadly, including through Vividion Therapeutics, which he co-founded with fellow Scripps chemists Jin-Quan Yu and Phil Baran in February 2017. A substantial component of Vividion's activity will be covalent chemistry-driven, Cravatt reveals.
Cravatt is especially excited by covalent inhibitors' prospects because 'there have been multiple successes in recent years'. 'Covalent chemistries developed for kinase inhibitors, you can make a strong argument that they have an advantage over reversible kinase inhibitors,' he says. Yet he's keen to go beyond kinases' 'very druggable pockets'. 'The question is can we progress against proteins viewed as undruggable with non-covalent chemistry?'
Andy Extance is a science writer based in Exeter, UK
1 J G Robertson, Biochemistry, 2005, 44, 5561 (DOI: 10.1021/bi050247e)
2 J Singh et al, Nat. Rev. Drug Discov., 2011, 11, 307 (DOI: 10.1038/nrd3410)
3 M E Flanagan et al, J. Med. Chem., 2014, 57, 10072 (DOI: 10.1021/jm501412a)
4 U P Dahal et al, Med. Chem. Commun., 2016, 7, 864 (DOI: 10.1039/c6md00017g)
5 B R Lanning et al, Nat. Chem. Biol., 2014, 10, 760 (DOI: 10.1038/nchembio.1582)
6 V Gupta and K S Carroll, Chem. Commun., 2016, 52, 3414 (DOI: 10.1039/c6cc00228e)
7 V Gupta and K S Carroll, Chem. Sci., 2016, 7, 400 (DOI: 10.1039/c5sc02569a)
8 U P Dahal et al, Chem. Res. Toxicol., 2013, 26, 1739 (DOI: 10.1021/tx400301q)
9 I M Serafimova et al, Nat. Chem. Biol., 2012, 8, 471 (DOI: 10.1038/NChemBio.925)
10 J M Bradshaw et al, Nat. Chem. Biol., 2015, 11, 525 (DOI: 10.1038/nchembio.1817)
11 J M Ostrem et al, Nature, 2013, 503, 548 (DOI: 10.1038/nature12796)
12 K M Backus et al, Nature, 2016, 534, 570 (DOI: 10.1038/nature18002)
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Read Lil' Horsemen
Halloween: A Family Experience
On October 13, 2013 October 12, 2013 By R. PettyIn Random Fun
When you think of a family activity, what comes to mind? A week-long beach vacation? A trip to Disneyland? A weekend camping trip? The holidays?
Most people think of Thanksgiving and Christmas when they hear the term "the holidays". But in my family, including my very close friends, the holidays start with Halloween — the best holiday of all. You don't have to shop, fight the crowds, and no one is grumpy. What's not to love?
This week, I'm focusing on the family aspect of Halloween and how you can gain quality time just by getting into costume and maybe trick-or-treating. It's one night a year, and you can be anything you want!
We have years of memories dressing up together…
2008: Our son was a death ninja, so I dressed up as a grim reaper and my husband dressed as the devil. He was brave enough to use face paint. Me not so much, so I used eyeshadow to give myself a more deathly look.
My son went through a stage for about five years where he was nothing but a different type of ninja for Halloween. We truly embraced it in 2009 and all dressed as ninjas!
2010: I had three costumes that year for work and parties (coming in later posts), so I decided to just dress festive for Halloween night. My son was a white dragon ninja, of course 😉
2010: Family reunion on Halloween. We had a coven of witches that year! I hope we can do that again because it certainly made the pictures more interesting, and everyone seemed to have fun!
2011: My witch dress, complete with socks and boots. I actually wore this dress to my high school freshmen homecoming. A good dress can be worn for many occasions!
My son's Scorpion ninja that complemented my witch. It was also the last year of the ninja lol. Although, we'll see this year…
2012: The first year we did our own thing lol. Mario, the grim reaper (inspired by the premiere of Lil' Horsemen), and Bellatrix Lestrange from Harry Potter. Mario received all the attention that night, and somehow my son and I still managed to go dark. Great minds think alike 🙂
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Computer Student Hopes to Live the 'Average American Dream'
Ryan Whitacre
BY TYLER KIMMEL
Ryan Whitacre, a 22-year-old computer information systems major from Scottdale, is used to getting things done with his hands. The California University of Pennyslvania senior seems to live by the "work hard, play hard" philosophy.
He said the computer science industry is "an industry where you're constantly learning, and I thought it'd be something I wouldn't get bored with when I got older."
Whitacre said he wants to get into the field of computer networking because it is more active than programming because one is constantly moving instead of sitting behind one computer screen.
Whitacre has always been interested and intrigued by computers, he said. Part of the reason stems from his father, Russell. Whitacre's dad is a self-taught computer programmer and Web designer. Russell was a finance and accounting major in college, but computers were his true calling. Whitacre said his father teaches three computer science classes at Pennsylvania Institute of Health and Technology.
Whitacre said his father has always had an interest in computers and that interest grew on him.
His major isn't the only job Whitacre uses his hands for. He has worked off and on for the last two years with Lantzy Heating and Air doing ductwork. Whitacre said that working in a cold, wet, basement, standing on ladders, and "a lot of heavy lifting" doesn't bother him.
"I really like the work because it's hard work, and it's nice to pick up a trade because when I'm older, I'd like to own my own house and I'll be able to do some of the work myself, rather than hiring someone else to do it," Whitacre said.
Besides work and school, Whitacre keeps his hands busy by doing his favorite hobbies. He enjoys lifting weights and playing basketball with his friends. He is also an avid hunter and fisherman and enjoys anything that is active and outdoors. One of his favorite parts of hunting is gutting his deer, he said.
"I start under the neck and cut the skin the whole way down," Whitacre said. "You can't cut too deep because you can puncture an organ and spoil the meat. After you cut the guts out, you take it to the butcher. There's nothing better than deer meat," he said.
Along with a passion for computers, Whitacre also inherited his passion for basketball from his father.
It's something I've been doing since I was a little kid," Whitacre said. "My dad and uncle got me into it because they were big basketball fans and I've been playing it ever since."
As for the future, Whitacre isn't asking for much, just a long and enjoyable life.
"I'd like to work for a respectable company in the computer science industry. I want the average American dream: a wife, kids, and a house," he said.


Home News Bootle is deeply dippy for Dippy!
Bootle is deeply dippy for Dippy!
He's Britain's best-loved dinosaur and Sefton Council thinks Dippy should be making his way to Bootle!
Although Dippy currently lives in the Natural History Museum in London, Sefton Council, along with Ykids and the operators of the Strand shopping centre in Bootle, have today (13/7/22) submitted an expression of interest to host Dippy for up to three years.
If successful, the diplodocus cast will move to the community space at the Strand in Bootle, where residents and visitors will be able to learn about climate change and biodiversity loss both worldwide and at a local level.
Alongside Dippy, a new education and visitor centre will offer a programme of activities, centred around Sefton's environmental challenges. Visitors will be able to dig for fossils in a giant sandpit, explore a Sefton Coast timeline, experience interactive educational exhibits and participate in workshops.
Dippy wouldn't be Sefton's only link to the prehistoric, though. Along the Formby coast, footprints of the humans that lived on the coast as long ago as 6000BC can be found. The prints, which have been exposed by tidal erosion, offer a unique insight into the prehistoric life of the area.
Dippy's temporary home in Bootle, as outlined by the expression of interest, will support the ongoing regeneration and recovery as part of the wider transformation of Bootle town centre. This would be just one of many exciting initiatives and projects, led by both Sefton Council and a range of partners, to breathe new life into Bootle and surrounding areas. It will build on the ongoing commitment of local voluntary groups to nurture the green spaces across the Borough and highlight Sefton's own natural history, from the prehistoric development of our coastline to the environment challenges of the present day.
If approved by the Natural History Museum, Dippy will attract his loyal fans, bringing visitors from all over the country to Bootle. He will be a positive attraction for the region, bringing economic benefits to the area.
Cllr Marion Atkinson, Sefton Council's Labour Cabinet Member for Regeneration and Skills said:
"This is a fantastic opportunity for Bootle which promises to bring focus and new visitors to an area of our Borough that has been hit hard recently.
"Dippy the dinosaur is an incredibly popular attraction at the Natural History Museum, and I'm pleased to support the expression of interest that has been put forward today. The Council and YKids would be very keen to welcome the Natural History Museum and its evaluation team to Bootle, to meet our communities and to see the space and the impact that this could have on our town centre.
"Sefton's coastline has a rich history and Dippy would find himself at home in our local area."
Cllr Trish Hardy, Sefton Council's Cabinet Member for Communities and Housing said:
"Dippy the dinosaur would be a very welcome guest in our community.
"If our expression of interest is successful, I have no doubt that Dippy would become an extremely popular attraction and a great way for people of all ages to learn more about our local area.
"Our coastlines are rich with history and Dippy would help to bring that history to life."
Claire Morgans from Ykids said:
"To be able to bring Dippy to Bootle would be a unique and exciting opportunity to teach children and young people in Sefton, and across the Liverpool City Region, all about the prehistoric history of our beautiful borough, and to engage them in a learning experience that might otherwise not be accessible to them. We're confident we have put forward a strong case to host Dippy in Bootle, and we're thrilled to be a part of this fantastic opportunity."
Shortlisting will take place at the start of August and Dippy will move into his new home in January 2023.
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Mich. Credit Union Reform Headed for Legislature
January 30, 2003, 5:05 p.m. EST 2 Min Read
The Michigan Credit Union League and regulators there are formulating a bill that would give state-chartered credit unions broad field-of-membership authority.
The bill, which is expected to be introduced in the Legislature within the next month, would let credit union boards determine their fields of membership. Regulators would be able to reject requests only because of safety-and-soundness issues.
The Michigan Office of Financial and Insurance Services has privately endorsed the provision, which is similar to one included in state charters in California.
Frank Fitzgerald, the agency's commissioner, would not discuss the details of its recommendation but confirmed that it agreed with the Michigan Credit Union League on major provisions in a sweeping proposal on credit union reform.
League officials said Mr. Fitzgerald has lent his support to the proposal. "They do not want to be in the business of setting fields of membership anymore," said its chief lobbyist, Patrick LaPine.
The bill is also expected to include items that would permit all state credit unions to offer trust services and to increase their investments in credit union service organizations to 7% of capital, from 5%. They would also be able to offer secondary capital accounts, operate under multiple trade names, retain their original names after a merger, and offer some services, such as check cashing and wire transfers, to nonmembers within their fields of membership.
Mr. Fitzgerald said his agency has been working closely with the Michigan trade group over the past year to draft a proposal to modernize the credit union statute.
He added that he has been discussing the effort with representatives of the banking community to avoid confrontation between the two traditional rivals.
"I think we're going to be able to talk this issue through," Mr. Fitzgerald said. "The relationship in Michigan between the credit union world and the banking world has been a good one. I hope that we can get to the point where we're all on the same page so that the legislation can pass."
In the past year the credit union group has conducted a comprehensive review to draft what would be the first major rewrite of the statute in more than 20 years, and it has lined up sponsors in the House and Senate who have agreed to introduce a bill, according to Mr. LaPine.
The aim, he said, is to move toward more parity with the federal statute to encourage Michigan's 280 state credit unions - two-thirds of the total - to retain their charters.
But the field-of-membership provision is likely to be the big point of contention. "That's the 800-pound gorilla," Mr. LaPine said. "It will be the spark point."


Bellefleur PS Z · mclain ward · Recent Results · wef · Jan 17, 2018
McLain Ward Repeats Opening 1.45m Win in Second Week of WEF
McLain Ward & Bellefleur PS Z. ph: Sportfot.
The second week of the 2018 Winter Equestrian Festival (WEF) began on Wednesday, January 17, with the opening class, the $8,000 Douglas Elliman Real Estate 1.45m Jumpers. Repeating his first week win, Olympic team gold medalist McLain Ward (USA) took the top spot, this time riding Bellefleur PS Z for Susan Heller and Lilly Ward. Week two of WEF continues through Sunday, January 21, at the Palm Beach International Equestrian Center in Wellington, FL.
There were 15 entries in the 1.45m Jumper class, which was held in a speed format. The course designer for the International Arena this week is Oscar Soberon of Mexico.
Nine of the 15 entries were clear, but it was Ward and Bellefleur PS Z, an eight-year-old Zangersheide mare by Berlin x Quidam de Revel, who were fastest around the course in 60.497 seconds. Laura Chapot (USA) took the next two spots in the results with Chandon Blue, owned by Mary Chapot, close behind in 60.606 seconds, and Out of Ireland, owned by The Edge, in 60.925 seconds.
Ward has been developing Bellefleur PS Z since she was six years old, and owns the mare with his godmother, Susan Heller.
"Well actually, Lilly owns her with [Susan]," he said. "The deal was Lilly had to be my owner so that I wouldn't sell her. She's a phenomenal mare. She's super careful, brave, really game, and she's stepping up the levels nicely.
"She's kind of suited to everything," continued Ward. "She's naturally fast, and she's very careful. It'll be interesting to see how far she goes because she's very game and everything we ask her to do, she seems to do really well."
Ward plans to keep building up Bellefleur's experience, with the goal of competing in the 1.50m classes.
"It was a nice galloping course which was nice for the opening day," said Ward. "I thought she handled it really well. They had difficult double verticals at the end, which probably last season would have been a challenge for her, but she handled it beautifully today."
The full results can be viewed here.


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Home Church
Bishop steps down after speaking of campaign forcing him to quit
Harry Farley 24 March 2017 | 2:13 PM
The assistant Bishop of Llandaff is resigning after speaking of a sustained campaign forcing him to quit.
David Wilbourne, a strong supporter of gay cleric Jeffrey John, will step down on Easter Sunday after 'considerable and increasing pressure to relinquish' his post for the past 18 months, he told the Church Times.
The electoral body met in Llandaff Cathedral for three days but failed to elect a candidate despite Jeffrey John winning more than half the vote and unanimous support from local representatives.Wikipedia
The Church in Wales denies there is any campaign against Bishop Wilbourne forcing him to quit and said his role had been there to assist the recently retired Archbishop of Wales, Barry Morgan, who was also Bishop of Llandaff.
The assistant bishop has backed Dr John, currently Dean of St Albans Cathedral, in a feud with bishops after he was recently blocked from being appointed Bishop of Llandaff.
Dr John wrote to the senior bishop in Wales, Dr John Davies, saying the only reason he was barred from the post was his sexuality.
'Ever since I knew that Jeffrey was in the frame for Llandaff, I thought it would speak mountains about our policy of inclusion. Wales has led on that; so I can't understand why the bishops aren't of the same mind,' he told the Church Times.
Dr John won more than half the votes in the electoral body appointing a new Bishop of Llandaff and unanimous support from local churchgoers on the panel. But he failed to win the two thirds necessary to be appointed and claims he was blocked by bishops after homophobic comments were made about him during the process.
The Church in Wales strongly denied allegations of homophobia during the election process and denies he was blocked.
In an official statement announcing his resignation, Bishop Wilbourne made no mention of the campaign against him.
'I realise it is time to hand over the baton to the newly appointed Bishop of Llandaff, so he or she can run free, enabling the Church which I have cherished these past years to flourish.
David Wilbourne will stand down as assistant Bishop of Llandaff on Easter Sunday after backing Jeffrey John.Church in Wales
'I therefore intend to finish my time as assistant bishop on Easter Day 2017, just before the Sacred Synod approves our new bishop.
'I do so with the greatest gratitude for all the faithful parish priests and people here, whose marvellous ministry I am daily humbled by.
'I pray that you are given the bishop you so richly deserve, one who, in the words of Cardinal Basil Hume, simply comes to where people are and takes them to places they never dreamt of going.'
The Church's senior bishop, the Rt Revd John Davies, Bishop of Swansea and Brecon, who has current oversight of the Diocese of Llandaff, thanked Wilbourne for his work in the Church in Wales.
He said, 'Bishop David makes it clear in his own statement why he has made the decision to step down, and it is important that we respect that decision and the prayerful manner in which he has reached it.'
It comes after the Chapter of Southwark Cathedral became the latest to back Dr John in the increasingly bitter row, a statement on Thursday read.
'Southwark Cathedral has a long and proud reputation of standing up for diversity and inclusion within the church. It was therefore with deep sadness that we read the reports of the failed appointment process for the vacant see of the Diocese of Llandaff and especially of the way in which it affected the Dean of St Albans, the Very Revd Dr Jeffrey John.'
In a strongly worded statement the Chapter called 'for a future in which discrimination on the grounds of sexuality, gender or ethnicity will cease'. The statement described Dr John as 'a person of deep wisdom, the highest integrity and startling honesty.
'His willingness to live within the requirements laid down by the House of Bishops of the Church of England, and the public assurances that he does so, has not stopped him being rejected as a candidate for episcopal ministry.
We believe that the church, through its lack of similar integrity, wisdom and honesty, is failing to recognise the God-given abilities from which we as a community benefited.'


Surging A's might be baseball's best story
Beane: 'We're gonna try to add' ahead of Tuesday's Deadline
By Mike Lupica
You want a fun fact on the Oakland A's, who have the lowest payroll in baseball and have still managed to change the way people are looking at the American League pennant race? When the A's entered play on Thursday, they were as close to the Yankees for the top
You want a fun fact on the Oakland A's, who have the lowest payroll in baseball and have still managed to change the way people are looking at the American League pennant race? When the A's entered play on Thursday, they were as close to the Yankees for the top AL Wild Card spot -- trailing by 5 1/2 games -- as the Yankees are to the Red Sox in the AL East standings.
On Thursday morning, I asked Oakland executive vice president of baseball operations Billy Beane if he was aware that his team really was that close to the Yankees.
"Well aware," he said.
The A's came from eight runs down to win on Tuesday night in Arlington. Then they came from four runs down to win on Wednesday night, again against the Rangers, when Khris Davis hit a two-out, two-strike home run in the ninth. And in a week when the big bullpen news in baseball was the Yankees adding Zach Britton to an already elite bullpen, consider this about the A's:
They are 25-7 since June 16, the best record in baseball. They're 40-0 this season when leading after seven innings, and are the only team in the Majors that is undefeated when leading after seven. They are 48-0 when leading after eight. Their closer, Blake Treinen, has 1.04 ERA, which ranks first among all relievers, and Lou Trivino's 1.33 ERA is fourth. On Saturday, Beane traded for Jeurys Familia, who used to close for the Mets. And Beane made it quite clear on Thursday that Familia might not be the last acquistion he makes before Tuesday's non-waiver Trade Deadline.
"Hey, I hope I'm not done," he said. "We're going to make every effort to do everything we can. It's my belief that it is your responsibility to respond to your team when it's playing the way our team is."
Then he said: "This team reminds me a lot of 2012 when, you might remember, we never spent a day in first place until we won the division on the last day of the season."
The A's were 12 games out of first place on July 1, 2012. This was an Oakland team that some thought might lose as many as 110 games before the season started. Beane admits that while the predictions about this year's A's weren't quite as bleak, there wasn't much of a spit-shine to them, either.
"We're sort of operating in the same space as always," Beane said. "It's the space where people are conditioned to overlooking us and disregarding us and now finding a way to succeed again. We're kind of a stealth team that way. Just not lately. Maybe the biggest difference, at least for now, between this team and the '12 team is that we've made our move earlier."
Beane paused, then said: "You know the corny expression, especially at this time of year, the one about how you want to be playing meaningful games in September? Well, we're playing meaningful games now."
Beane has seen his manager, Bob Melvin, use 12 different starting pitchers this season; has watched the world start to take notice of not just the power hitter that Davis is right now, but also the one he's become, with an MLB-high 112 home runs since '16; has seen the back-end of his bullpen, now enhanced by Familia, shut down teams better than the Yankees or anybody else.
Beane says that his payroll at the start of the season was at $66 or $67 million, and is probably at $69 million now. It is, of course, less than a third of what the Red Sox, who have MLB's best record this season, are spending.
When I pointed that out, Beane laughed.
"Our payroll," he said, "is their tax."
So there you have it. Third in the AL Wild Card standings. Third in the AL West, behind the Astros and Mariners (the A's still have 10 games left against Seattle). Still dead last in payroll. I've said this before about Beane -- one of the transformative front-office figures in baseball history, even without a World Series title -- and said it with all due respect to all the other smart general managers and presidents of baseball operations out there:
Let all of them try to spend what he spends and win.
I asked him if it's starting to be cool again in the Bay Area to root for the A's.
"Very," he said. "Our series with the Giants last weekend, I think we averaged 50,000 a game and had the biggest crowd in baseball this season."
They did. The crowd was 56,310 -- not just the largest crowd of the season, but also the biggest baseball crowd in the history of the Oakland Coliseum -- and the A's won in extra innings. In a summer that has the Red Sox and Yankees each on pace to exceed 100 wins, in a season that the Astros are trying to repeat, a season in which Manny Machado was just traded to the Dodgers, there is no bigger or better story right now than the A's.
"When you're in the position we're in, I really do believe you gotta jump on it," Beane said. "You can't think, 'Oh, let's not get ahead of ourselves.' No. You know why? Because the teams you're playing don't care about some kind of five-year rebuilding plan you might have going. That's why we're gonna try to add to this group of we can."
The last time we spoke, Beane, a rock-and-roll music fan, compared himself and his team to The Ramones. He reminded me of that reference Thursday.
"The Ramones didn't sell as many records as some of the other groups, but they were still pretty cool," Beane said.
His A's are selling some records now. Cool.
Mike Lupica is a columnist for MLB.com.


Spotlight : August 1998
Patrick Tatopoulos: The Man Behind The Monster
Written By Scott Essman
Read PART ONE Of The Interview
Patrick Tatopoulos (at right) poses with the 1/6 scale Godzilla.
"It was basically my version of GODZILLA - the way I think it should be now," recalled Patrick Tatopoulos of his original creature design. "For years, people have seen Godzilla in movies, but I wanted to show them something new." That he did, and once Toho Studios had approved of Tatopoulos' new Godzilla designs, the artist was faced with the challenge of creating a believable monster who was to appear 350 feet tall as it romped around Manhattan. "GODZILLA was definitely my biggest project," Tatopoulos admitted. "I felt that a lot of the responsibility was on my shoulders since we were creating the title character."
In December 1996, a 20,000 square-foot facility in Culver City in which the various practical aspects of the character were to be created was established as "the Godzilla shop." Tatopoulos, who was assigned to supervise the look of the CG animation as well, had to quickly assemble a team of top-notch sculptors, moldmakers, suit fabricators, art directors and production coordinators required to undertake the mammoth proportions of the show. "I was lucky since, at that time, Stan Winston was wrapping THE LOST WORLD, and Rick Baker was completing MEN IN BLACK, so the craftspeople who finished working in those shops were able to come to my new shop. At its peak, my crew, with 172 members, was the biggest ever assembled," he recalled.
After many discussions with director Roland Emmerich, the original plan for the numerous character effects was to split the film 50%-50% between Tatopoulos practical creatures and CGI. "Roland had just put together Centropolis Effects, his own CGI company," explained Tatopoulos, "so it was only natural that he wanted GODZILLA to put them on the map." Acknowledging CGI as another
The animatronic beast with a taxi in its jaws, for the climax of the film.
filmmaking tool, Tatopoulos noted its necessity in a project with as many dimensions as GODZILLA. "Even though I'm not as huge a fan of CGI as I am of practical effects, the only thing I'm concerned about is using the technique that works best for the situation " he said. "Ultimately, as a designer, I care about having a character that looks good throughout the whole movie."
Upon forming his core team, Tatopoulos set out to create two scales of Godzilla in his shop: an articulated suit worn by a performer, and an oversize mechanical character operated by a team of puppeteers. "We decided that the suit-size creature would be 1/24-scale and used for action shots with the same scale model buildings," said Tatopoulos. "However, we felt that it would be too small for insert shots and closeups, so we agreed to build a 1/6-scale, 35-foot-tall, hydraulic creature from the hips up." Added to this task was an extensive sequence involving Godzilla's offspring, the babies, or baby-zillas, for which Tatopoulos team would need to create eight suits and a ninth hydraulic creature. "We had so many different items to build in such a short period, it was like working on five films at once!" said mechanical supervisor Guy Himber.
Under Jake Garber, supervisor of the shop's art department, James Kagel coordinated the sculpting crew who worked from Tatopoulos' baby-zilla designs, all similar to prevent a continuity headache. "We created eight babies to take the part of 250," Tatopoulos noted. "My concept was generic so they could be interchangeably used in the film." Dave Kindlon designed the baby- zilla heads, with radio-control servos and custom motors built onto lightweight carbon-fiber frames. The heavy foam latex suits were fabricated with spandex undersuits to make them more resistant, and special leg extensions helped the babies achieve predatory snapping motions when puppeteered. "We had months of training; first we studied videotapes of lizards, iguanas and other reptiles to get a feel for how they moved," Tatopoulos explained.
"Roland and I tested acrobats and stunt people from Cirque De Soleil to wear the baby-zilla suits." The performer entered the suit from behind, fitting into the arms and legs from an open back. Next, the creature's head, spine, and tail attached like a giant backpack. Lastly, the actor was outfitted with leg extensions - towards the end of shooting, it became pragmatic to attach the leg extensions before the backpack - and finally the hands went on like gloves. On set, in addition to the suit performer, each baby had two puppeteers to actuate facial movements, plus a dresser to help the performer into the suit. Three hero babies featured articulated tongues and nictitating membranes on their eyes, while background babies were capable of simple mouth, eyelid and eye movements. A ninth completely hydraulic one designed by Tim Ralston was able to achieve more quick actions and possessed abilities such as breathing and tail motion. "The fully hydraulic baby was on a motion base from the waist up," Guy Himber explained. "A company called Mediamation provided a computer control and recording system to puppeteer it with the ability to repeat specific movements."
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Home MTSU>MTSU News Two MTSU Faculty Members Receive Prestigious Grants
MTSU>MTSU News
Two MTSU Faculty Members Receive Prestigious Grants
MTSU faculty members Seth Jones and Hanna Terletska hold a distinction no other Middle Tennessee State University professors have ever obtained — National Science Foundation Early Career Development (CAREER) grant recipients.
The NSF CAREER awards support junior faculty who exemplify the role of teacher-scholars through research, education and the integration of education and research within the context of the mission of their organization. Jones is in the Womack Educational Leadership Department; Terletska is in the Department of Physics and Astronomy.
Given annually, the award comes with a federal grant for research and education activities for five consecutive years. Combined, their grants total nearly $1.2 million.
The recognition is considered the NSF's most prestigious awards for early-career faculty. The NSF receives more than 50,000 competitive proposals for funding each year and makes about 12,000 new funding awards.
"Congratulations are in order for these two outstanding MTSU faculty members at this point in their careers," university President Sidney A. McPhee said. "This is a testament to their determination to be highly successful researchers and educators, and a mentor to their students. I believe this will be a catalyst for other faculty researchers to apply for their own grants as well."
The organization selects CAREER recipients based on their "potential to serve as academic role models in research and education and to lead advances" in their fields and organizations.
The NSF awarded $499,879 to Terletska, an assistant professor, for her "Beyond Ideal Quantum Materials: Understanding the Critical Role of Disorder and Electron-Electron Interactions" proposal. The development plan is a fundamental research, education and outreach program that focuses on theoretical and computational study of functional quantum materials with strong electron-electron interactions and disorder.
Jones, an assistant professor, received a five-year, $700,000 NSF grant for his "Supporting Statistical Model-Based Inference as an Integrated Effort Between Mathematics and Science" proposal that seeks to design opportunities for middle school math and science teachers to coordinate their instruction to support a more coherent approach to teaching statistical model-based inference.
Jones' award began Feb. 1 and ends Jan. 31, 2025. Terletska's award starts May 1 and ends April 30, 2025. Both will include student involvement.
Provost Mark Byrnes said that "winning two CAREER grants in the same year is a remarkable achievement for MTSU and demonstrates the high-quality research conducted by our faculty."
David Butler, vice provost for research and dean for the College of Graduate Studies and vice provost for research, said NSF CAREER Awards "are very rare and difficult to obtain as they are for the top junior scholars in their fields."
"We are extremely proud of the efforts by Drs. Terletska and Jones on their remarkable accomplishments to date," Butler added. "Their success is a symbol of how MTSU is transforming into a research university, producing valuable research and development for the state of Tennessee and its citizens, fulfilling the role of a publicly-supported state institution."
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Kallang roar back with up to 10k fans
But strict safety measures will be in play as FAS says fans' health takes 'utmost priority'
Sazali Abdul Aziz
https://str.sg/3NjX
Just over a week from the tournament's first game, the Football Association of Singapore (FAS) yesterday announced ticket details for the AFF Suzuki Cup.
In a media statement, it said that tickets for each match day, priced at $25 for adults and $15 for children aged 12 and under, would go on sale from noon today (see box on right).
Singapore will kick off the biennial 10-team tournament against Myanmar at the National Stadium next Sunday.
While the announcement omitted the number of spectators allowed to attend the games, the FAS later said in response to queries that 10,000 fans will be allowed for each match day at the 55,000-capacity National Stadium. At the 6,000-capacity Bishan Stadium, 1,000 will be admitted for each match day.
Each match day features two games, both either from Group A or B. The National Stadium will host all but one game from Group A - in which Singapore are drawn - while Bishan will serve as the main venue for Group B matches.
Noting that the permitted number of fans per match is less than a fifth of each stadium's capacity, an FAS spokesman said this "ensures that fans are adequately spaced out with one-metre safe distancing between groups at all times, in line with prevailing safe management measures".
Away fans have been allocated about 20 per cent of the spectator capacity for Singapore match days at the National Stadium, the spokesman added.
In its media statement, the FAS said that only those who are fully vaccinated will be allowed into games, and refunds would not be issued to those who fail to provide proof of vaccination and are denied entry.
Safe management measures will be enforced strictly through seating plans and allocation. Fans at the National Stadium will sit in pairs while those at Bishan will sit singly, with one-metre safe distancing.
At the National Stadium, fans will be assigned to sectors with no more than 500 people each, with no mingling allowed across sectors. This will be enforced through the use of coloured wrist tags for each spectator, which will also serve as identification that allows re-entry into the stadium for that match day.
Ticket sales on the first three days are exclusively for Singapore fans. The FAS had opened pre-registration for ticket purchases to Singapore fans on Nov 18 - it received over 6,000 applications - and those who indicated their interest received a link yesterday to purchase their tickets.
FAS general secretary Yazeen Buhari acknowledged that the process of announcing details had taken "longer than usual".
Thanking the fans for their patience, he explained: "Fans' health and safety continues to be our utmost priority, especially in today's circumstances, and we are confident that the security protocols and safe management measures that will be put in place will ensure a safe and enjoyable match-day experience for all."
However, yesterday's announcement left some fans upset. Supporters' group SingaBrigade announced in a Facebook post that they would not attend the Lions' games as a group, citing unhappiness over not being allowed to bring drums to the matches. They also felt the price of tickets was too high.
SingaBrigade are the main national team supporters' group. In pre-pandemic times, they were a visible presence as they often unfurled a giant Singapore flag while the National Anthem was sung ahead of home games.
"We are not walking away from Singapore football but would like to send a message to them not to take football fans lightly," the group wrote, without identifying the target of their message other than stating "relevant parties".
In any case, Singapore fans unable to attend games in person are likely to be able to catch a live telecast. The Sunday Times understands that Mediacorp has reached an agreement with Suzuki Cup rights holder Sportfive to broadcast the Lions' games. It could also broadcast games involving other teams on its digital platform MeWatch.
A Mediacorp spokesman indicated that it would only be able to provide more details later.
Four-time regional champions Singapore are in Group A with Myanmar, five-time winners Thailand, the Philippines and Timor Leste.
Group B comprises defending champions Vietnam, Malaysia, Indonesia, Cambodia and Laos.
The top two teams from each group will qualify for the two-legged semi-finals before a two-legged final, with the champions of Asean crowned on Jan 1.
The final four games will be played at the National Stadium.
DEC 5-JAN 1 SUZUKI CUP TICKET DETAILS
• National Stadium (Group A): From noon for Singapore fans. From Wednesday for the public including non-Singaporeans
• Bishan Stadium (Group B): From Wednesday for the public
$25 for adults per match day, $15 for children aged 12 and under per match day
www.fas.org.sg/tickets
20 per cent off for S'pore fans purchasing a bundle (all four S'pore group-stage matches)
Only fully vaccinated fans are allowed in. No refunds for those who fail to provide proof of vaccination and are turned away
A version of this article appeared in the print edition of The Sunday Times on November 28, 2021, with the headline Kallang roar back with up to 10k fans. Subscribe
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› Politics › U.S.-Israel and Iran: Will There Be War?
U.S.-Israel and Iran: Will There Be War?
Is Iran really the devil? The U.S. and Iran have a volatile relationship, and the Trump administration is showing readiness to take military action. But how are we to interpret the Iran situation?
Tensions are escalating between the U.S. and Iran. President Trump issued an order to strike Iran after they allegedly shot down a U.S. drone. He stopped the strike just 10 minutes before commencement, but one such unforeseen military conflict can begin at any moment.
The Cause: Trump's Withdrawal From the Nuclear Deal
This recent conflict began when the U.S. withdrew from the Nuclear Deal.
In 2015 during the Obama administration, Iran signed a deal with a group of countries (U.S., U.K., France, Germany, China and Russia) that Iran would restrict uranium enrichment operations that are required to create nuclear weapons in exchange for lifting sanctions. The enrichment levels were set so that it would take over 1 year before they reached levels usable for nuclear weapons.
In May 2018, however, the Trump administration unilaterally decided to withdraw from the Deal on the grounds that it was flawed because it could only restrict Iran's nuclear developments for 15 years.
After that, they imposed a list of 12 demands on Iran including the suspension of missile developments and government support towards military groups such as the Hezbollah in Lebanon. The U.S. restored sanctions on Iran in order to pressure them into accepting the new conditions.
To no one's surprise, Iran resisted. They have refused to negotiate under pressure, and have demanded that sanctions be lifted as a condition for opening negotiations. On 8 July, Iran announced that they began uranium enrichment operations at levels above those agreed to in the Deal. Trump in turn threatened that, "Sanctions will soon be increased, substantially!"
Then Israel, a long-time adversary of Iran, came into the mix. Prime Minister Netanyahu claimed that Iran is planning to use enriched uranium to create nuclear weapons, and requested the U.K., France and Germany to reinforce sanctions.
Iran has been denying their intention to hold nuclear weapons, but they have also warned that they will begin operating more centrifugal machines depending on how the U.S. moves.
This is a highly complex situation, so the Liberty Magazine spoke to three specialists about tips on how to interpret what is happening. Their vastly different opinions can give us insight into the situation.
"If Israel Threatens Iran, The World Must Keep An Eye On Them And Request Nuclear Disarmament" — Master Okawa's Lecture in Tokyo
Iran Has Contributed to Peace and Security in the Middle East, Says Iranian Vice President
U.S. vs Iran: Japan's Religious Duty As Mediator
Category: Politics, Religion, World
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