180 gram vinyl LP in Gatefold packaging
"You’re Mine You" marked Sarah Vaughan’s second recorded collaboration with Quincy Jones, following a Mercury album titled "Vaughan and Violins", which was taped in Paris, France, on July 7-12, 1958, and featured the singer backed by a string section. This isn’t the case with the album presented here, on which there are just a few touches of strings and a strong big band occupies the forefront.
According to All Music Guide critic Scott Yanow, “This LP finds Sarah Vaughan backed by big-band and string arrangements from Quincy Jones that could easily have been used for a Frank Sinatra date. Vaughan’s voice is typically wondrous and sometimes a bit excessive on the ballads but in top form on the more swinging numbers. In the repertoire are such tunes as ‘The Best Is Yet to Come’, ‘The Second Time Around’ and ‘Baubles, Bangles and Beads’. The set should please those who love the sound of Sassy’s remarkable voice.”
SARAH VAUGHAN, vocals
Orchestra arranged & conducted by QUINCY JONES
New York, January 1962.
01 YOU’RE MINE YOU
02 THE BEST IS YET TO COME
04 SO LONG
05 THE SECOND TIME AROUND
06 I COULD WRITE A BOOK
07 ONE MINT JULEP (*)
02 BAUBLES, BANGLES AND BEADS
03 FLY ME TO THE MOON
06 ON GREEN DOLPHIN STREET
07 MAMA, HE TREATS YOUR DAUGHTER MEAN (*)
(*) BONUS TRACKS Same personnel and date, but not included on the original LP. Originally issued in 1962 on the 45rpm single Roulette 4413.


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Wine tour in Costa del Sol
wine sun and happiness
The wine tour will take you through 3 wonderful white villages:
Torrox, which has the reputation of having the best climate in Europe will be the starting point of the wine tour.
Competa which produces some of the best wines in the Province of Malaga
Sayalonga where you will have lunch in a restaurant that offers typical dishes
The wine tour in Costa del Sol begins with a visit to the historic center of Torrox , very typical of white villages, to then take you to Competa and to a wine producer. You will taste this moscatel wine with its producer, whose pride is to have delivered it to the wedding banquet of Felipe
Then you will have lunch with a typical meal in Sayalonga , where you will discover an absolutely unique place in Spain (surprise!) During the digestive walk.
Departure Tour from : Torre del Mar, Torrox and Nerja
Below is a photo of Cipriano, your guide and driver, during a visit with him.
- Language: Spanish, English, German
- Semi private group: 2 to 8 people maximum
- Hours: 9:00 a.m. - 4:00 p.m.
- Duration: approximately 7 hours
- Typical lunch: included, with a drink
- Round trip transport: included
- The guide picks you up on the coast between Torre del mar and Nerja
- Price: 58 € per person

domain: travel


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I spent a while in the garden yesterday doing some tidying up for the winter and got the last of the tender plants safely tucked up in the shed/summer house. I usually cut the fuchsias right back at this time of year but they had so many lovely flowers still on them that I just gave them a tidy up and put them at the front where I could see them from the garden.
Anyhow, because I have drawn so many of them this year, I can still have their blooms during the winter! One of my favourites has got to be Swingtime and I've coloured the one in this card in "Swingtime colours"...carmine and ruby.
In case you haven't seen it yet, the Fuchsia Window die is one of my new designs in the Pick of the Bunch range for Tonic Studios. The die cuts a lovely frame/window with a fuchsia shape at on end and ivy at the other. These can be embossed / stamped with the coordinating Clear Stamp Die Toppers / or both as in this card. I've also used leaves from the Window Basket Die set, beautiful Petal Pairs and the "waste" from the Daisy Border punch.
The silver border down the sides was created with the Daisy Border 2 punch and the corners are the Multi Detail Heart punched shapes.

domain: design


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Without resorting to boasting, it is virtually perfect. Please ask us about our complete and total devotion to accuracy.
National Pharmacy prides itself in its ability to serve clients anywhere in Ontario. There are many satisfied first tier clients all across the province. With careful planning, modern shipping and expediting, next-day service is always available. In an emergency, when local arrangements are necessary, we will make them. In addition, National Pharmacy is in the [...]
Personal service is what distinguishes National’s service from other LTC pharmacies. Please ask us about what this means in the course of our service to you.
Unsurpassed in quality, our services are highly specialized, derived from a network of Ontario pharmacies dedicated to long-term care. Customers recognize the pharmacy’s total dedication to residential care; it does not cater to the retail public. We are devoted to serving the customer accurately, promptly-always responsive to their needs whenever and wherever they occur.
An important facet of National’s services is the ability and willingness to tailor services to the needs of individual homes. Our medication systems have been revised and refined over the years and much of our computer software has been custom designed. We believe we offer the most advanced, complete, and knowledgeable pharmacy services available to [...]
They are: Specially trained in providing geriatric and psychiatric care. Specially trained in palliative care and pain management. Constantly monitoring all new prescriptions for drug allergies, proper dosage, drug interactions, and duplication in therapy. Experienced in delivering a formalized method for handling drug interactions. Mandated to review the medication profile of each resident every three [...]
That varies depending on the engagement. Some pharmacists visit our clients weekly. Others are there less often, depending on the needs of the individual facility. Whatever the schedule may be, National’s pharmacists are in constant touch with our clients. There is nearly always daily telephone contact and quite often the communication occurs more often.
It aids accuracy and creates less work within the home, helping nurses and other health professionals focus on care. National Pharmacy offers the most innovative and personalized drug distribution available in Ontario. Here are some of the examples of our clinical services personified in our drug distribution system: POUCH PAK™ Drug Distribution System Fax transmission [...]

domain: health


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Expression of a long variant of CRACR2A that belongs to the Rab GTPase protein family in endothelial cells.
Bottom Line: Unexpectedly, short interfering RNA designed to deplete CRACR2A had no effect on CRAC channels in endothelial cells but reduced the abundance of a protein with about twice the mass of CRACR2A.It made a positive contribution to endothelial tube formation.The data suggest that endothelial cells contain a long variant of CRACR2A which is an EF-hand-containing Rab protein that lacks impact on CRAC channels.
Affiliation: School of Medicine, University of Leeds, Leeds LS2 9JT, UK.Show MeSH
Mentions: To determine if CRACR2A-L has functional significance in endothelial cells we performed an assay in which HUVECs form tube, capillary-like, structures on a bed of fibroblasts, mimicking aspects of angiogenesis (Fig. 4A). Depletion of CRACR2A-L did not prevent tube formation but reduced the overall length of tubes and the number of branch points (Fig. 4B and C). The data suggest that CRACR2A-L is a functional protein of endothelial cells.
Affiliation: School of Medicine, University of Leeds, Leeds LS2 9JT, UK.

domain: biology


According to State Rep Jeff Irwin, whom I just traded emails with, it looks as though the controversial Voter ID law being pushed through the Michigan House this lame duck session by Republican lawmakers, will be coming up for a vote tomorrow – Wednesday, December 7 – Pearl Harbor Day. Given that the House is […]
Tag Archives: Constitution
Who are our Electors who will choose our next President, what are the rules that constrain them, and how many are likely to go rogue against Trump?
Unless something truly remarkable happens, Donald Trump will be sworn in as the 45th President of the United States on January 20, 2017. This, given the very real threat he poses to our nation, is incredibly distressing to many of us. And, with that in mind, it’s probably not surprising that quite a few very […]
In politics, as in business, it’s long been accepted practice to release bad news on Fridays in hopes of keeping media scrutiny to a minimum… And, I’m sure it was with this in mind that President-elect Donald Trump, this past Friday, released word that he’d agreed to pay a $25 million settlement to former students […]
NSA whistleblower Edward Snowden comes clean on why he turned over classified government documents to the press, just how much the intelligence community knows about us, and what his actions will likely cost him
Earlier today, the identity of last week’s much-talked-about National Security Agency whistleblower was made public. His name is Edward Snowden, and he’s a former technical assistant for the CIA, who, most recently, worked for the NSA through the defence contractor Booz Allen Hamilton. If you haven’t seen it yet, I’d highly recommend that you watch […]
Upon taking office, President Obama issued a memorandum on the subject of transparency: “My Administration,” he said, “is committed to creating an unprecedented level of openness in Government. We will work together to ensure the public trust and establish a system of transparency, public participation, and collaboration. Openness will strengthen our democracy and promote efficiency […]


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While doing research on Lt. Tony Rucker, whose U.S. Cavalry troop out of Ft. Bowie was responsible for the discovery of mineralization in the Mule Pass Mountains (Bisbee), I came across this interesting article about how little the local populace believed what the federal government had to say.
The article was in the Arizona Weekly Miner out of Prescott, but was reprinted from the Citizen in Tucson, and was datelined Jan. 16, 1877. It reported that Lieut. J.A. Rucker had returned to Camp Bowie, where his Sixth Cavalry unit was stationed, and had reported killing 10 Chiricahua Apaches “on the Chiricahua” instead of 8, as previously reported.
(What “on” the Chiricahua meant is ambiguous. The area south of Fort Bowie had been the Chiricahua Reservation until just a few months earlier. All of the Apaches had moved or had been moved to other reservations, and Geronimo was on the loose, having headed to Mexico rather than San Carlos, so any Chiricahuas on the former reservation likely would have been his hostiles. Or it could have meant the Chiricahua mountain range, long the homeland of that Apache group.)
The Citizen also reported that Rucker had captured one Apache boy, livestock, merchandise and Mexican silver coins. “This is really the only successful piece of Indian fighting since Gen. Crook left the Territory,” the paper said. Crook had left Arizona in 1875 to take a command on the Great Plains. He would return in 1882.
It was here that the Citizen took a jab at the government: “At the same time the killing of 10 Indians on the Chiricahua when we have repeatedly been reassured by the highest authority, that there were only 3 Indians out is a little astonishing.”
The paper also said that what was recovered and what was said by the little boy indicated the band was that of Geronimo, “the worst in the Territory.”


NZ Chapter Event: Te Huia – Hamilton to Auckland Commuter Services
March 10 @ 12:30 pm - 1:30 pm NZDT
Join the Railway Technical Society Australasia and David Shepherd to discuss the work leading up to the introduction of the Hamilton to Auckland Commuter train services. This presentation is being held as an RTSA New Zealand online meeting – register for the event here.
Te Huia is the passenger rail service that connects Waikato to Auckland. Capable of carrying over 500 passengers per day, Te Huia will transform the journey of Waikato commuters travelling between Hamilton, Huntly and Auckland. Commencing on Tuesday 6 April 2021, this service will shape the future of rail public transport in the Waikato and help reduce New Zealand’s carbon footprint.
A substantial amount of work has had to be undertaken to achieve what will be New Zealand’s first new intercity commuter service in several decades. Carriages have been refurbished in KiwiRail’s Woburn workshops, a new station has been built and existing ones refurbished. New mechanical facilities for maintenance and servicing of the trains have been built from scratch and stabling infrastructure created.
About the Speaker
David Shepherd, Programme Director – Strategic Commuter Rail, KiwiRail
David will talk about both the above works as well as the underlying business case for the service, the goals of it and the aims for the future.
With over 20 years of private and SOE commercial business management and leadership experience, David has worked in a number of industries including passenger transport, customer service, and logistics sectors. Currently Programme Manager for Commuter Rail in KiwiRail. David is working with stakeholders to deliver the first new long-distance commuter rail in New Zealand for 30 years. Previously David has managed Scenic Trains and TranzMetro, the Commuter Rail operation in Wellington New Zealand.
Register using the Engineering New Zealand link below!


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A Newport man has been arrested on suspicion of murdering a 57 year old man.
Gwent Police were called to an address at approximately 3.30pm on Monday in Brynderwen Road, in the Newport area.
On arrival, officers discovered the body of Anthony Bubbins.
Gwent Police have launched a murder inquiry.
A man from the Newport area has been located in the Devon area and has been arrested on suspicion of murder.
He currently remains in police custody and will be brought back to the Gwent Police force imminently.
Anyone with information is asked to call 101.

domain: news


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Afternoon tea is a quintessentially British affair, and Gloucestershire is overflowing with splendid venues offering some of the tastiest treats in the UK.
If you’re looking for some inspiration, we’ve rounded up 18 places to enjoy afternoon tea across the county and the Cotswolds.
Promising an indulgent afternoon filled with an array of sweet and savoury treats, Tewkesbury Park’s Posh Afternoon Tea includes a selection of sandwiches including ham and Tewkesbury mustard, smoked salmon and cream cheese, and cucumber; scones with lashings of locally made jam, and Cotteswold Dairy’s very own clotted cream; plus, there’s a selection of home made cakes available to finish the experience. If you’re celebrating something special, guests can add on a glass of Taittinger Champagne for a sparkling experience.
There are also cream teas available to enjoy with bottomless tea and coffee, perfect to tuck into in Tewkesbury Park’s opulent lounges upon comfortable and stylish seating, overlooking the golf course and stunning Cotswold hills beyond.
Country house hotel, Hatherley Manor, offers a relaxed setting for afternoon tea. Enjoy a selection of finger sandwiches, homemade cakes and fruit scones smothered in jam and cream, along with freshly brewed tea or coffee.
During the winter, guests can enjoy afternoon tea in front of the wood-burner, while the gardens are a beautiful spot over the summer months. And, if you’re looking for a gift for someone with a sweet-tooth, vouchers for afternoon tea at Hatherley Manor are ideal.
A visit to The Fairview Gardener near Gloucester isn’t just about planting as the garden centre and nursery also has a charming tea room where you can indulge in a spot of afternoon tea.
Served daily from 2pm, the afternoon tea for two invites diners to enjoy a delicious selection of sandwiches and salad, along with homemade cakes, mini scones and proper loose-leaf tea or coffee. Bookings must be made in advance.
With views overlooking Stroud Water Canal, Stonehouse Court Hotel near Stroud offers a charming setting for afternoon tea. Guests can take tea on the terrace during the summer or get cosy in the stylish surrounds of Bar 1601 cocktail lounge.
Choose from cream tea or savour afternoon tea, with the option to add a glass of Champagne for the ultimate indulgence. If you’re planning a birthday party, hen do or baby shower, the venue has private dining rooms that are ideal for afternoon tea celebrations.
Expect tables laid out with china tea sets and food served on vintage cake stands when enjoying afternoon tea at Lavender Bakehouse in Chalford. Sample delicate sandwiches, sweet and savoury scones, and a mini selection of cakes, with the option to have a glass of Prosecco too. Be sure to book in advance for afternoon tea.
Barnsley House near Cirencester offers a delightful setting for indulging in afternoon tea in elegant surroundings. Savour your cake and sandwiches with tea or coffee, along with the option of Pimm’s, a G&T, or Champagne for an extra special touch.
Afternoon tea at five-star hotel Ellenborough Park is served in the spectacular setting of the Great Hall. Expect sandwiches filled with smoked salmon and lemon crème fraiche, and ham and red onion marmalade, along with freshly baked cakes, scones with Devonshire cream and pastries.
With a roaring fire and beautiful gardens, The Painswick hotel is a delightful choice for afternoon teas, whatever the weather. Choose from sweet and savoury afternoon teas, with the option to add prosecco, Champagne or even a cocktail.
Cheltenham’s Malmaison offers a classic afternoon tea re-imagined, with diners able to savour treats such as smoked salmon bagels, egg mayonnaise sub rolls, salted caramel brownies, scones, and a seasonal fruit shake. There’s also the opportunity to indulge with Chez Mal’s Cocktail Afternoon Tea, which is perfect for special celebrations.
Retreat to the Art Deco setting of The Ivy in Cheltenham to treat yourself to a delicious afternoon tea. Diners can expect savouries delights such as truffled chicken brioche roll and smoked salmon on rye bread, while the sweet treats span raspberry cheesecake, and chocolate and salted caramel mousse.
The Lygon Arms in Broadway is the perfect place to savour a traditional afternoon tea experience, right in the Cotswolds. Diners can look forward to finger sandwiches and dainty pastries, while the hotel also offers children’s afternoon teas, and special themed ones during the school holidays.
Located in the quaint villages of Chipping Norton and Broadway, The Tea Set is perfect if you’re searching for a quintessential Cotswold afternoon tea. Tuck into homemade scones, dainty cakes and sandwiches, served on vintage china and tiered stands.
Tudor Farmhouse in the Forest of Dean offers diners the choice of classic afternoon tea, along with an afternoon grazing menu, which features a choice of sandwiches, a charcuterie board, and cream teas. The restaurant prides itself on serving home-cooked seasonal food, made from local ingredients.
Lords of the Manor Hotel offers a luxurious backdrop for enjoying afternoon tea in the Cotswolds, with full afternoon tea and cream tea available. Make sure you leave time to explore the award-winning gardens which are set over eight acres.
Nestled in a picture-perfect setting just outside of Cheltenham, Cowley Manor is a delightful choice for afternoon tea. In addition to delicate sandwiches and plain and fruit scones with clotted cream, diners can look forward to an array of cakes too. Add a glass of Champagne for the ultimate indulgence.
Soak up original architectural features and delightful Art Deco touches when enjoying afternoon at The Daffodil, a converted picture house in The Suffolks area of Cheltenham. Served on Friday and Saturday afternoons, guests can expect traditional sandwiches, tasty cakes and optional Champagne.
With tea rooms in Stow-on-the-Wold, Burford, Cheltenham Promenade and Cheltenham John Lewis & Partners, there are plenty of opportunities to sample Huffkins’ afternoon tea offering. Along with serving classic tea-time delights, there’s also Teddy Bears’ Picnic afternoon tea for children aged three and over.
The elegant lounge area at The Fish Hotel is the setting for afternoon teas at the luxury bolthole near Broadway. Along with traditional tea-time treats, the hotel offers Tipsy Tea with tea infused cocktails, and if you want to take your four-legged friend along with you, there’s also a Doggy Afternoon Tea on offer.
Thursday 01 April 2021
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domain: food


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300,000 more homes will be in fuel poverty this Christmas
Calls on Government to act as more families are facing a choice between 'heating or eating'
There will be 300,000 more households in fuel poverty this Christmas than at the same time last year, a government advisory group has revealed.
At the Fair Energy summit today, hosted by The Independent and Policy Review Intelligence, Ed Davey, the Energy Secretary, will remind energy companies about new rules which mean they will have to be more open about the reason why electricity and gas bills are increasing. He says companies are exaggerating the expense of the Government's energy efficiency measures.
His comments will follow the shocking claim from the Government's Fuel Poverty Advisory Group that 300,000 homes will be pushed into fuel poverty by Christmas. A household is considered to be in fuel poverty if it needs to spend more than 10 per cent of its income on fuel for adequate heating.
The group also warns that unless the Government tackles the problem of people being forced to choose between heating and eating, nine million households could fall into fuel poverty by 2016. It is estimated that six million households are already in fuel poverty.
Ahead of today's Fair Energy summit, Derek Lickorish, chairman of the Fuel Poverty Advisory Group, added: "With a cold winter, welfare reforms cutting incomes, and all at a time of austerity measures and other rising household costs, the plight of the fuel poor has never been more serious," he said. "Millions are living in misery due to high energy bills, yet time is running out for the Government to fuel-poverty-proof the homes of those on the lowest incomes."
Mike O'Connor, chief executive of Consumer Focus, warned: "Fuel poverty levels will rise unless determined action is taken. Six million households plan to cut back on their heating this winter due to fears about costs."
At today's summit – which brings together consumer groups and energy company bosses to thrash out solutions to the problem of rising energy prices and fuel poverty – Mr Davey will say: "Ensuring that consumers get a good deal, with affordable bills from suppliers genuinely competing for their custom, is one of my top priorities."
He will point out that wholesale energy costs make up around half of household energy bills and have been the major factor driving recent increases in consumer energy bills.
Meanwhile policy costs – the impact on consumer bills of the obligations that Government places on energy companies – account for only a small portion of bills, around seven per cent, according to the Energy Secretary.
"I am frankly fed up with commentators suggesting the Government is deliberately increasing bills, when in fact we are doing everything we can to reduce them," Mr Davey will say.
A report published today by the Institute for Public Policy Research, a think-tank, suggests that the new Energy Company Obligation (ECO) will leave two million fuel-poor households out in the cold.
The ECO will oblige energy suppliers to improve the energy-efficiency of fuel-poor homes to tackle fuel poverty and reduce carbon emissions.
The summit is being held in London today and will be broadcast live at www.independent.co.uk.
- 1 Ireland gay marriage vote: 'No' campaign appears to concede amid reports of 'yes' landslide victory
- 2 Purity balls: Girls in the US making virginity pledges as fathers vow to 'protect purity'
- 3 Picture of couple posing with beached dolphin 'that later died' causes outrage
- 4 16-year-old girl beaten and burned alive by lynch mob in Rio Bravo, Guatemala
- 5 Arsenal fan asks the Queen for tickets to the FA Cup final - gets a reply from Buckingham Palace
Ireland gay marriage vote: 'No' campaign appears to concede amid reports of 'yes' landslide victory
Maryland mother found pushing her dead child on a swing in a playground
Purity balls: Girls in the US making virginity pledges as fathers vow to 'protect purity'
Picture of couple posing with beached dolphin 'that later died' causes outrage
16-year-old girl beaten and burned alive by lynch mob in Rio Bravo, Guatemala
As a white man, I'm surprised more women aren't tweeting the hashtag #KillAllWhiteMen
Scotland may have to leave the EU even if it votes to stay in, David Cameron confirms
Report finds that Britain's wages are the most unequal in Europe
The day that Britain resigned as a global power
Almost a third of school pupils believe 'Muslims are taking over our country', study claims
Gay marriage 'Bert and Ernie' cake bakery found guilty of discrimination in Northern Ireland
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My Fair Lady au Théâtre du Châtelet...
The Sound of Music - Musical Theatre...
Christine Arand as Cecilio in Lucio...
...several created vivid impressions: Christine Arand, a fiery, statuesque soprano, as Armida - New York Times
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domain: entertainment


Day: November 24, 2015
Party-list group Agham (Alyansa ng mga Grupong Haligi ng Agham at Teknolohiya para sa Mamamayan) has commended local scientist Aisa Mijeno for her invention of a lamp powered by saline solution.
The age of autonomous vehicles is fast approaching, and city leaders need to take steps to prepare as the disruptive technology becomes a reality, according to new survey results by the World Economic Forum released on Tuesday, Nov. 24.
Built-in smart sensors automatically pause the music when you slip off the headphones, preserving battery life when they?re not being worn, then gently fading in your tunes when you put them back on.
Sen. Francis “Chiz” Escudero said the kind of service offered by PLDT at the venues of the APEC meetings in Manila proves that telcos have the capability to provide a better Internet service to subscribers.


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Cuisine traditionnelle hawaïenneCulinary
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Oahu, known as The Gathering Place, is nothing short of a foodie paradise, and in the past few years Honolulu has emerged as one of the major culinary meccas in the U.S. Stroll through foodie ’hoods like Kakaako, Kaimuki and Chinatown to discover a melting pot of trendy eateries and mom-and-pop diners dishing up local specialties like plate lunch and loco moco (white rice topped with a hamburger patty, fried egg and brown gravy). From downtown Honolulu to Waikiki, book a table at one of the iconic fine-dine restaurants that put Hawaiian cuisine on the map, including Roy’s and Chef Mavro.
If your travels take you to Kauai, assemble an epic Hawaiian-style picnic at the island’s famed sunshine markets, and treat yourself to a memorable meal at hotspots like Merriman’s or Eating House 1849. Maui’s mix of roadside food stands and gourmet restaurants is enhanced by the abundant produce grown in the island’s Kula region. The island of Hawaii offers dining choices as diverse as its landscapes; just remember to finish your meal with a cup of homegrown Kona coffee. And don’t let the smaller populations of Lanai and Molokai fool you: these deeply rooted islands serve up tons of local flavor – from pillowy doughnuts and fresh bread at Kanemitsu’s Bakery in Kaunakakai to high-end sushi from celebrity chef Nobu Matsuhisa at Nobu Lanai.
Food festivals throughout the Hawaiian Islands showcase our local food scenes. Prestigious events like the Hawaii Food & Wine Festival and Kapalua Wine & Food Festival gather top-notch chefs, sommeliers and winemakers from around Hawaii (and the world). From poi to pancakes, learn all about the “staff of life” at the East Maui Taro Festival, and sample a real Hawaiian delicacy in all its forms at the Waikiki Spam Jam. The Kona Coffee Cultural Festival is good to the last drop, while beloved events like the Maui Onion Festival, Lanai Pineapple Festival and Kauai Coconut Festival pay homage to our local crops.
Speaking of celebrated chefs, you can even dine at restaurants run by two former Top Chef contestants: Lee Anne Wong’s Koko Head Café in Honolulu and fan-favorite Sheldon Simeon’s Tin Roof in Kahului, Maui. And of course, a trip to Hawaii isn’t complete without experiencing the sensory delights of an authentic luau – nightly celebrations of our islands’ rich culture and cuisine that are nothing short of ono (delicious).
Explore Restaurants by Island
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Let Hawaii Forest & Trail show you an authentic Oahu, utilizing our unparalleled land access and interpretive guiding approach to provoke authentic place-based experiences that illuminate the island’s unique regions through in-depth interactions with our nature and culture. Our Hawaii Oahu tours offer a different perspective.
Dinner at Manta is an occasion every night with a dynamic exhibition kitchen to showcase farm-fresh deliciousness with bold flavors to match stunning sunset and ocean views along with our 48-bottle wine selection via the Enomatic wine tasting experience.
Hali‘imaile General Store is Chef Bev Gannon’s original and most acclaimed restaurant featuring eclectic American food with Asian overtones, the essence of modern Hawaii food. Founded in 1988, “The Store” has been a Maui destination for both visitors and locals.
Take a Fun Filled Wagon Ride through one of Oahu's most Beautiful Farms and learn about the history, people and crops of this special place! Visit our Farm Café for Fine Country Gifts, Fresh Island Fruit and Tasty Treats from our Fields!
Kahi Ola Mau Farm is the home of Honoka'a Chocolate Co. Located just mauka of the historic plantation town of Honoka'a, we offer farm tours and tastings of the small-batch artisan chocolates that we make on-site in our farm store, made from cacao beans from around the globe, including Hawaii.


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WHO Approved, Sinopharm Vaccine Made In China Can Enter Covax
UMMATIMES - The World Health Organization (WHO) approved the Sinopharm vaccine from China for emergency use.
The agreement allows the Sinopharm vaccine to enter Covax. "This expands the list of Covid 19 vaccines that Covax can buy," said WHO Director General Tedros Adhanom Ghebreyesus, quoted by ABC News, Saturday (8/5).
To note, WHO has provided emergency approval for the COVID-19 vaccine developed by Pfizer-BioNTech, AstraZeneca, Johnson & Johnson, and Moderna.
The decision to approve the Sinopharm vaccine was taken by a WHO technical advisory group that began meeting on April 26, 2021 to review the latest clinical data as well as Sinopharm's manufacturing practices.
Tedros said that after Sinopharm was approved, the Expert Strategic Advisory Group (SAGE) recommended that adults over 18 receive two doses of Sinopharm vaccine.
SAGE found a 78.1 percent efficacy after examining two doses in a phase 3 clinical trial.
Previously, the Beijing Biological Products Institute, which developed the Sinopharm vaccine, has announced that its efficacy has reached 79.34 percent.
According to an ABC News report, China has deployed about 65 million doses of Sinopharm vaccine and more than 200 million doses of Sinovac injections.
Both of them have been exported to many countries, especially in Latin America, Asia and Africa.

domain: medical


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Lysosomes are membrane-bound oribelles with roles in processes affiliated in degrading and also recycling to move waste, cellular signalling and energy metabolism. Defects in gene encoding lysosomal proteins cause lysosomal storage disorders, in i beg your pardon enzyme replacement therapy has proved successful. Cultivation evidence likewise implicates duties for lysosomal dysfunction in much more common illness including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and also metabolic disorders. V a emphasis on lysosomal dysfunction in autoimmune disorders and neurodegenerative conditions — consisting of lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer condition and Parkinson condition — this review critically analyses progress and also opportunities for therapeutically targeting lysosomal proteins and also processes, specifically with tiny molecules and peptide drugs.
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Discovered in the 1950s by Christian de Duve, lysosomes room membrane-bound engine containing many hydrolytic enzymes the can breakdown biological polymers such as proteins, lipids, nucleic acids and also polysaccharides1,2. Lysosomes have long been recognized to have actually a an essential role in the degradation and recycling the extracellular material via endocytosis and also phagocytosis, and intracellular material via autophagy (reviewed elsewhere2,3,4,5) (Fig. 1). The commodities of lysosomal degradation through this processes can be trafficked come the Golgi apparatus because that reuse or for release from the cell through lysosomal exocytosis, i m sorry is crucial in immune device processes. In addition, the has come to be clear more recently the lysosomes have critical role in other cellular processes including nutrient sensing and also the manage of power metabolism3,5,6,7 (Fig. 1).
a | functional lysosomes are connected in the deterioration (endocytic and also autophagic) and regulation that exogenous and endogenous to move material, including recycling processes. Extracellular product endocytosed by the endosomes and also intracellular cargo internalized by the autophagosomes fuse v lysosomes because that degradation, i beg your pardon produces power (ATP production) and source molecules because that the macromolecules. Mechanistic target of rapamycin complex 1 (mTORC1) plays a key role in lysosomal nutrient sensing signal (lysosome-to-nucleus axis) come regulate energy metabolism. Factors such as energy levels, type of pH, ion channel regulation and others decision the fate of the catabolic process. Throughout lysosomal exocytosis, the lysosomal content favours plasma membrane (PM) repair, bone resorption, immune solution and removed of pathogenic stores. b | The lysosome is the ultimate cabinet compartment that digests unwanted protein materials generated by macroautophagy, microautophagy (pathways during which the cytoplasmic product is trapped in the lysosome through a process of membrane invagination) and also chaperone-mediated autophagy (CMA). In general, lipid droplets (LDs) space degraded by lipophagy, a subtype the macroautophagy, which is set off by cytosolic lipases. CMA has also been prove to get involved in the deterioration of LDs in i m sorry perilipin (PLIN2/3) proteins room phosphorylated (P) through AMP-activated protein kinase (AMPK) v the aid of the HSPA8 chaperone. Mechanistic target that rapamycin complex 2 (mTORC2) and AKT (also recognized as protein kinase B) are an adverse regulators the CMA, wherein they exert their impact on the translocation complex of CMA. In situations of starvation, an adverse regulators are controlled by pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP). Lysosomal stability results the transcription element EB (TFEB) translation come the cell core in i beg your pardon TFEB binds to the combination lysosomal expression and also regulation (CLEAR) motifs to regulate the warrior of genes. EF1a, elongation aspect 1a; Lys, lysosome; Rac1, Ras-related C3 botulinum toxin substrate 1.
Alterations in lysosomal functions, one of two people in the combination processes involved in the basic pathways mentioned above or concerned the duty of lysosomal enzymes and non-enzymatic proteins, can an outcome in large detrimental effects, consisting of failure come clear perhaps toxic cellular waste, inflammation, apoptosis and dysregulation of moving signalling8. Such defects have actually been implicated in many diseases, varying from rarely lysosomal storage obstacle (LSDs), i m sorry are resulted in by the dysfunction of particular lysosomal proteins, to more common autoimmune and also neurodegenerative disorders5,9,10. Regardless of some limitations, superior results have actually been completed in treating number of LSDs through enzyme replacement therapy (ERT). In addition, an extensive efforts have been focused on therapeutically targeting the autophagy processes upstream the lysosomes11,12,13,14. However, there has so far been much less attention on investigate the potential to directly target lysosomes with small molecules and also peptide drugs.
Nevertheless, with recent advances in understanding of lysosomal function and dysfunction in diseases, promising novel avenues for therapeutic treatment through targeting lysosomes specifically are beginning to emerge. This evaluation will provide a short overview the lysosomal biogenesis, structure and function, and describe the duty of lysosomal dysfunction in LSDs and other, more common diseases. Specifically, the article will emphasis on organ-specific and also non-organ-specific autoimmune diseases, including lupus, rheumatoid arthritis (RA) and also multiple sclerosis (MS), as these have not been broadly reviewed elsewhere, however will also briefly highlight neurodegenerative disorders such as Alzheimer disease (AD) and Parkinson condition (PD), to further illustrate the breadth and also inter-base.net of the arising therapeutic opportunities. The existing ‘toolbox’ that pharmacological agents the modulate lysosomal functions and emerging novel targets and strategies in this collection of indications will be highlighted. It should be detailed that therapeutic viewpoints to treat inflammatory and autoimmune conditions aim come inhibit the deleterious too much lysosomal activity, whereas lysosomal activation would be the score in the treatment of neurodegenerative diseases. Although beyond the limit of this review, such viewpoints may have applications in other diseases in which lysosomes might play a role, including cancer, metabolic diseases and also ageing (reviewed elsewhere15,16).
The development of mature lysosomes is a complex process, which requires the fusion of late endosomes the contain product taken up in ~ the cell surface ar with transport vesicles that bud native the trans-Golgi network5,8,17. This vesicles contain virtually 60 different hydrolytic enzyme (grouped right into nucleases, proteases, phosphatases, lipases, sulfatases and others), which room synthesized in the endoplasmic reticulum and also delivered come the carry vesicles via diverse systems, such together mannose-6-phosphate tags that are known by mannose-6-phosphate receptors (MPRs) in ~ the membrane8,18 or glucocerebrosidase (GCase) that is transported to lysosomes by lysosomal integral membrane protein-2, an ubiquitously expressed type III transmembrane glycoprotein largely located in endosomes and lysosomes19.
Mature lysosomes have an acidic inner pH, in ~ which the lysosomal hydrolases space active, and a lining well-known as a glycocalyx the protects the internal lysosomal perimeter from the acidic atmosphere of the lumen5,8,20. This acidic setting is kept through the task of a vacuolar-type proton adenosene triphosphatase (v-ATPase), which harnesses energy from hydrolysing ATP to drive the translocation the protons through a V0 membrane domain (reviewed elsewhere5,21). Other an essential lysosomal proteins include structural protein such as lysosome-associated membrane protein 1 (LAMP1); proteins associated in trafficking and also fusion, such together soluble N-ethylmaleimide-sensitive element attachment protein receptors (SNAREs) and also RAB GTPases; transporters such together LAMP2A, which has actually a crucial role in chaperone-mediated autophagy (CMA); and ion networks such as the chloride channel ClC7 and also the cation channel mucolipin 1, a member of the transient receptor potential (TRP) family members that is likewise known as TRPML1 (refs22,23). Most of the proteins are ceded through the clathrin adaptor protein 3-alkaline phosphatase (ALP) pathway, yet some proteins space translocated through the lysosome-associated-protein transmembrane-5, a protein the is preferentially expressed in immune cells3,24.
Although the ide still stays controversial, 2 lysosome types — traditional or secretory — are regularly distinguished based on their physical, biochemical and also functional properties. Catabolism is the main role of standard lysosomes, and several various other lysosome-related oribel (LROs), such as melanosomes, the so late endosomal major histocompatibility facility class II (MHCII) compartment (MIIC), revolt granules from neutrophils, eosinophils, basophils, mast cells, CD8+ T cells and platelets, complement these functions8,25,26,27,28,29. Many of the LROs plot as professional secretory organelles. LROs share v lysosomes the bulk of typical attributes (acidic environment, lysosomal transmembrane proteins, combination property to phagosomes and also others), in enhancement to specific properties result from their specific cargoes (for example, melanosomes save melanosome-specific transmembrane glycoprotein, and natural killer cells and also CD8+ T cell contain perforins and granzymes). The comprehensive mechanisms the biogenesis and secretion that LROs continue to be unclear, although it is well-known that hereditary defects in LROs are affiliated in rarely autosomal recessive disorders characterized by lessened pigmentation, such as Chediak–Higashi disease and Hermansky–Pudlak syndrome30. Secretory lysosomes contain many much more proteins in addition to those consisted of in typical lysosomes, and also they take part in lot of cell features such as plasma membrane repair, tissue and also bone regeneration, apoptotic cell death, cholesterol homeostasis, virus defence and also cell signalling8.
Lysosomal biogenesis and function are regulation by the straightforward helix–loop–helix leucine zipper transcription factor EB (TFEB) and also the coordinated lysosomal expression and regulation (CLEAR) network4,31,32 (Fig. 2). Because that example, autophagy, a critical process in immunity and autoimmunity33, is transcriptionally regulation by TFEB31. Interestingly, lysosomal exocytosis, i beg your pardon is important in numerous immune functions, also depends on TFEB activation31,32. Moreover, it has been demonstrated the TFEB orchestrates lysosomal Ca2+ signalling34. The fact that many lysosomal procedures are dependence on TFEB activation strengthens its duty as a master regulator in lysosomal functions. Like various other transcription factors, TFEB undergoes phosphorylation and dephosphorylation via various cytosolic and also lysosomal pathways (Fig. 2), processes regulated by mechanistic target that rapamycin complex 1 (mTORC1), a understand controller of cabinet growth35,36.
After your synthesis in the unstable endoplasmic reticulum (RER), the substrates (cargo) that room intended to be degraded with the endo-lysosomal pathway room transported come lysosomes via the trans-Golgi network (TGN). Amongst the crucial enzymatic systems that are involved in the lysosomal enzyme transportation of cargos native Golgi come lysosomes, the finest studied is the mannose-6-phosphate (M6P) receptor (MPR) system, i beg your pardon binds recently synthesized lysosomal hydrolases in the TGN and also delivers them to pre-lysosomal compartments. A couple of components synthesized in the so late Golgi compartment are yielded directly to lysosomes via the 3-alkaline phosphatase (ALP) pathway. Lysosomal components, such as enzymes (lytic enzymes and also kinases), membrane-bound proteins/complexes (mechanistic target the rapamycin (mTOR)), transporters and ion channels (vacuolar-type proton adenosene triphosphatase (v-ATPase), TRPML1 and osteopetrosis linked transmembrane protein 1 (Ostm1)) and chaperone-mediated transportation space the best-known targeting sites for lysosomal dysfunction. As shown in the figure, numerous pharmacological antagonists and also agonists exert tasks that possibly correct lysosomal dysfunction and therefore represent potential efficient pharmacological tools. CLEAR, coordinated lysosomal expression and regulation; CQ, chloroquine; HCQ, hydroxychloroquine; mTORC1, mTOR facility 1; PtdIns(3,5)P2, phosphatidylinositol-3,5-bisphosphate; RAPTOR, regulatory-associated protein the mTOR; SER, smooth absorbent reticulum; TFEB, transcription aspect EB.
Lysosomes space at the crossroads of various degradative pathways, consisting of endocytosis (phagocytosis) and autophagy (Fig. 1). Three main creates of autophagy have been described: macroautophagy (the most broadly characterized form), microautophagy and also CMA. At the initiation of macroautophagy, a double-membrane sequestering compartment termed the phagophore, which has cytoplasmic material, is formed and also matures right into a vesicle called the autophagosome. The cargo is degraded right into vacuoles issued native the blend of autophagic vesicles and lysosomes (called autolysosomes), and the resulting quick products space released ago into the cytosol because that reuse or, follow to sometimes contested observations, maybe dispatched into the MIIC for ultimate processing and MHCII molecule loading for presentation come CD4+ T cells37,38. In contrast to macroautophagy, microautophagy is defined by direct lysosomal engulfment that cytosolic material into lysosomes, via the development of characteristics invaginations that the lysosomal membrane. The third major kind of autophagy is CMA, which requires the recognition of substrate protein containing a KFERQ-like motif through a HSPA8/HSC70-containing complicated (Fig. 1b). In CMA, 2 proteins have a key role: HSPA8 guarantee the selectivity that proteins, which will certainly be degraded via the CMA pathway; and also LAMP2A translocates the targeted cytosolic proteins throughout the lysosomal membrane (reviewed elsewhere7). The terminal step of autophagy is called autophagic lysosome reformation, in i m sorry tubular proto-lysosomes room extruded from autolysosomes (containing lysosomal membrane components) and mature right into functional lysosomes39. This step is not exclusively a lysosomal biogenesis process; it also includes a collection of elements that are tightly correlated with the regulation the autophagy40.
In combination with autophagy, lyosome are involved in both innate and adaptive immune functions, including international material acknowledgment (bacterial, parasitic and also viral), activation of pattern recognition receptors (such together Toll-like receptors (TLRs) and also nucleotide oligomerization domain-like receptor), antigen processing and presentation, especially in the paper definition of MHCII molecules, T cabinet homeostasis, antibody production and also induction of assorted immune signals (co-stimulation and cytokine secretion)41. As well as being a degradative organelle, the lysosome has recently been recognized as a to move signalling platform3,42. That plays an important role in nutrient sensing v mTORC1 and other added protein complexes, or the so-called ‘lysosome nutrient sensing machinery’. The discovery of a stress-induced lysosome-to-nucleus signalling mechanism through TFEB further supports the vital role of lyosome in to move signalling36.
The lysosome rectal a main position in the maintenance of to move homeostasis, being associated in the exemption of infectious agents native penetrating organize tissue and concomitantly cultivating immune regulation. Lysosomes must because of this be able to respond quickly, with raised or decreased functions, to miscellaneous metabolic problems aimed in ~ protecting cells from death or damage. Lysosomes are an extremely diverse in size and also shape. For factors that space not totally understood — possibly according to their place in the cytosol43 and/or their composition — part lysosomes in a solitary cell are much more prone to act and defend cells. Given the wide range of attributes of lyosoms in all metabolic compartments that the cell, any kind of dysregulation the their activity could lead to the impairment of various elements of the cellular metabolic machine (including the transport and biogenesis of street (glycolysis), lipids, proteins and nucleic acids) and of metabolic pathways, phagocytosis, endocytosis and autophagy. Although the basic mechanisms are much from being totally deciphered, it has actually been seen that lysosomal dysfunction or defects in blend with engine containing cargo are generally observed abnormalities in proteinopathic neurodegenerative diseases. Dysfunctions of lysosomes can impact the proper task of various other organelles such together peroxisomes and also mitochondria, leading to extreme production that reactive oxygen varieties with pathological features linked with ageing, cancer, chronic inflammation, neurological diseases, masculine infertility and infections.
Such dysregulation is thus central to LSDs, and also implicated in a wide selection of other disorders, consisting of autoimmune and also neurological disorders, in which the autophagy–lysosomal network under the manage of TFEB has actually attracted considerable attention.
Lysosomal storage disorders
LSDs room a heterogeneous group of about 50 inherited metabolic disorders, which have actually an incidence the ~1 in 5,000 live births44. These disorders and also their treatment have actually been reviewed generally elsewhere45,46, and so will only be covered relatively briefly here. The mutations responsible for many LSDs have actually been greatly elucidated (Tables 1,2), and many result in the dysfunction that a details lysosomal hydrolase, causing the build-up of the substrate of the hydrolase. For example, in Gaucher disease, the sphingolipid glucocerebroside accumulation in cell (particularly macrophages) and organs, consisting of the liver and spleen, owing to deficiency in the enzyme GCase24,66. In particular LSDs, the resultant pathology have the right to be explained by the inter-base.net of molecules that accumulate (Tables 1,2). Thus, the variety of cerebrosides and gangliosides the deposit in the central nervous mechanism (CNS) that patients v sphingolipid warehouse disorders, together as form II (acute infantile neuronopathic) Gaucher disease, underlies the significant neurological symptom of together disorders67,68. In patients through Pompe disease, which is brought about by α-glucosidase deficiency, the high level of non-degraded glycogen that accumulate in muscles could explain the it was observed myopathy69,70. However, how the undegraded material accumulates and causes the it was observed cellular and organ pathology in numerous other LSDs remains unclear.
The accumulation of such undigested macromolecules or monomers in LSDs instigates the development of secondary products, which at some point escape native the endosomal–autophagic–lysosomal pathways9,71 and also lead to multiple results that affect most organs, including the brain, liver, spleen, heart, eyes, muscles and bone (Table 2). Most, if no all, organelles are changed in LSDs, including endosomes, autophagosomes and also lysosomes, and their features in lysosomal formation/reformation and blend of endosomes or autophagosomes come lysosomes space abnormal. Alterations in numerous autophagy procedures have also been explained in LSDs. Thus, deregulated mitophagy, which outcomes in the build-up of damaged mitochondria, wake up in LSDs, leading to major inflammatory aftermath in details tissues67,72. Perturbations in mitochondrial dynamics are typically observed, which have actually been attached to the enhanced production that reactive oxygen species, ATP production and also Ca2+ imbalance. In LSDs, diminished macroautophagy task (with a decreased autophagic flux) fairly than hyperactive autophagy processes, as watched in countless autoimmune diseases, seems to be responsible because that the accumulation of non-degraded cytoplasmic proteins such as α-synuclein, huntingtin (HTT) and others73. Mucolipidosis kind IV (Table 2), a disease characterized by major neurological and ophthalmological abnormalities, is led to by mutations in the MCOLN1 gene and also is inherited in one autosomal recessive manner. This gene encodes a non-selective cation channel, mucolipin 1, which has recently been displayed to be forced for efficient blend of both so late endosomes and autophagosomes with lysosomes74,75. Impaired autophagosome degradation results in the build-up of autophagosomes in LSDs76. Microautophagy procedures that execute not involve de novo synthetic of nascent vacuoles additionally appear to be impaired in LSDs, and also were notably revealed in main myoblasts indigenous patients v the muscle-wasting problem Pompe disease77. Finally, defective CMA components, such as LAMP2A, could additionally lead to lysosomal dysfunction. For example, mutations in the LAMP2 gene have been asserted to reason Danon disease (inherited in an X-linked dominant pattern)51. Additional investigations are essential to assistance this assertion.
Lysosomes are affiliated in pathways main to the immune system, including the destruction of intracellular and also extracellular material, plasma membrane repair, cell death signalling, cabinet homeostasis and also death. Although the straight involvement of lysosomes in immunity is far from totally understood, it has long been supposed that lysosome dysfunction will have actually a significant impact in immune conditions (Table 2). Strikingly, however, this field has no been broadly explored. However, elevated levels of lysosomal enzyme task have been reported to occur in several autoimmune diseases, such together RA, systemic lupus erythematosus (SLE), dermatomyositis and psoriasis3,14,17,18,20,21,22,23.
As discussed, autophagosomes formed throughout the autophagy process must fuse v lysosomes to create peptide epitopes for further processing, clear perhaps deleterious apoptotic debris, fuel the amino mountain pool and also produce energy (Fig. 1). Any deviation in this facility processing will certainly affect an essential immune cabinet functions, such together the control of cytokine release, autoimmune cabinet anergy and also programmed cell fatality of kind I (apoptosis) and kind II (autophagy). Secretory lysosomes regulate the release of both pro-inflammatory and also anti-inflammatory cytokines, in a process that is dependence on the type of stimulation. In addition, lysosomes degrade glucocorticoid receptors, which are necessary to tie glucocorticoids, return the reasons are not known78. In this facility system, lyosoms execute anti-inflammatory action via the phospholipase A2 and cyclooxygenase-2 pathways, and also induce inflammation through the IL-1β–caspase-1 pathway. In both conditions (pro-inflammatory and also anti-inflammatory), lysosomes act together indirect precursors for autoimmunity. However, induction and suppression of inflammatory signals room stimulus dependent78.
Lysosomal cathepsins have actually a main role in degrading organic macromolecules in the lysosomes and also in the immune response. Over there are about 12 members in this big protease family, most of which room endopeptidases that can cleave peptide bond of their protein substrates79,80. Cathepsins A and also G space serine proteases, cathepsins D and also E room aspartic proteases and also cathepsins B, C, F, H, K, L, O, S, V, X and W are cysteine proteases. For example, cathepsin S is responsible for the deterioration of antigens (and autoantigens) in antigen-presenting cells (dendritic cells, macrophages and also B cells), and also is because of this involved at an upstream level in the presentation that MHCII–(auto)antigenic peptide complexes come CD4+ T cells81. Cathepsin together preferentially cleaves peptide binding with aromatic residues in the P2 position and also hydrophobic residual water in the P3 position. That is central in antigen processing, bone resorption, tumour invasion and metastasis, and turnover that intracellular and also secreted proteins involved in growth regulation. Cathepsin L-deficient mice display less adipose tissue, reduced serum glucose and also insulin levels, much more insulin receptor subunits, an ext glucose transporter form 4 and more fibronectin than wild-type controls82. Cathepsin G is primarily well-known for its role in killing and also digestion that engulfed pathogens83. That is likewise involved in connective organization remodelling in ~ sites the inflammation84. Anti-neutrophil cytoplasmic antibodies reacting through cathepsin G have actually been identified in some patients v SLE85.
Abnormal antigen processing and presentation is recognized to be among the upstream events that perturb immune responses in SLE86. Due to the fact that this procedure is mediated with lysosomes, it was rational to speculate that lysosomal functions might be transformed in lupus. Interestingly, hypotheses were elevated in the 1960s ~ above the ‘lysosomal fragility’ in lupus, but without much more pursuit87. The composition and fluidity the the lysosomal membrane room effectively crucial in the regulation that lysosomal combination with other vesicular organelles and also for lysosomal absorb of macromolecules. The integrity of the lysosomal membrane additionally ensures the avoidance of relax of lysosomal enzymes right into the cytoplasm. Some lysosomal enzymes released indigenous ‘fragile’ lysosomes to be regarded potentially harmful in lupus88.
Lysosomes space abnormal in splenic B cells from Fas-deficient Murphy Roths large (MRL)/lpr mice, a mouse design of lupus, contrasted with B cells from healthy CBA/J mice89. TFEB expression was increased, describe an amplified biogenesis of lysosomes, and the lysosomal volume was raised. The expression level of LAMP1 and cathepsin D were additionally increased. These outcomes reinforce ahead data reflecting that the expression and task of some lysosomal enzyme (such together cathepsins S, L and B) that play essential roles in antigen handling are altered in lupus and other autoimmune diseases90,91.
Substantial sports of the acidic endo-lysosomal pH also occur in MRL/lpr mice, being elevated by 2 pH devices in splenic B cells53,92. This pH readjust could dramatically influence the task of soluble lysosomal hydrolases (such together cathepsins) and also lysosomal membrane proteins (such as LAMPs) the are crucial for lysosome activity. PH may also impact the elimination of immune complexes that accumulate in lupus together a result of deficits in complement, lower expression the scavenger receptors, increased expression that Fcγ receptors and other reasons93. This immune complexes, i m sorry contain non-selective IgG antitoxin or autoantibodies connected with autoantigen (including some apoptotic debris), deserve to initiate inflammation that tissues as soon as deposited (for example, in the kidneys and the skin) and also generate a cascade of deleterious effects, such as the release of harmful cytokines and chemokines54.
Recent studies have actually highlighted the crucial role the mammalian target of rapamycin facility 2 (mTORC2) in the disruption of lysosome acidification the occurs in this process94. In common conditions, the regulation that lysosomal acidification calls for cleavage the the RAB tiny GTPase RAB39a, occurring on the surface of phagocytic vesicles by locally activated caspase-194. This finely regulated procedure requires the association of cofilin with actin that surrounds the vesicle and recruits caspase-11, which then activates caspase-1 (ref.94). In lupus-prone macrophages, chronically active mTORC2 enhances cofilin phosphorylation, in order to hampering that association through actin and affecting the downstream cascade of events leading come the proper acidification the lysosomes94. The prominence of mTORC1 and also mTORC2 has been established earlier in lupus T cells, and in particular, in this context, mTORC1 task was increased whereas mTORC2 task was reduced95.
In addition, lysosomal cathepsin K was seen to add to the pathological occasions that build in Faslpr mice, one more model that lupus disease, in component through its task in TLR-7 proteolytic processing and also subsequent impacts on regulatory T cells. Cathepsin K-deficiency in Faslpr mice reduced all kidney pathological manifestations (glomerulus and also tubulointerstitial scores, glomerulus match C3 portion and IgG deposition, chemokine expression and also macrophage infiltration) and decreased the levels of potentially pathogenic serum autoantibodies96.
In line with these internal alterations the lysosomes, significantly those regarded cathepsin functioning, deregulation the autophagy has been report to contribute to lupus pathology92,97,98,99,100. Autophagy failures have been described in the lymphocytes of MRL/lpr mice and (NZBxNZW)F1 mice56,92,97,101 (two voluntarily murine models of systemic autoimmunity of distinct genetic origins and also that display various MHC haplotypes) and in T and also B lymphocytes that patients v SLE97,98,100. Murine and also human T cell from the peripheral blood proved a far-ranging accumulation of autophagic vacuoles compared with normal97. The underlying reasons for the dysfunctions in autophagy observed in lupus are not plainly understood, but several independent investigations have identified risk loci extending autophagy-linked gene in patients through lupus102,103,104,105,106.
Recent studies have demonstrated an increase in the level that macroautophagy in salient gland T lymphocytes and in tears and also conjunctival epithelial cells of patient with primary Sjögren’s syndrome (SjS)107,108. Change of CMA activity was also recently found to happen in the outstanding glands that MRL/lpr mice that build a secondary SjS-like disease56. Lysosomes, which as questioned are mechanistically involved at the downstream level that both macroautophagy and CMA, were discovered to be transformed in salivary glands. Flow cytometry analyses revealed that the mean pH of acidic engine in MRL/lpr salivary glands to be significantly greater compared through those in mouse manage glands and the ATP content was substantially diminished in MRL/lpr outstanding gland cells56. Furthermore, quantities of several leukocyte glycosidases and also proteases to be revealed to be enhanced in leukocytes of patients with SjS in compare with healthy controls55. Notably, elevated levels of the lysosomal enzyme glucosidase, β-glucuronidase and also dipeptidyl peptidase i are affiliated in the organization injury in SjS55. Enhanced expression of lacrimal gland cathepsin S was additionally reported, i m sorry may have actually application as a diagnostic tool in SjS91. Two members the the RAS oncogene family, RAB3D and also RAB27, were found to be implicated in the regulation the cathepsin S secretion levels in SjS109. In vitro researches on lacrimal gland acinar cells suggested further that secreted IFNγ native acinar cells rises cathepsin S expression and also that IFNγ engendered the MHCII-mediated antigen presentation in ocular pathogenesis that SjS110.
Lysosomal cathepsins have crucial roles in the induction and diagnosis the RA, and levels of several cathepsins (B, D, G, K, L and S) that are present in the serum and synovial fluid of patients have been proposed as a basis for RA diagnosis111,112,113,114,115,116. Cathepsin S and also cathepsin l are very expressed in synovial macrophages and also thymic cortical cells. They every exert important roles in the positive selection of T cells and antigen presentation, respectively, and participate in the local inflammation and matrix degradation that wake up in joints116. Cathepsin B is associated in collagen degradation, which leader to joint devastation in RA112,117. Expression that cathepsin G, which participates in share inflammation v its chemoattractant activity, has actually been presented to be increased in the synovial liquid of patients with RA when compared with individuals with osteoarthritis115. Autoantibodies reacting v cathepsin G were likewise identified in patients v RA85. Contrasted with patients through osteoarthritis, cathepsin K expression was discovered to be elevated in RA113, and genetic deletion the this specific cathepsin was displayed to minimize inflammation and bone erosion in RA conditions via TLR mediation118.
Neurological autoimmune diseases
MS, myasthenia gravis, Guillain–Barré syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), neuromyelitis optica and also neuropsychiatric lupus are neurological diseases induced by abnormal autoimmunity62,119,120,121,122,123. Neurological autoimmunity versus various proteins, such together myelin in ms or N-methyl-d-aspartate receptor in neuropsychiatric lupus62,123,124, can impact various structures within the CNS and peripheral worried system, with diverse consequences. Although the exact cause of amyotrophic lateral sclerosis (ALS) still stays unknown, research studies support the presence of autoimmune mechanisms, and ALS is therefore likewise included in this section. Indeed, autoantibodies versus ganglioside GM1 and also GD1a, sulfoglucuronylparagloboside, neurofilament proteins, FAS/CD95 and voltage-gated Ca2+ networks have every been report in patients v ALS (reviewed elsewhere125).
In general, the origin of the failure in immune tolerance that occurs in this collection of neurological diseases is not known. Just recently have actually investigations found that autophagy processes are altered in several of these diseases59,62,126,127,128,129,130. In MS and in experimental autoimmune encephalomyelitis, an experimental model the MS, upregulation of the protein kinase mTOR has been described, and treatment through rapamycin/sirolimus (an immunosuppressant the inhibits mTOR and also consequently stimulates macroautophagy) ameliorates part clinical and histological signs of the disease131. Raised levels the macroautophagy markers to be measured in the blood and brain of patients v MS122,132. However, impaired macroautophagy was uncovered in the spinal cord of experimental autoimmune encephalomyelitis mice133. In a rat version mimicking human being CIDP, both macroautophagy and CMA procedures were found to it is in hyperactivated in lymphatic device cells and also non-neuronal cells (sciatic nerves) that peripheral nervous mechanism cells59. In ALS, current data are conflicted62. Some data indicate an activation that macroautophagy procedures with an accumulation of autophagosomes in brain tissues that patients v ALS, or rise of autophagic vacuoles, aggregated ubiquitin and also SOD1 proteins associated with MAP1LC3B-II in engine neurons that mice emerging an ALS-like disease134,135. In contrast, other data imply a reduction of autophagy activity136,137. Mutations in SQSTM1, valosin-containing protein, dynactin (a protein complicated that activates the dynein engine protein, enabling intracellular transport) and RAB7 (a member of small GTPases that is crucial in the procedure of endosomes and also autophagosomes maturation) have additionally been described in ALS138,139,140,141. More studies are compelled to far better understand the type and extent of autophagy dysfunction in this family members of facility diseases.
There are just a few published studies on lysosomal dysfunction in neurological autoimmune conditions (Table 2). These notably incorporate lysosome fragility, which to be observed in patients v MS in the white issue of cerebral tissue, an area of the CNS the is mainly consisted of of myelinated axons142. Lysosome fragility was additionally suspected in SLE (see above) and also other rheumatic autoimmune diseases, albeit in other organs53,58,92. As detailed above, far-ranging variations in lysosomal pH have been measured in autoimmune conditions such together lupus and SjS, but to our understanding such studies performed in the brain or aspects of the peripheral nervous mechanism of patients or pet models v neurological autoimmune diseases have not been published78.
In CIDP, it has actually been presented that Schwann cells dedifferentiate right into immature states and that this dedifferentiated cells activate lysosomal and proteasomal protein deterioration systems143,144. Based upon these observations, Schwann cells have actually been declared to actively participate in demyelinating procedures via this dedifferentiation process, yet the mechanism involved remains undefined145. In the rat design of CIDP mentioned above, it was presented that LAMP2A expression was substantially increased in the sciatic nerve macrophages and reduced macroautophagy to be observed in Schwann cells and macrophages59.
In MS, studies conducted on white issue demonstrated the lysosomes are affiliated in myelin sheath degeneration and in the fragmentised protein formation. Lysosomal ede was observed close to the degenerated products of astrocytes146, and also an build-up of lipids to be found60. It has actually been hypothesized that lysosomal swelling/permeabilization might cause the release of hydrolases in the cytosol, where they affect native proteins147.
In ALS, patients also show dysfunctions in the endo/lysosomal pathways, which influence both lower and also upper motor neurons (Table 2). Cathepsin B was particularly found come be affiliated in the motor neuron degeneration, whereas cathepsins H, L and also D to be not considerably affected148. A cDNA microarray analysis on post-mortem spinal cord specimens of four sporadic patients with ALS revealed major changes in the expression that mRNA in 60 genes including increased expression that cathepsins B and D149. Number of disease-causing mutations in genes pertained to autophagy have actually been identified, such together SOD1, TDP643, FUS, UBQLN2, OPTN, SQSTM1 and C9orf72 (refs61,150), however none the them password for lysosomal proteins. So, a an important remaining issue is to plainly determine whether the lysosomal abnormalities that room observed are linked to intrinsic defaults of lyosoms or an outcome from upstream dysregulation in autophagosome formation and also fusion61,62,151.
Insufficient clearance the neurotoxic protein by the autophagy–lysosomal network has been implicated in plenty of neurodegenerative disorders152. In disorders such as AD, Huntington condition (HD) and also PD, amendment or misfolded protein abnormally accumulate in specific regions of the brain. Buildup of aggregated protein is additionally seen in ALS (see above). These abnormal proteins type deposits in intracellular inclusions or extracellular aggregates, which are characteristic because that each disease153,154,155. Although there has actually been an extensive research in this field, it is quiet unclear why innovative ‘quality-control’ systems, such as the lysosome–autophagosome mechanism in particular, fail in details circumstances to protect the brain against such protein accumulation156.
In AD, one of the most common neurodegenerative disorders, some alterations in the endo/lysosomal pathways have been described (reviewed elsewhere157,158). The amyloid precursor protein (APP) is cleaved through β- and also γ-secretases into amyloid-β peptide (Aβ) fragments, specifically Aβ40 and Aβ42 (ref.159). These fragments are found in the amyloid plaques that are one of the hallmarks of ad (the various other being neurofibrillary tangles include phosphorylated tau), and have been widely considered to have an essential role in ad pathogenesis159,160. Cell-based experiments have actually demonstrated the lysosomal cathepsins have actually a role in the generation of Aβ peptides (through cathepsins D and also E) and also the destruction of Aβ peptides (by cathepsin B)161. Lysosomal dysfunction has actually been it was observed in patients with AD162,163, and build-up of the Aβ42 fragment in neuronal cell was displayed to bring about lysosomal membrane alterations, which cause neuronal cell death63. In this context, that is remarkable that inhibition of cathepsin D, i m sorry is affiliated in the lysosomal dysfunction and notably in the cleavage the the tau protein into tangle-like fragments, diminishes that hyperphosphorylation in the mind of patients through AD164. In addition, patient with advertisement with an inherited kind of the disease may bring mutations in the presenilin proteins (PSEN1 and PSEN2), application or apolipoprotein E, resulting in increased production the the longer form of the Aβ fragment (reviewed elsewhere165). Mutation the PSEN1, because that instance, leader to straight disruption that the lysosomal acidification as result of impaired delivery of the V0A1 subunit that v-ATPase, a proton pump responsible for controlling the intracellular and extracellular pH that cells. The acidification deficit reasons excessive release of lysosomal Ca2+ through TRPML1 channels, which has many deleterious effects166. This findings strongly assistance the hypothesis that dysfunction the endo/lysosomal pathways is pivotal in AD.
Approximately 15% that patients v PD have a family background of the disorder, back the underlying molecule mechanisms remain unclear. In the paper definition of lysosomal dysfunction, the is remarkable that the most usual of the known PD genetic mutations space in GBA1 (encoding the lysosomal β-GCAse) — the same gene that underlies Gaucher disease — which are existing in as much as 10% of patients through PD in the united States167. GBA1 mutations are also associated with dementia with Lewy bodies167. Several various other genes connected to PD are straight or indirectly related to the endo/lysosomal machinery, such together mutations in SNCA (coding for α-synuclein)63,168. A hallmark of PD is the presence in neurons the protein inclusions referred to as Lewy bodies, i beg your pardon are largely composed that fibrillar α-synuclein. The α-synuclein protein is normally degraded through the lysosomes through the CMA pathway, yet macro-aggregates of α-synuclein mutants, which screen a longer half-life contrasted with the non-aggregated wild-type protein, are not degraded through this pathway and, rather, would be degraded via the macroautophagy pathway169,170,171,172. It was further shown that the mutant proteins bind to LAMP2A and inhibit the translocation of other substrates and, therefore, their last degradation170. Biochemical analyses suggest that α-synuclein is largely degraded by lysosomal proteases and also notably by cathepsin D, rather than through non-lysosomal proteases (for example, calpain I)173,174. Buildup of α-synuclein to be observed in cathepsin D-deficient mice, whereas, vice versa, the accumulation of α-synuclein aggregates was lessened in transgenic mice the overexpressed this cathepsin, leading to protection that dopaminergic neuronal cell from damage175.
HD is a rare autosomal-dominant neurodegenerative an illness caused by an aberrant expansion of CAG trinucleotide repeats within exon 1 the the HTT gene, which outcomes in the manufacturing of aggregation-prone HTT mutants (mHTT) that space detrimental to neurons176,177. Conversely, HTT has actually a protective role against neuronal apoptosis, buildup of mHTT, however, induces pathophysiological consequences including lysosomal and autophagy dysfunctions. Thus, mHTT perturbs post-Golgi trafficking to lysosomal compartments through delocalizing the optineurin/RAB8 complex, which, in turn, affect lysosomal function177. Too much mHTT induces buildup of clathrin adaptor complex 1 in the Golgi and an increase of clathrin-coated engine in the vicinity that Golgi cisternae177. The task of numerous cathepsins such together B, D, E, L and also Z has likewise been attached to HD63,80,174,177,178,179. Cathepsin D is responsible because that full deterioration of HTT however is less reliable at degrading mHTT, which is processed by cathepsin L180,181. Cathepsin Z likewise cleaves HTT and also elongated polyglutamine tracts182,183. Thus, lysosomal modulators exhilaration on cathepsin task might have beneficial effects in the therapy of HD. Notably, hyperexpression of cathepsin D (and cathepsin B) was shown to protect primary neurons against mHTT toxicity179. Alterations in macroautophagy, mitophagy and also CMA have likewise been implicated in HD184,185. CMA task was raised in solution to macroautophagy failure in the early stages that HD186, a an outcome supported by the findings that HSPA8 and also LAMP2A have necessary roles in the clearance that HTT187 and that shRNA-mediated silencing of LAMP2A raised the aggregation the mHTT188. Other studies focusing on the HTT secretory pathway revealed that mHTT cheap is mediated by the Ca2+-dependent lysosomal exostosis device via the synaptotagmin 7 sensor in neuro2A cells189. The extracellular release of mHTT was properly inhibited by the phosphoinositide 3-kinase and also sphingomyelinase inhibitors Ly294002 and also GW4869. HD-dependent perinuclear localization of lyosome was also demonstrated190.
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Increasing evidence thus implicates lysosomal (and autophagy) dysfunction in the pathogenesis of neurodegenerative disorders62,63,127,128,130,191,192. TFEB has received particular attention in this regard193,194,195, with current data arguing that TFEB is selectively shed in patient with advertisement (as well as ALS)196. Raising TFEB activity might as such prevent neuronal death and restore neuronal duty in certain neurodegenerative diseases, including PD194.


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GP Investments to Sell Fogo de Chão (Latin America)
Source: GP Investments
GP Investments, an alternative asset investment firm in Latin America, has reached an agreement to sell 100 percent of FC Holdings, the holding company for Brazilian steakhouse Fogo de Chão Churrascaria, to U.S.-based private equity firm Thomas H. Lee Partners for an enterprise value of US$400 million. In partnership with co-investors, GP Investments acquired a 35 percent stake in Fogo de Chão in 2006 through its third fund and subsequently purchased the remainder of the company in 2011. GP Investments expects to generate a cash-on-cash multiple of approximately 3.4x from the sale, with a 25 percent estimated IRR.

domain: finance


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Aishwarya Rai Bachchan to Work with Nagarjuna, Mahesh Babu and Shruti Haasan?
By Ankita Mehta | January 31, 2014 8:13 PM EST
As per the latest buzz, Aishwarya Rai Bachchan is all set to work with two of the biggest stars of the Southern film industry, Nagarjuna and Mahesh Babu.
Aishwarya Rai Bachchan [
However, it is being said that Nagarjuna and Mahesh Babu will be the protagonists.
"Aishwarya Rai has confirmed her participation in the project," a source from Mani Ratnam's office told Deccan Chronicle.
The title of the film has not been decided yet and it is going to be a Tamil-Telugu bilingual. A representative of Aishwarya has confirmed that the actress has given her consent, but did not reveal the details of the film, except that the shooting will go on floors by September or October.
However, the news has not been confirmed by Aishwarya yet.
Even Nagarjuna wasn't aware of Aishwarya's role in the film. "I didn't know about Aishwarya being approached. I did receive a message of condolence from Mani Ratnam when my father died. Perhaps he felt it wasn't the right time to talk about Aishwarya being roped in," the actor told DC.
There have also been reports that actress Shruti Haasan will be working in the same film and will be mostly featured opposite Mahesh Babu.
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To contact the editor, e-mail:
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A total of 1221 cocoa farmers across the producing states in the country attended the flag-off of inputs distribution for the cocoa farmers under CFAN-Wema Bank-CBN Anchor Borrowers Support Programme.
The farmers were selected from Oyo, Osun, Ondo, Ekiti, Delta, Edo, Ogun, Abia, Cross River and Kwara. Addressing the beneficiaries at the ceremony in Akure, the National President of Cocoa Farmers Association of Nigeria (CFAN), Comrade Adeola Adegoke, said this was the first time such incentive would come to cocoa farmers.
This, he noted, was to re-energise, reactivate and boost cocoa production as the scheme had readily captured all necessary farming inputs and loans as kind of stimulation.
According to Adegoke, cocoa revolution was initiated by the Premier of the old Western region, Chief Obafemi Awolowo, through which lots of legal projects, especially Free Western education were executed.
Adegoke urged the youths to embrace cocoa revolution to salvage the economy.
He lamented that the major cash crop was dying gradually in Nigeria, which formerly occupied second position in production but now in eight position.
The CFAN President emphasised on the need to embrace cocoa irrigation, stressing that each farm should have a borehole as agriculture generally would not thrive without water.
While commending both the Central Bank of Nigeria(CBN) represented by Mr Olu Aina and Wema Bank for their kind gesture in lifting cocoa higher, he promised to key into the system that would help his committee represent CFAN well.
According to him, the loan is for 18 months.
At the event, the former Governor of Ondo state, Olusegun Mimiko, who is Nigeria’s Cocoa Ambassador, recalled that he was trained through cocoa proceeds to become what he is today, stressing that efforts should be geared towards its revolution.
SOURCE: DAILY TRUST

domain: agronomy


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Late at the Library: Delia Derbyshire Day
In partnership with the Delia Derbyshire Day and The BRITISH LIBRARY
Saturday 30 November – 7.30pm – 10.30pm | Venue: The British Library | Tickets from £8 | BUY TICKETS
Ph Credit : Delia at work © Andrea Pazos
An evening of live audio visual performance and bold new music.
An evening of live audio visual performance and bold new music inspired by the work and archive of the electronic music pioneer. Line-up includes Bishi, Architects of Rosslyn, Caro C and Andrea Pazos, Kat Lovell and Izzy Bolt, plus DJs Lorraine James and Lisa Busby.Delia Derbyshire Day is a Manchester-based organisation which pays homage to Delia Derbyshire (1937-2001). Their work is centred around the Delia Derbyshire Archive which is held at John Rylands Library in Manchester.
Part of our Season of Sound, the British Library’s annual celebration of all things audio.


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Process flow for the SIMOX fabrication of microdisk structures (cross-sectional view).
Cross-sectional schematic depicting the coupling region between a buried waveguide and a microdisk resonator.
SEM picture of the fabricated microdisk resonators on the top silicon layer with bus waveguides underneath.
Top view of the fabricated add-drop filter.
Experimental setup used to characterize the add-drop filter.
Filter characteristics of the fabricated add-drop filter.
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Lockheed Martin unveils new F-21 Fighter Jet
US defence giant Lockheed Martin unveiled the F-21 multi-role fighter jet at Asia’s biggest air show Aero India-2019. Lockheed Martin will manufacture the plane in collaboration with Tata Advanced Systems under India’s flagship programme Make in India.
F-21 Fighter Jet
- The company states that the F-21 fighter jet is specifically configured for the Indian Air Force and will strengthen India’s path to an advanced airpower future.
- F-21 would fulfil the Indian Air Force’s unique requirements and integrates India into the world’s largest fighter aircraft ecosystem with the world’s pre-eminent defence company.
- The F-21 provides “unmatched” Make in India opportunities and strengthens India’s path to an advanced airpower future together with unrivalled industrial opportunities and accelerates closer India-US cooperation on advanced technologies.
India’s RFI for 110 fighter jets
India had floated Request for Information for procuring 110 fighter aircraft for its air force. Six global aviation majors which have responded to the RFI are Boeing’s F/A-18E/F Super Hornet, Lockheed Martin’s F-21 Fighting Falcon, Dassault Aviation’s Rafale, Eurofighter Typhoon, Saab’s Gripen and Russian United Aircraft Corporation’s MiG-35.
The RFI mandates that the procurement of the 110 aircraft should have 15 per cent aircraft in flyaway condition and the remaining 85 per cent to be made in India by a Strategic Partner. Lockheed has teamed up with Tata Advanced Systems for the F-21, and Boeing has teamed up with Hindustan Aeronautics, India’s state-run aerospace company, as well as Mahindra Defense Systems for the local manufacture of the Super Hornet.
Category: Defence Current Affairs
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