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Add some sunshine to your winter by jetting off to one of these much loved winter sun destinations. Choose from an active water sports holiday, an exotic tour of a far off place or just kicking back and relaxing while topping up on some much needed vitamin D.
High on the winter sun hit list are diving at some of the world’s top dive sites in Egypt or Thailand, or soaking up the sights in Mexico, Argentina or Brazil. Go on safari in Tanzania or South Africa, or just chill in a Caribbean paradise in St Lucia or Barbados. If you don’t mind a long haul flight, join the thousands exploring the beaches, vistas and warm welcomes of Australia and New Zealand.
For something a little closer to home, the Canary Islands are bathed in sunshine all year round, making your winter sun break just a short flight away.
Overlooking the central pool feature, Koh Samui's largest private pool, with contemporary Thai furnishings, this very comfortable and stylish two double bed en suite villa is the ideal home in Choeng Mon, with an easy walk to the beach. Self catering holiday rental Samui- the tropical island where it is always summer!
The location cannot be bettered. …see more
Unique, alone and remote. With the Nature around and Private Beach, LaraHomestay is ideally for relax and recover trips. Amazing view to the sea from any corner of your room. Perfect foods and closely host. We bring you Home …see more
In Bang Muang there are a health station, a pharmacy, a private clinic, a dentist, a post office, a petrol station, a few massage shops, and the Thai Life spa. Thai Life also rents mountain bikes and motorcycles.
The hinterland of Bang Muang is ideal for bicycle riding In Bang Muang you can find a dozen restaurants of various kinds.
Fully furnished two bedroom with cable, air, wifi, pool, clubhouse, fitness center, security, concierge, Located in one of the newest condo complexes in Davao, a short walk to the new SM mall and is close to everything yet far enough to be a quiet and peaceful getaway. Large pool, clubhouse with function rooms, fitness center, basketball courts, garden area & 24-hour security …see more
Chiang Mai Thailand, Rice Barn, Relaxing, Meditate, Quiet Area, Large garden, WIFI & Satellite TV, Kitchen, home setting,
friendly, Night Safari, Elephant camps, Washing Machine, kids, We can arrange taxi or driver service, just let us know. …see more
Extremely comfortable and wonderfully spacious 234 square metre 3 bed/bath sea-view apartment in fantastic and extremely well managed condominium development located right on a beautiful beach in lovely Najomtien, just a few kms to the south of Pattaya. Fantastic holiday spot on stunning beach. With many watersports available and lovely beachfront restaurant. …see more
Excellent quality accommodation on a well maintained development with communal pool and gym. Apartment is on the 5th floor and has elevator access. Accommodation not suitable for children or disabled persons. …see more
Our studio unit is ideal for one or two persons (or maybe for a family of 3) who need a small-but-cozy place for a short or specific period of time for business or leisure travel. Check in and check out can be flexible. For more details/enquiries please ask.. …see more
Alanya/Mahmutlar beach Apartment
The appartment is a 4 persons appartment but there is on the sofa which can be made as an exstra bed place for one more person in the appartment.
There would be an exstra charge for the exstra person so ask me. Palmenbau Apartment is just 3 minutes walking from all the shops and saterday market.
Busstop 50 meters.
There is a daily maid service on call all day for cleaning & any assistance you may need.
All the buzz, colour & fun of being part of an amazing local Thai community
Up close to local outdoor Thai markets shops and Thai food restaurants
Only 5 minutes to subway
Guest have access to the entire house and garden
maid service allday for cleaning & any assistance you need …see more
Location is very easy place to get around and convenience place if you need any grocery during your stay. It is in the heart of Makati and you are in the place where plenty of bars and restaurant and much more Great place to stay …see more
Ideal for families who want home comforts; while enjoying a quiet, relaxing holiday close to nature. A perfect area for running or riding a bike. Enjoy being away from the tourists while getting more of a local feel for the area. …see more
Beach shop 5/10 minutess walk. 4 bed/4bath detached villa, own pool in Mahmutlar. Overlooking banana plantations, Taurus Mountains, Sunset and Castle views from roof terrace. 20 mins bus to Alanya, Easy access all amenities, water sports. Beach, Mountains, Forest, Walking , Watersports, Fishing, Sailing, History, Night Life, Playgrounds,Parks …see more
This double room has a safety deposit box, an electric kettle and air conditioning. The balcony provides a city view.
Room facilities: Balcony, City view, DVD Player, Cable Channels, Flat-screen TV, Safety Deposit Box, Air Conditioning, Iron, Desk, Wardrobe/Closet, This double room has a safety deposit box, an electric kettle and air conditioning. The balcony provides a c …see more
The Inspiration boutique resort is located at the southern tip of Phuket island, called Promthep Cape. It is surrounded by tropical forest and only a few small buildings. Here you can experience tropical nature, peace and quiet. NaiHarn beach is 7 min driving away. Cleaning and replacement of bed linen and towels is provided once per week free of charge. …see more
Fancourt in South Africa is the place to go for the ultimate golfing break, it is ranked as one of the top 18 golfing resort in the world (destination golf 2012/13). It offers 3 top ranked golf courses, driving range and short game practice area.
The lodge rental includes a golf buggy for your stay …see more
Ocean and Island views from the Villa. Coconut Villa is located between the two best beaches on Koh Mak both around 250 meters walk.. Plenty of local activities , Swimming, Diving Kayaking fishing or lasing on the beach or the Terrace. …see more
Quiet , Safe place , cultural 12 poolside accommodations with a 10-minute-walk to Kata Beach, about 500 M. Providing you service with English speaker who are Thai and Indonesian native.
Learn more about activities you can do in Phuket as diving , surfing , elephant trekking! …see more
Shop/Beach 5/10 mins walk 5 bed/5 bath detached villa, own pool Mahmutlar, Alanya. Surrounding Banana plantations, Taurus Mountains, Sunset, Castle views from Roof terrace 20 mins bus to Alanya Easy access all amenities, water sports. Larger Group? Sister Villa 2 mins. Beach, Mountains, Forest, Golf, Skiing, Watersports, Fishing, Sailing, Triathalon, History, Night Life. …see more
Baan Moon is a dream house recognized as one of the most beautiful spots on Koh Chang. It is conveniently located in the center of the island and is perfect for people looking for a peaceful, unique and relaxed place to stay for their holidays. You can also access the beach directly from the house by kayak or by swimming across the lagoon. …see more
2 Bedroom , 2 bathroom villa with private pool in a quite location on the outskirts of Pattaya . Within a 10 - 15 min drive of Pattaya and all the tourist amenities. Perfect for those who want all the facilities of Pattaya but a quiet retreat at the end of the day …see more
Situated in a quiet residential suburb, close to all the local amenities, Somerset Mall and Somerset Town Centre. Lots of bird life in the large grounds. Close to the N2 and R44 with easy access to the Airport (20 mins), Cape Town (25 mins), Stellenbosch (15 mins). …see more
Crack open a coconut & enjoy yet another sunrise over our tropical view. Dine 'al fresco' on our spacious terrace or large garden visited daily by monkeys & lots of exotic birds. This modern luxurious home is set in a tranquil garden only a 5min walk from Mirissa Beach. Mirissa is perfectly placed for blue & sperm whale-watching expeditions thanks to being on a migratory route …see more
The Headland Villas offer the perfect tropical location for a relaxing holiday.
Situated at Taling Ngam Beach on the idyllic western coast of Koh Samui,the spectacular views are the highlight of the Headland for a perfect tropical location for a relaxing holiday. Local Tax and Services apply for Thailand bookings. These charges will be added to each booking quotation. …see more
Exclusive, intimate, beach-front apartment. Bright, clean and airy. Perfect for a couple or small family. Balcony and master bedroom face the sea. Two pools and beautiful gardens lead to the beach. The apartment is equipped with a fully functional kitchen. …see more
This captivating 2-bedroom apartment is built in an art Deco Style, has views of the mountains to the East and of the city to the West, and has been upgraded to High Comfort standards with quality materials. It is very commodious and convenient. …see more
Villa Moonshadow is one of Koh Samui's most exclusive and prestigious properties including 5* service and 2 staff living discretely onsite the property..The breathtaking design and extended sea view into the horizon makes every visitor speechless. Due to safety reasons there are no children under 12 years allowed to stay at Villa Moonshadow.
Beautiful 4 bedroom villa recently built in traditional Thai style with modern contemporary interior on Koh Chang island, Thailand. The property benefits from 4 double bedrooms, 3 en-suite bathrooms, air-con, landscaped gardens & is a stones throw from the beach. If the dates you are interested in are booked, contact us anyway as we have access to similar properties too …see more
The villa house of Koh Chang Long Stay Resort will serve you with unique house for each villa house will provide one bedroom and one living room with a small kitchen which is equipped with all modern amenities to make your stay as comfortable as possible. A lot of things to do in Koh Chang such as kayaking, fishing, diving, snorkeling, elephant riding, spa etc., …see more
self catering Koh Samui, serviced apartment Koh Samui, beach holiday Thailand, family accommodation Koh Samui, 2 bedroom villa Samui, 2 bedroom apartment Koh Samui This quiet area of Samui is a great place to stay yet close enough to explore the rest of the island. …see more
If you want to be away from the night life of Lamai to get a good sleep then this is the place to stay. We are 2 minute walk to the nearest beach at Hia Thanon, and a 5 minute ride to the centre of Lamai. We have our own bar/restaurant with in the garden and pool area. I am English speaking lady that can help with your Holiday. We will arrange to collect you from the airport. …see more
Has the best breakfasts. You discover the real Thai rural life. Is great for families and children as they have freedom to roam in nature and easily enjoy a Great swimming pool rather than be confined to a hotel room. A personalized service much better than any hotel We can can organize tours in a more personalized and tailored way. A Green Dream like eco environment …see more
"Affordable Luxury" A new beautifully furnished 4 bedroom detached villa with private garden and shared swimming pool located approx. 15 minutes drive from the city centre. Fully equipped with very high quality furniture and fittings throughout.
The villa was simply perfect - group of 9
The villa is very beautiful and location is very good …see more
Huge 170 sqm 3 bedroom / 2 bath unit available now for low or high season rental. The apartment has 3 bedrooms, 2 bathrooms, a large living room and a fully-equipped kitchen with a total living area of apx. 170 sqm.
Boracay Island, Philippines Beachfront Apartment, quiet side
1 kingsize bed, 1 singlebed
1 bathroom and toilet, luxurious and spacious
1 small extrabathroom, with shower and toilet
Minibar, fully airconditioned, wireless internet, if weather allows Internet is possible if weather allows.
Our direction is "the blue lagoon villas" tulubhan cove …see more
Top floor apartment with unbeatable seaview. Living room, kitchen, bathroom with bathtub, bedroom with king size bed and terrace overlooking coconut trees with Lamai beach being the focal point. We can arrange 15% discount for boat tickets to organised trips to nearby islands like Angthong Marine Park. …see more


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Your Swervedriver is not my Swervedriver. My Swervedriver only started last year with a song or two deep in SiriusXM’s 1st Wave, a channel that concerns itself with post-punk and New Wave. The fact that anything from the Oxford band’s earliest 1990s output shows up in their library is just bending the rules of time on par with Blur’s “There’s No Other Way” or music from Depeche Mode’s Violator. Your Swervedriver, if I had to guess, involves much more emotional commitment: loving their four albums that tied up the 20th century in a dream-pop bow, lamenting their 21st-century absence, and embracing their return with 2015’s I Wasn’t Born to Lose You.
And so our roads converge here with Future Ruins, the second installment of Swervedriver 2.0. I don’t know if I’m fully converted, but I can at least understand their fans’ long-standing admiration of the sound. There’s a bunch of different pop-hyphenate styles swirling around and through this album. My issue seems to be that there’s often not one rising to the surface of a song to give it some definition. Too many tracks like “The Lonely Crowd Fades in the Air” have so much compositional blur, and Adam Franklin’s lyrics and multitracked vocals so much relaxed delivery (like the “talk to me” mantras of “Spiked Flower”), that they get equally muddy.
Even when there is more structure, Swervedriver load up Future Ruins with thematic abstraction begging for even a proper chorus (“Drone Lover,” “Golden Remedy”) and very deliberate, contemplative playing (the title track). The two fastest songs on here are among the best, the effortless zig-zag of “Marywinter” and “Good Times are So Hard to Follow,” a Byrds-like cut run through Dinosaur Jr.’s distortion filters. There’s also the effective poetic narrative “Everybody’s Going Somewhere and No One’s Going Anywhere” that could have been lifted from R.E.M. at the end of the Bill Berry era.
You can absolutely hear Swervedriver’s feedback loop with the bands they influenced in their absence—their power-pop contemporaries, the mainstreamed muscle that bled into the turn of the millennium, and then indie-rock’s revisions and revivals. My only wish for Future Ruins is that those sounds weren’t all playing at once.
Adam Blyweiss is associate editor of Treble. A graphic designer and design teacher by trade, Adam has written about music since his 1990s college days and been published at MXDWN and e|i magazine. Based in Philadelphia, Adam has also DJ’d for terrestrial and streaming radio from WXPN and WKDU.

domain: artistic


Feb 24, 2002
© 2017, Roadracing World Publishing, Inc.
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From a press release:

Superside engine using Catalytic Converter

Reduced emissions from Superside race engine

Another step forward in technology for Superside machines was used in the testing sessions in Cartagena with the first international look at the new Rennteam Eilers machine.

The machine uses the excellent new Suzuki GSX-R1000 engine, but with a specially designed catalytic converter that reduces exhaust emissions. This is a unique for motorcycle sport, and uses the catalytic converter together with fuel injection to obtain to high horsepower requirements for Superside.

Dieter Eilers, together with the Rennteam Eilers team have been working since the middle of last year to combine the new Suzuki engine with the catalytic converter from HJS. They choose to use the smaller but newer 1000cc engine partly to comply with proposed rule changes, but also to add fuel injection to their engine management plan.

"In the future motorcycle sport will only work without pollution. I think that it will move forward like car racing. As in the past, Superside will lead these major changes with technology in the paddock", commented Dieter.

Eilers tested the new specification with his two passengers, Helmut Engelmann and Andy Kolloch in Spain with good results, getting down to a 1:48.544 at the two-day sessions.


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James Bond museum opens atop the Austrian Alps
With the 25th James Bond film currently in production, filmmakers thought it was high time 007 had his own museum. NBC’s Keir Simmons travels up thousands of feet to the Austrian Alps where fans can now immerse themselves right into the iconic movies for a sensory, immersive and thrilling experience.
JK Rowling opens up about her roots and ‘Fantastic Beasts’05:13
Ken Burns, Tom Brokaw talk about ‘Mayo Clinic’ documentary05:24
Neil Patrick Harris talks new children’s book, ‘The Magic Misfits’04:14
Sissy Spacek and Robert Redford talk about working together for 1st time04:55
J.K. Rowling and ‘Fantastic Beasts’ cast stop by the TODAY plaza04:07
Justin Theroux breaks his silence on split from Jennifer Aniston00:33

domain: celebrity


COLORADO SPRINGS, COLO.) – As the Olympic year comes to a close, six of the United States’ top young boxers will face off with competitors from across the globe at the 2012 Youth World Championships, November 29-December 7 in Yerevan, Armenia. The event will feature elite boxers from ages 17-18 with all of the participants having been born in 1994 and 1995.
The six boxers representing the United States in Armenia are light flyweight Norberto Torres (Inverness, Fla.), flyweight Edmundo Vasquez (Las Cruces, N.M.), bantamweight Gary Salazar (Fresno, Calif.), lightweight Maliek Montomgery (Macon, Ga.), light welterweight Julian Rodriguez (Paterson, N.J.), and light heavyweight Anthony Sims, Jr. (Ypsilanti, Mich.). The boxers won their spots based upon their finishes at the 2012 USA Boxing National Championships in February and National PAL Championships last month in Toledo.
In preparation for the event, the team held a training camp with new International Teaching Coach Pedro Roque Otano in Puerto Rico before departing for Armenia on Thanksgiving. In addition to honing their skills with the United States coaching staff, the squad trained and sparred with their Puerto Rican counterparts.
All of the top Olympic-style boxing nations in the world will compete in the event with full squads from each of the seven AIBA confederations vying for gold in Armenia. All of the participants will weigh in on Wednesday prior to the official event draw and boxing will begin on Thursday.
Three personal coaches of the 2012 Youth World Championships team members will lead the team into action with Christopher Barela (Las Cruces, N.M.), Michael Montgomery (Macon, Ga.), and Gilberto Salazar (Fresno, Calif.) joining the squad in Armenia. Dr. Robin Goodfellow (Albion, Mich.) has joined the team as both Team Manager and Physician for the international event.
The Youth World Championships, which take place every two years, began in 1979 with Yokohama, Japan hosting the inaugural event. The 2010 edition was the largest in the event’s history and full participant numbers for the 2012 event will be announced following the event draw.
Preliminary round action will run from November 29-December 2 with quarterfinal competition on December 3 and 4. Following the rest day, semifinal action will be contested on December 6 and the event will conclude with championship bouts on December 7.
The Youth World Championships will be the first major international event for all of the U.S. competitors and will give them key experience heading into a new quadrennial. For additional information on the 2012 Youth World Championships, go to www.aiba.org
United States Roster
108 lbs: Norberto Torres, Inverness, Fla.
114 lbs: Edmundo Vasquez, Las Cruces, N.M.
123 lbs: Gary Salazar, Fresno, Calif.
132 lbs: Maliek Montgomery, Macon, Ga.
141 lbs: Julian Rodriguez, Paterson, N.J.
178 lbs: Anthony Sims, Jr., Ypsilanti, Mich.
2012 Youth World Championships Schedule
November 28 – Pre-event weigh-in and official draw
November 29 – December 2- Preliminary round bouts
December 3-4 – Quarterfinal bouts
December 5 – Rest Day
December 6 – Semifinal bouts
December 7 – Championship bouts
USA Boxing, as the national governing body for Olympic-style boxing, is the United States’ member organization of the International Amateur Boxing Association (AIBA) and a member of the United States Olympic Committee (USOC).


New Toyota Prius 2016 Review Interior… – Japanese manufacturer has finally unveiled the new, fourth generation of the most popular hybrid in the world, the Prius. In short, the new model is based on a new Tngai platform, the design is fundamentally affect the model of peace, and efficiency is increased by approximately 10% compared to its predecessor. New 2016 Toyota Prius model that many have been waiting, and here is finally here. The information that we got to share with you and the rest will wait for later. So far, no details regarding the propulsion power but also it will soon be on the agenda.
Review of New Toyota Prius 2016
The external appearance of the final production model is not a big surprise considering that a few days ago the Internet began to circulate photos of the car without protective masks. With some modern elements, particularly light, is still visible subordination aerodynamics in the design of the exterior, ie it was called. liftback form.
The new Prius is 60 mm longer, 15 mm wider and 20 lower than its predecessor, and offer increased space both inside the passenger compartment and in the trunk. Travel comfort and safety will contribute to the new suspension and generous equipment, especially when it comes to driver assistance systems such as systems for warning of an unintentional cover into another lane, active cruise control based on radar, automatic high beam, a system that recognizes traffic signs, pedestrians and FIG.
Using the new modular Toyota New Global Architecture, or Tngai platform has brought a whole range of benefits to this model, and there is most outstanding is the fact that the chassis is now 60% stiffer, the center of gravity of the car is lowered, it is possible to lower a drive assembly and the like.
When we touched powertrain say that Toyota is currently not excessively enter into details and is officially confirmed only that his efficiency be increased by 10%, a thermal efficiency of 40%. Also, some parts are smaller and more compact, and the same goes for the new nickel-metal hydride battery which has increased durability and shorter charging time.
Exterior and interior pictures
New Toyota Prius 2016 Release Date
The sale of this car will start by the end of this year, of course, first in Japan and then early next year and reach to other world markets. About the car over after the Frankfurt motor show. The price that we can expect is about $25,000. Depending on the level of equipment that’s going to have New Toyota Prius 2016 model will range and price.
If you need more information about this model, visit caranddriver.


About This Source - CGTN
This story is an English language news item from CGTN. CGTN is a Chinese state-funded broadcaster.
Recent from CGTN:
Confirmed COVID-19 cases worldwide have topped 20 million, with more than 730,000 people dead. The U.S. still tops the list, with more than five million, a quarter of global cases. The number jumped from four million to five million in 17 days. It means the U.S. has more COVID-19 cases than Ireland has people. Some countries in Asia and Europe had to deal with a second wave of infections, while Africa and Latin America are also trying to slow down the spread. Faced with the grim milestone, the World Health Organization chief urged all governments and citizens to act now.
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In This Story: COVID-19
Covid-19 is the official WHO name given to the novel coronavirus which broke out in late 2019 and began to spread in the early months of 2020.
Symptoms of coronavirus
The main symptoms of coronavirus are:
- a persistent new cough (non productive, dry)
- a high temperature (e.g. head feels warm to the touch)
- shortness of breath (if this is abnormal for the individual, or increased)
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Below are stories from around the globe related to the 2020 outbreak of novel Coronavirus – since the WHO gave the Covid-19 naming. Most recent items are posted nearest the top.
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In This Story: Ireland
Geopolitically, Ireland is divided between the Republic of Ireland (officially named Ireland), which covers five-sixths of the island, and Northern Ireland, which is part of the United Kingdom. As of 2016, 4.8 million people live in the Republic of Ireland, and 1.8 million live in Northern Ireland.
The Irish climate is influenced by the Atlantic Ocean and thus very moderate, and winters are milder than expected for such a northerly area, although summers are cooler than those in continental Europe. Rainfall and cloud cover are abundant.
A strong Irish culture exists, as expressed through Gaelic games, Irish music and the Irish language. The island’s culture shares many features with that of Great Britain, including the English language, and sports such as association football, rugby, horse racing, and golf.
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In This Story: World Health Organization
The World Health Organization is a specialized agency of the United Nations responsible for international public health. The WHO Constitution, which establishes the agency’s governing structure and principles, states its main objective as “the attainment by all peoples of the highest possible level of health.”


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November 12, 2018
Australian Markets Weekly – Housing softening but economy read less clear
We open this week to news that auction clearance rates in Sydney and Melbourne continue to run in the mid-to-low 40%s.
- The weekend’s preliminary weekly CoreLogic clearance rates for Sydney and Melbourne of 48.4% and 48.3% respectively, suggest that when Thursday’s final weekly rates are released, they’ll not be far from 42.5%/45.5%. The resale market remains soft, as buyers stay away. Further, auction volumes continue to run at the low end or below, recent year turnover ranges for this time of the year.
- CoreLogic’s high frequency resale hedonic prices unsurprisingly continue to decline. So far in the month, Sydney prices are down 0.4%, Melbourne prices are down 0.2%; taking Sydney to down 7.5% y/y and Melbourne to down 5.0% y/y. These are still small declines relative to previous rises and defy media headlines of collapse.
- This week we also take a wider look into housing developments. We summarise how the current cycle is playing out in terms of prices, activity and prospective demand. It’s hard to deny the resale market seems soft and the dwelling construction pipeline looks likely to shrink in coming months as building approvals continue to fade.
- The wheels are now in motion for dwelling investment to become a drag on Australia’s economic growth in 2019. NAB’s forecast of 2.7% y/y GDP growth for 2019 incorporates a 5.3% y/y decline in dwelling investment, following our expectation of a 2.7% rise over 2018.
- This week the market will be paying close attention to a trio of important releases. First is the NAB Business Survey for October tomorrow, followed by the Wage Price Index for Q3 on Wednesday and the Labour Force report for October on Thursday.
- After a rise last week and at times testing 0.73, the AUD opens this week closer to 0.72, pulled back by a risk-averse session on Friday night and some renewed demand for the USD. While market sentiment will no doubt be important, this week’s key Australian wages and unemployment releases could have an important influence.
- Wages will again by dissected to gauge whether there is any evidence that wages are edging higher, NAB (and the market) looking for annual growth to rise from 2.1% to 2.2% (2.3%). The NAB Business Survey and the Labour Force release provide their own slants on growth momentum into the December quarter and the degree of spare capacity. NAB expects above-market employment growth (+25k vs mkt: +20k), coming with an unemployment rate we expect to remain steady at 5.0% aided by significant sampling rotation effects (exiting sample having a 5.6% unemp. rate).
- Offshore, Wednesday’s trio of Chinese October economic activity releases will be dissected both from the point of view of any tariff impacts as well as early flow through of policy stimulus. In the US, Fed Chair Powell is speaking on Wednesday, offering the opportunity to reflect on the emergence of inflation and the growth outlook with the Mid Term elections concluded. US CPI and Retail Sales are also due.
Customers can receive Australian Markets Weekly and other updates directly in their inbox by emailing firstname.lastname@example.org with the name of their NAB relationship manager.
For further FX, Interest rate and Commodities information visit nab.com.au/nabfinancialmarkets

domain: news


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- Primary research
- Open Access
Circular RNA UBAP2 contributes to tumor growth and metastasis of cervical cancer via modulating miR-361-3p/SOX4 axis
Cancer Cell International volume 20, Article number: 357 (2020)
Increasing researches have reported that circular RNA UBAP2 (circUBAP2) may be a potential prognosis biomarker and participate in the development of several cancers; however, the role of circUBAP2 in cervical cancer (CC) remains largely unclear.
We applied qRT-PCR and Western blot to examine expression levels of circUBAP2, miR-361-3p, SOX4, Bax, Bcl-2, Cleaved caspase 3, N-cadherin, Vimentin and E-cadherin. Cell proliferation, apoptosis, invasion and migration were analyzed by MTT assay, Flow cytometry, and Transwell assay, respectively. The interaction between miR-361-3p and circUBAP2 or SOX4 was confirmed by luciferase reporter assay and pull-down assay. Murine xenograft model was established by injecting SiHa cells which stably transfected sh-circUBAP2.
CircUBAP2 was up-regulated in CC tissues and cell lines and high circUBAP2 expression predicated poor outcome. Knockdown of circUBAP2 suppressed cell proliferation, migration, invasion and EMT, while induced apoptosis in CC in vitro, and inhibited tumor growth and metastasis in vivo. MiR-361-3p directly bound to circUBAP2 or SOX4, and circUBAP2 could regulate SOX4 expression by sponging miR-361-3p in CC cells. Furthermore, rescue assay results demonstrated that the inhibitory effects of circUBAP2 knockdown on cell growth and metastasis were partially reversed by miR-361-3p down-regulation or SOX4 up-regulation in CC.
CircUBAP2 represents a prognostic marker and contributes to tumor growth and metastasis via modulating miR-361-3p/SOX4 axis in CC, which indicates a potential therapeutic target for CC treatment.
CircUBAP2 is up-regulated in cervical cancer tissues and cell lines and highly expressed circUBAP2 predicates poor outcome.
CircUBAP2 silence inhibits the cervical cancer cell growth and metastasis in vitro and in vivo.
CircUBAP2 can regulate SOX4 expression by interacting with miR-361-3p in the cytoplasm in cervical cancer cells.
CircUBAP2 deletion inhibits the cervical cancer cell progression in vitro via severing as a ceRNA of miR-361-3p to regulate SOX4.
As the second most common female malignancy worldwide, cervical cancer (CC) has become the leading cause of cancer-related mortality among females in developing countries . Despite advances in the screening techniques and current treatments, including surgery, radiotherapy and chemotherapy, the overall survival of CC patients remains unsatisfactory because of recurrence and metastasis [2, 3]. In recent, reports have suggested infection with high-risk type human papillomavirus (HPV), such as HPV 16 and 18, increases the risk of CC . However, the viral infection is not enough to explain the progression of CC , the pathogenesis of CC remains vague.
Circular RNAs (CircRNAs) are novel, endogenous, non-coding RNAs that were recently identified and display widely prevalent expression in the eukaryotic transcriptome [6, 7]. CircRNAs have a covalently closed loop structure without a 5′ cap and a 3′ polyadenylated tail, which makes them resistant to regular mechanisms of linear RNA decay . Previously, circRNAs were considered as accidental splicing byproducts with low abundance and little functional potential . However, with the development of new technologies, circRNAs have been identified to be more abundantly expressed compared with their linear counterparts , and emerging evidence has revealed circRNAs regulate gene expression in many biological processes and involve in the initiation, prognosis and development of diverse diseases, including tumors [11, 12]. In recent, circRNAs are one of the novel objects which have recently been evaluated in CC, many circRNAs, like has-circ-0018289, hsa-circRNA-101996 have been identified to contribute to the progression of CC via sponging target microRNA (miRNA) [13, 14], indicating the regulatory role of circRNAs in CC tumorigenesis. CircUBAP2 is one type of circRNA; recently, accumulating researches have reported that circUBAP2 may be a potential prognosis biomarker and participate in the development of several cancers, such as osteosarcoma, lung cancer, and triple-negative breast cancer [15,16,17], suggesting the potential mechanism of circUBAP2 in tumor progression. However, the role of circUBAP2 in CC is still largely unclear.
Many circRNAs have been found to contain diverse types and quantities of miRNAs binding sites, which allow them to specifically sponge to miRNAs, thereby repressing miRNAs activity and promoting the relative expression of corresponding target genes of the miRNAs , and based on this regulation, the circRNA-miRNA-mRNA function axis has been identified. Recently, miR-361-3p was identified to be decreased in CC patients and high expressed miR-361-3p was an independent, favorable indicator of long-term overall survival in CC . SOX4, a member of the SOX (sex-determining region Y-related HMG box) transcription factor family, has been revealed to be malformed expressed and involved in the progression and drug-resistant of CC . All the studies indicated the potential role of miR-361-3p and SOX4 in the tumorigenesis in CC.
In this study, we investigated the expression pattern of circUBAP2 in CC tissues and cell lines and aimed to explore the regulatory role of circUBAP2 in vitro and vivo as well as its underlying mechanisms.
Materials and methods
Patients and samples
A total of 58 pairs of CC tissues and adjacent normal tissues who were undergoing surgical resection were collected from Ningbo Clinical Pathology Diagnosis Center, and all cancer tissue specimens were diagnosed as CC by pathological examination. Immediately, all fresh specimens were kept at − 80 °C for further experiments. This study was permitted by the Ethics Committee of Ningbo Clinical Pathology Diagnosis Center, and all patients had signed the written informed consent.
CC cell lines C-33A, HeLa, SiHa and normal cervical epithelial cell line End1/E6E7 were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA) and then were incubated in Dulbecco’s Modified Eagle’s Medium (DMEM; Gibco, Carlsbad, CA, USA) containing with 10% fetal bovine serum (Gibco), 2 mM l-glutamine and 1% penicillin/streptomycin (Gibco) at 37 °C with 5% CO2.
Quantitative real-time polymerase chain reaction (qRT-PCR)
Total RNA from cells or pull-down samples was isolated using TRIzol (Thermo Fisher Scientific, Inc., Waltham, MA, USA) following the standard procedure. PrimeScript RT reagent Kit (Takara, Dalian, China) was used to synthesize the complementary DNA in accordance with the standard protocol. The reverse transcription was conducted at 37 °C for 15 min, followed by 85 °C for 5 s, according to the manufacturer’s protocols. Then quantitative PCR was performed by using SYBR green PremixEx Taq II (Takara). The reaction mix (25 μL final volume) consisted of 12.5 μL SYBR® Premix Ex TaqTM II (2×), 1 μL of each primer, 2 μL of the cDNA preparation, and 8.5 μL dH2O. The thermocycling conditions were as follows: 95 °C for 5 min, followed by 50 cycles of denaturation at 95 °C for 15 s and then 60 °C for 30 s. The fold changes were normalized with U6 or GAPDH and qualified by 2−ΔΔCt method. The specific primer sequences were listed as follows: circUBAP2, forward 5′-AGCCTCAGAAGCCAACTCCTTTG-3′ and reverse 5′-TCAGGTTGAGATTTGAAGTCAAGAT-3′; miR-361-3p, forward 5′-CACTCCAGCTGGGTCCCCCAGGTGTGATTC-3′, and reverse 5′-CTCAACTGGTGTCGTGGAGTCGGCAATTCAGTTGAGAAATCAGA-3′; SOX4, forward 5′-GGTCTCTAGTTCTTGCACGCTC-3′, and reverse primer 5′-CGGAATCGGCACTAAGGAG-3′; U6, forward 5′-CTCGCTTCGGCAGCACA-3′, and reverse 5′-AACGCTTCACGAATTTGCGT-3′; GAPDH, forward 5′-AAGAAGGTGGTGAAGCAGGC-3′, and reverse 5′-GTCAAAGGTGGAGGAGTGGG-3′.
Isolation of nuclear and cytoplasmic fractions
The nuclear-cytoplasmic fractionation was conducted using the Nuclear and Cytoplasmic Extraction Reagents kit (Thermo Fisher Scientific Inc.) following the manufacturer’ s protocol. After that, total RNA from the nuclear and cytoplasmic fractions was extracted and detected as described above.
RNase R treatment
Total RNA (2 mg) was cultured with or without 3 U/mg of RNase R (Qiagen, Valencia, CA, USA) at 37 °C for 20 min. The resulting RNA was purified with the help of an RNeasy MinElute Cleanup Kit (Qiagen).
The miR-361-3p mimic, miR-361-3p inhibitor and mimic negative control (mimic-NC) were obtained from RIBOBIO (Guangzhou, China). The short hairpin RNA (shRNA) targeting circUBAP2 (sh-circUBAP2) (shRNA#1: 5′-GCTTCTAAGCTTTCTGAAACA-3′; shRNA#2: 5′-CAGCTTCTAAGCTTTCTGAAA-3′; and shRNA#3: 5′-CCCAGCTTCTAAGCTTTCTGA-3′) and shRNA scramble control (sh-NC), pcDNA and pcDNA-SOX4 overexpression vector (pcDNA-SOX4) were synthesized by Genepharma (Shanghai, China). Cell transfection was conducted by using Lipofectamine RNAiMax (Life Technologies Corporation, Carlsbad, CA, USA).
Cell proliferation was analyzed using MTT assay (Beyotime, Shanghai, China). Transfected cells (2 × 103 cells/well) were plated into 96-well plate, followed incubation with 20 μL of MTT solution for the indicated times and then DMSO was added into each well to resolve the generated formazan. Finally, the absorbance was examined at 490 nm using a microplate reader (Bio-Rad, Hercules, CA, USA).
The Annexin V-FITC/PI apoptosis detection kit (BD Biosciences, San Jose, CA, USA) was used to determine the apoptosis rate of HeLa and SiHa cells after transfection following the standard protocol. Briefly, transfected cells were harvested, and washed in PBS, and followed by staining with 10 μL Annexin V-FITC and PI in the dark for 15 min. Finally, cell apoptosis was analyzed using FlowJo software within 1 h on the FACScan Flow cytometer.
The in vitro cell migration and invasion assay of HeLa and SiHa cells were performed as reported previously . For migration assay, transfected HeLa and SiHa cells in serum-free medium were seeded in the transwell upper chamber, and then DMEM medium harboring 10% FBS was added into the lower chamber as chemoattractant. Subsequently, the migrated cells were fixed with 5% glutaraldehyde for 10 min and stained with 0.5% toluidine blue, and counted in six randomly selected visual fields under microscope. For invasion assay, the philosophy of measurement was similar to the above steps of cell migration, except that upper transwell chambers were pre-coated with 0.8% Matrigel (BD Bioscience).
Western blot assay
Cells were lysed by RIPA lysis buffer (Beyotime) to isolate proteins, and then protein concentrations were analyzed using the bicinchoninic acid (BCA) protein assay kit (Takara). Extracted proteins were separated by an SDS-PAGE minigel, and then transferred onto PVDF membranes. After blocking by 5% fat-free milk powder in TBST buffer, membranes were interacted with primary antibodies against SOX4 (ab80261, Abcam, Cambridge, MA, USA), PCNA (ab29, Abcam), Bax (ab32503, Abcam), Cleaved caspase 3 (ab2302, Abcam), Bcl-2 (ab692, Abcam), N-cadherin (ab18203, Abcam), Vimentin (ab92547, Abcam), E-cadherin (ab15148, Abcam), as well as GAPDH (ab181602, Abcam) at 4 °C overnight, followed by incubated with the HRP-conjugated secondary antibody (ab205781, Abcam). Finally, signal visualization was performed by ECL Substrates (Millipore, Billerica, MA, USA).
Luciferase reporter assay
The full circUBAP2 sequences and SOX4 3′-UTR containing wild-type or mutant miR-361-3p binding sites were cloned into the pMIR-Report plasmid (Promega, Shanghai, China). Then HeLa and SiHa cells were plated into 48-well plates and co-transfected with 300 ng constructed plasmid vector and 30 nM miR-361-3p mimics or mimic-NC using Lipofectamine RNAiMax. Finally, the firefly luciferase activity was analyzed using a dual-luciferase reporter kit (Promega).
CircUBAP2 or oligonucleotide was transcribed with Biotin RNA Labeling Mix and T7 RNA polymerase in vitro (Roche Diagnostics, Basel, Switzerland) and then sublimated with the help of an RNeasy Mini Kit (Qiagen) following the standard protocol. After that, the synthetic Bio-circUBAP2 probe and Bio-control probe were transfected into HeLa and SiHa cells. After 48 h later, cells were lysed, and total cell lysates were interacted with streptavidin-coated magnetic beads, followed by eluted, isolated and evaluated using qRT-PCR analysis.
Xenograft experiments in vivo
BALB/c nude mice (aged 4–6 weeks, N = 10) were used to establish xenograft model. Briefly, 2 × 106 SiHa cells transfected with sh-NC or sh-circUBAP2 were subcutaneously injected into 6 nude mice. Tumor volumes were calculated every 5 days and after 5 weeks, the mice were killed and tumor weights were analyzed. Additionally, 1 × 106 sh-circUBAP2-SiHa or sh-NC-SiHa cells were intravenously injected into another 4 nude mice through tail vein, respectively. After 60 days, the lung tissues of each mouse were removed by surgery, and metastasis nodules of nude mice lung from each group were counted. The animal protocols were permitted by the Institutional Animal Care and Use Committee of Ningbo Clinical Pathology Diagnosis Center.
The immunohistochemistry procedure was followed as described earlier [21, 22]. The paraffin sections of tumor tissue specimens of mice from the control and experimental group (4-μm-thick) were routinely deparaffinized and hydrated. Then methanolic H2O2 (45:5) was utilized to treat the sections to quench activities of endogenous peroxidase at room temperature for 30 min. After being blocked with goat serum for 1 h at room temperature, rabbit anti-Ki67 antibody (ab15580, Abcam) raised in rats for overnight at 4 °C, followed by incubation with goat anti-mouse IgG H&L (HRP) (1:800; Abcam) for 2 h at room temperature after washing with PBS. 3, 3′-Diaminobenzidine (Sigma-Aldrich, St. Louis, MO, USA) was utilized as a substrate. The sections were stained with DAB, washed with distilled water, and then counterstained in hematoxylin solution. A light microscope were used to visualize images.
All statistical data were presented as the mean ± standard deviation (SD) and analyzed using the GraphPad Prism 7 (GraphPad Inc., San Diego, CA, USA) from at least three times independently experiment. Significant differences between groups were analyzed using one-way analysis of variance (ANOVA) followed by Dunnett’s test or Student’s t test. The correlations were analyzed using Pearson’s rank test. Survival curves were determined by a Kaplan–Meier plot followed by the log-rank test. P < 0.05 suggested statistically significant.
CircUBAP2 is up-regulated in CC tissues and cell lines and highly expressed circUBAP2 predicts poor outcomes
The expression of circUBAP2 in CC tissues and cell lines was measured. Results showed that circUBAP2 was elevated in CC tissues as well as CC cell lines, including C-33A, HeLa and SiHa, compared with adjacent normal tissues and normal cervical epithelial cell line End1/E6E7 (Fig. 1a, b). Then the correlation between circUBAP2 and overall survival was analyzed and we found highly expressed circUBAP2 would result in poor survival in CC patients (Fig. 1c). All the findings suggested circUBAP2 might play an important role in CC progression. In addition, to verify the existence of circUBAP2, total RNA from proliferating SiHa and HeLa cells was treated with RNase R exonuclease and the level of RNA was detected using qRT-PCR, and then we demonstrated the circUBAP2 existed in a circular form because of the resistance to digestion by RNase R (Fig. 1d, e). Moreover, qRT-PCR analysis of nuclear and cytoplasmic RNAs indicated that circUBAP2 was preferentially localized in the cytoplasm and that UBAP2 was primarily localized in the nucleus in SiHa and HeLa cells (Fig. 1f, g). All the findings indicated that circUBAP2 was existed and levels of linear and circular UBAP2 transcript were modulated independently. Thus, to explore the potential biological functions of circUBAP2 in CC, we silenced circUBAP2 in SiHa and HeLa cells using a shRNA that lowered circUBAP2 levels without affecting the expression of the UBAP2 linear species was discovered (Fig. 1h, i).
CircUBAP2 silence inhibits the CC cell progression in vitro
After silencing circUBAP2 with sh-RNA, the proliferation, apoptosis, metastasis abilities of SiHa and HeLa cells were analyzed. Subsequently, MTT assay results showed knockdown of circUBAP2 inhibited cell proliferation in SiHa and HeLa cells (Fig. 2a, b), and a reduction of PCNA expression in SiHa and HeLa cells after transfection with si-circUBAP2 was also observed (Additional file 1: Fig. S1B). Then flow cytometry analysis indicated down-regulated circUBAP2 stimulated apoptosis in SiHa and HeLa cells (Fig. 2c). In the meanwhile, western blot results further validated that circUBAP2 deletion promoted apoptosis in CC cells due to the increased expression of Bax and Cleaved-casp-3 and decreased expression of Bcl-2 (Fig. 2d, e). Furthermore, a transwell assay revealed that silencing circUBAP2 suppressed cell migration and invasion in CC cells (Fig. 2f, g). Besides that, the promotion of E-cadherin level but inhibition of N-cadherin and Vimentin levels in SiHa and HeLa cells were investigated, the hallmark of epithelial-mesenchymal transition (EMT) is the loss of epithelial surface markers, most notably E-cadherin, and the acquisition of mesenchymal markers including Vimentin and N-cadherin, thus, interference of circUBAP2 also repressed EMT in CC cells (Fig. 2h, i). Therefore, we illustrated that circUBAP2 silence could suppress the CC cell progression in vitro by inhibiting proliferation, migration, invasion and EMT as well as promoting apoptosis.
CircUBAP2 severs as a sponge of miR-361-3p and directly suppresses its expression in the cytoplasm in CC cells
To explore the underlying molecular mechanism of circUBAP2 mediating CC cell progression, the miRNA target of circUBAP2 was predicated using the starBase2.0 program, and the putative binding sites of miR-361-3p on circUBAP2 were investigated (Fig. 3a). Then, luciferase reporter assay was performed and results showed miR-361-3p mimic transfection reduced the luciferase activities of the WT-circUBAP2 reporter vector but not MUT-circUBAP2 reporter vector in SiHa and HeLa cells (Fig. 3b, c). Moreover, The RNA pull-down assays further confirmed the direct interaction between miR-361-3p and circUBAP2 because of significant enrichment of miR-361-3p in both SiHa and HeLa cells (Fig. 3d). Subsequently, the expression of miR-361-3p was determined in CC tissues and a decrease of miR-361-3p expression was investigated in CC tissues compared with the adjacent normal tissues (Fig. 3e), besides that, a negative correlation between miR-361-3p and circUBAP2 was also discovered in CC patients (Fig. 3f). After that, down-regulated miR-361-3p expression was also detected in CC cell lines compared to the normal End1/E6E7 cell line (Fig. 3g). In addition, decreased circUBAP2 promoted miR-361-3p expression in SiHa and HeLa cells also was identified (Fig. 3h). Therefore, all the data suggested circUBAP2 served as a sponge of miR-361-3p and directly suppressed its expression in the cytoplasm in CC cells.
MiR-361-3p directly interacts with SOX4 and negatively regulates its expression in the cytoplasm in CC cells
Afterwards, we further determined the underlying mechanism of miR-361-3p and according to the prediction of the starBase2.0 program, SOX4 contained the wild or mutant type binding sequence of miR-361-3p (Fig. 4a). Subsequently, we conducted the luciferase reporter assay and the results indicated miR-361-3p mimic transfection reduced the luciferase activity of SOX4 3′UTR-WT compared with that of the control group in SiHa and HeLa cells, while the regulatory effect of miR-361-3p was disappeared in SOX4 3′UTR-MUT (Fig. 4b, c), suggesting the interaction between miR-361-3p and SOX4. Besides, qRT-PCR analysis showed a remarkably elevated expression of SOX4 mRNA in CC tissues (Fig. 4d), and, co-expression analysis showed a negative correlation between miR-361-3p and SOX4 in CC (Fig. 4e). After that, the expression of SOX4 was also measured in CC cell lines and we found, whether the mRNA or protein, SOX4 also was up-regulated in SiHa and HeLa cells compared to the End1/E6E7 cell line (Fig. 4f, g). Furthermore, miR-361-3p mimic transfection could inhibit SOX4 expression at both mRNA and protein levels in SiHa and HeLa cells (Fig. 4h, i). In all, all the data revealed that miR-361-3p interacted with SOX4 and suppressed SOX4 expression.
CircUBAP2 deletion inhibits the CC cell progression in vitro via serving as a competing endogenous RNAs (ceRNA) of miR-361-3p to regulate SOX4
Based on the interaction between circUBAP2 and miR-361-3p or miR-361-3p and SOX4, we hypothesized that circUBAP2 deletion might affect the CC cell progression via severing as a ceRNA of miR-361-3p to regulate SOX4. Therefore, to verify this hypothesis, first, SiHa and HeLa cells were transfected with pcDNA or pcDNA-SOX4, and pcDNA-SOX4 significantly elevated SOX4 expression (Additional file 1: Fig. S1A). Next, SiHa and HeLa cells were transfected with sh-NC, sh-circUBAP2, sh-circUBAP2 + miR-361-3p inhibitor, or sh-circUBAP2 + SOX4 pcDNA. After transfection, the expression of SOX4 was examined, and we found sh-circUBAP2-induced reduction of SOX4 expression was rescued by miR-361-3p inhibitor or SOX4 pcDNA transfection in SiHa and HeLa cells (Fig. 5a), indicating circUBAP2 could act as a ceRNA of miR-361-3p to regulate downstream target SOX4 in CC cells. Afterwards, cell proliferation, migration, invasion, EMT and apoptosis abilities were analyzed. We found circUBAP2 knockdown inhibited the proliferation of SiHa and HeLa cells by reducing the expression of PCNA, while this effect was abolished by miR-361-3p down-regulation or SOX4 up-regulation (Fig. 5b, c, Additional file 1: Fig. S1B). The suppression of apoptosis of SiHa and HeLa cells caused by circUBAP2 knockdown, evidenced by the increase of apoptosis rates, Bax and cleaved caspase-3 levels, as well as the decrease of Bcl-2 level, was also reversed after the introduction of miR-361-3p inhibitor or SOX4 pcNDA (Fig. 5d–g). In the meanwhile, transwell assay and western blot analysis showed decreased miR-361-3p or overexpressed SOX4 could also reverse circUBAP2 silence-mediated inhibition of migration, invasion as well as EMT in SiHa and HeLa cells (Fig. 5h–k). Altogether, these results illustrated that circUBAP2 deletion could inhibit the CC cell progression in vitro via acting as a ceRNA of miR-361-3p to regulate SOX4.
CircUBAP2 promotes CC cell growth and metastasis in vivo
To investigate the biological functions of circUBAP2 in vivo, SiHa cells stably transfected with sh-circUBAP2, or the corresponding empty vector were subcutaneously injected into nude mice. We found that tumor lumps in the sh-circUBAP2 group were smaller than those in the sh-NC group (Fig. 6a), and after 35 days, the mice were sacrificed and the average weight of tumor lumps incubated with sh-circUBAP2-SiHa cells was significantly lighter than that of the sh-NC-SiHa cells (Fig. 6b), indicating circUBAP2 deletion significantly reduced tumor growth. Besides, we recorded the weight of mice every 5 days, and there was no significant change in body weight, suggesting shRNA has no apparent toxicity on mice (Fig. 6c). Additionally, molecular analysis suggested that sh-circUBAP2 notably reduced the expression of circUBAP2 and SOX4, but elevated miR-361-3p expression in tumor masses compared with the sh-NC group (Fig. 6d, e), revealing circUBAP2 knockdown suppressed CC tumor growth in vivo by regulating miR-361-3p and SOX4 expression. Importantly, as depicted in microphotographs and histograms in Fig. 5f, circUBAP2 knockdown suppressed the level of Ki67 in the tumor masses, further strengthening the inhibitory effect of circUBAP2 on SiHa tumor growth. In addition, to explore the effect of the metastatic inhibiting ability of circUBAP2 silence on SiHa cells, another two groups of 5 mice were intravenously injected in the tail vein with sh-circUBAP2 or sh-NC SiHa cells, respectively. After 8 weeks, the mice were sacrificed, and we demonstrated that lungs metastatic nodules were significantly fewer in sh-circUBAP2 group than that in the sh-NC group (Fig. 6g). Therefore, these results indicated that circUBAP2 could promote CC growth and metastasis in vivo.
CircRNAs are naturally occurring, versatile and diverse endogenous non-coding RNAs, and have covalently linked ends relative to linear RNAs [23, 24]. In recent years, accumulating evidence has investigated that circRNAs are crucial contributors in normal cell differentiation, tissue homeostasis and disease progression , and are implicated in several diseases, particularly in cancer , which may function as a diagnostic or predictive biomarker and therapeutic targets for cancers. In fact, aberrant expression of circRNAs in diverse cancer types and tissues has been identified, which involves in the oncogenesis in many cancers by sponging target miRNA or regulating downstream pathways. For example, circRNA-ITCH is significantly decreased and antagonizes lung cancer proliferation by inhibiting the activation of Wnt/β-Catenin pathway . CircRNA MTO1 directly sponges to miRNA-9 to inhibit the progression of hepatocellular carcinoma . CircPVT1 is highly expressed in gastric cancer tissues and may induce cell proliferation by targetedly interacting with the members of the miR-125 family . However, up to now, there was no report to reveal the regulatory role of circUBAP2 in CC. Thus, in this project, we focused on the function of circUBAP2 as well as its underlying mechanism in CC progression.
Using the qRT-PCR analysis, we found circUBAP2 was increased in CC tissues and cell lines, and highly expressed circUBAP2 was related to the poor prognosis, indicating circUBAP2 might function as an oncogene in CC development. Immediately, to verify this hypothesis, circUBAP2 functions in CC cell proliferation, apoptosis and metastasis were analyzed using loss-of-function assay. As expected, circUBAP2 deletion inhibited cell proliferation, metastasis reflected by the repression of migration, invasion and EMT abilities, as well as stimulated apoptosis in CC cells. Additionally, we also further analyzed the role of circUBAP2 in vivo by using a xenograft model, which was established by injecting stably transfected sh-circUBAP2 SiHa cells and the results demonstrated that circUBAP2 deletion suppressed CC cell growth and metastasis in vivo, which further suggesting circUBAP2 acted as an oncogene in CC development.
Functional circRNAs often act as miRNA sponges to regulate protein expression of the key genes at the transcriptional or post-transcriptional level that are vital for carcinogenesis . In this study, according to the prediction and confirmation of the starBase2.0 program and luciferase reporter assay, we discovered circUBAP2 directly interacted with miR-361-3p and targetedly inhibited miR-361-3p expression in CC cells. It has been revealed that miR-361-3p functions as a tumor inhibitor in many cancers such as retinoblastoma and non-small cell lung cancer by severing as a target or directly interacting with target genes [30, 31]. However, the role of miR-361-3p in CC is still overlooked. In our study, rescue assay was conducted and we identified that down-regulated miR-361-3p could reverse circUBAP2 deletion-mediated suppression on CC cell progression. Thus, we illustrated miR-361-3p might also act as a tumor suppressor in CC and circUBAP2 promoted CC progression through sponging miR-361-3p.
SOX4 has been revealed to be a downstream target of miR-133a to contribute to NEAT1/miR-133a axis-mediated CC progression , indicating the promotional effects of SOX4 on CC development. In this study, SOX4 was confirmed to be a target of miR-361-3p and was negatively modulated by miR-361-3p in CC cells. After that, co-expression analysis demonstrated that circUBAP2 severed as a ceRNA of miR-361-3p, thereby regulating downstream target SOX4 in CC cells in vitro and in vivo. Thus, circUBAP2/miR-361-3p/SOX4 loop was firstly investigated. In the meanwhile, we also identified that overexpressed SOX4 could attenuate circUBAP2 deletion-mediated suppression on CC cells growth and metastasis by rescue experiments. Therefore, it was suggested that circUBAP2/miR-361-3p/SOX4 axis was implicated in CC progression. SOX4 is regarded as an oncogene and has been found to be overexpressed in many types of malignancies . SOX4 can activate multiple developmental pathways, including PI3K, Wnt, and TGFβ signaling, thus contributing to cell growth, EMT, and apoptosis inhibition in cancers. Besides that, SOX4 has been shown to interact with a wide variety of transcription factors, like p53, β-catenin and SMAD3, to impact tumor cell survival, stemness, and metastasis [33, 34]. These may be the potential mechanisms by which circUBAP2/miR-361-3p/SOX4 axis works; however, further researches are still needed to confirm.
Although some conclusions have been drawn from our study, the shorting comings should be pointed out. First, the expression patterns of circUBAP2, miR-361-3p and SOX4 presented are based on a limited number of tissues. Second, this study only investigated the effects of circUBAP2/miR-361-3p/SOX4 pathway on CC cell proliferation, apoptosis and metastasis, whether or not the pathway involved in other cellular processes, such as cell cycle, and metabolism, to regulate cancer progression remains vague. Regarding the shortcomings of the present study, a larger cohort of the disease analysis is essential to validate these conclusions, and new studies should be conducted to explore the roles of circUBAP2/miR-361-3p/SOX4 pathway in other cellular processes, as well as how this axis controls all these pathways.
To sum up, we found circUBAP2 was elevated in CC tissues and cell lines and higher expressed circUBAP2 might be a prognostic biomarker for overall survival of CC. Additionally, we firstly demonstrated circUBAP2 contributed to the CC growth and metastasis in vivo and in vitro, and then we also identified a critical circUBAP2/miR-361-3p/SOX4 axis in CC development (Fig. 7), which will help us better understand the molecular mechanism underlying the CC progression as well as prognosis and provides a novel therapeutic strategy for CC treatment.
Availability of data and materials
All data generated or analysed during this study are included in this published article.
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Chen J, Li Y, Zheng Q, Bao C, He J, Chen B, Lyu D, Zheng B, Xu Y, Long Z, et al. Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer. Cancer Lett. 2017;388:208–19. https://doi.org/10.1016/j.canlet.2016.12.006.
Chen W, Wang J, Liu S, Wang S, Cheng Y, Zhou W, Duan C, Zhang C. MicroRNA-361-3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC. J Exp Clin Cancer Res. 2016;35:76. https://doi.org/10.1186/s13046-016-0357-4.
Zhao D, Cui Z. MicroRNA-361-3p regulates retinoblastoma cell proliferation and stemness by targeting hedgehog signaling. Exp Ther Med. 2019;17(2):1154–62. https://doi.org/10.3892/etm.2018.7062.
Yuan LY, Zhou M, Lv H, Qin X, Zhou J, Mao X, Li X, Xu Y, Liu Y, Xing H. Involvement of NEAT1/miR-133a axis in promoting cervical cancer progression via targeting SOX4. J Cell Physiol. 2019;234(10):18985–93. https://doi.org/10.1002/jcp.28538.
Hanieh H, Ahmed EA, Vishnubalaji R, Alajez NM. SOX4: epigenetic regulation and role in tumorigenesis. Semin Cancer Biol. 2019. https://doi.org/10.1016/j.semcancer.2019.06.022.
Moreno CS. SOX4: the unappreciated oncogene. Semin Cancer Biol. 2019. https://doi.org/10.1016/j.semcancer.2019.08.027.
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This study was permitted by the Ethics Committee of Ningbo Clinical Pathology Diagnosis Center and all patients as well as hospitals had written the informed consents.
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Informed consent was obtained from all patients.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Additional file 1: Fig. S1
(A) The expression of SOX4 in SiHa and HeLa cells transfected with pcDNA-SOX4 or pcDNA was detected using western blot. (B) The expression of PCNA in SiHa and HeLa cells transfected with sh-NC, sh-circUBAP2, sh-circUBAP2 + miR-361-3p inhibitor, or sh-circUBAP2 + pcNDA-SOX4 was measured using western blot. *P < 0.05.
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Meng, L., Jia, X., Yu, W. et al. Circular RNA UBAP2 contributes to tumor growth and metastasis of cervical cancer via modulating miR-361-3p/SOX4 axis. Cancer Cell Int 20, 357 (2020). https://doi.org/10.1186/s12935-020-01436-z
- Cervical cancer

domain: medical


text:
Exploring new perspectives in urban development
Students of a wide variety of cultural backgrounds take part in the ACU Summer School held at CUHK.
Forty-five bright-minded students from a wide variety of cultural backgrounds gathered at the CUHK campus for intensive learning and idea exchange during 1 to 9 July at the ACU Summer School 2018.
Jointly hosted by the Association of Commonwealth Universities (ACU) and CUHK’s Faculty of Social Science, Urban Studies Programme and the Office of Academic Links, the programme welcomed the diversified student group coming from 19 nationalities worldwide to explore the topic ‘Designing and Creating Sustainable Communities’ in Hong Kong, one of the most densely developed metropolises in the world.
In addition to themed lectures and workshops hosted by CUHK academics, local practitioners and overseas experts from Australia, Canada and South Africa, students also took field trips to visit various sites in the city, including those in Sai Ying Pun, Wanchai, Fanling and Tin Shui Wai, to gain first-hand knowledge on the opportunities and challenges in urban planning faced by the residents and stakeholders in those communities. Through the programme, students were guided to look into urban issues from multiple perspectives and explore solutions to manage the world’s resources.
Prof. Hendrik Tieben leads a field trip to Sai Ying Pun for the students to learn about initiatives to engage the local community in urban planning.
Guest lecturer Mr. Howard Tam explains the concept of design thinking to students of the ACU Summer School.
Students dress up in their home countries’ traditional clothing at the farewell dinner of the ACU Summer School.

domain: sociology


text:
© 2007 Lawrence Tuczynski
|Japanese Title:||Ashura-jô no hitomi|
|CD Label:||Victor Entertainment, Inc.|
|Music by:||Yoko Kanno|
|Number of tracks:||13|
|Number of discs:||1|
|Year of release/manufacture:||April 13, 2005|
|Year Movie Released in Japan:||April 16, 2005|
October 02, 2007
A plot summary of the film can be found at http://www.imdb.com/title/tt0459744/plotsummary.
Track 1 starts off as a vocal track that sounds like a mixture of pop and traditional Japanese music. Fairly catchy tune. Track 5 has some nice saxophone work and feels a little like slow jazz. Track 7 had a bit of Eastern, Indian, feel to it. Clocking in at a little over 45 minutes this isn't a very long soundtrack. Hopefully the music works better in the movie. I have never seen the movie but listening to this CD, while certainly not bad, it doesn't seem to do well as stand alone music that you would listen to very often. Most tracks were slow and dreamlike.
Ashura-jô no hitomi


What is happening at Ballam Park?
As part of Council’s Integrated Water Management Action Plan, a bioretention system will be constructed at the north-eastern section of Ballam Park. Bioretention systems use plants, water circulation and aeration to naturally treat stormwater before it reaches the ocean.
A feasibility study was undertaken with Melbourne Water to determine how a bioretention system at Ballam Park could improve water quality. It found that the system will significantly reduce stormwater contaminants before they reach the stormwater drain which flows from Langwarrin into Port Phillip Bay.
The project creates an opportunity to enhance the bioretention system with an ornamental lake, artwork, lighting and park furniture. In June 2021 Council resolved to develop the area around the bioretention system into a new experience at Ballam Park.
Community engagement on the concept designs was open from 29 June to 26 July 2023.
Community Engagement Report
Community Engagement was open from 29 June to 26 July 2023.
The Engage Frankston page was viewed 297 times with 40 people completing the survey and 9 following the page for updates.
The community engagement opportunity was promoted in Frankston City News which is delivered to over 60,000 homes. Information flyers were delivered to 500 neighbouring properties.
A project page was created on Engage Frankston that included full colour images of the concept plans for the project and an email sent to subscribers with a registered interest in environmental and open space projects.
Participants were then asked to select their favourite design features from the concept plans. This process allowed Council to create a prioritised list of features, from most to least favoured. Participants could also make a comment about the project.
Features supported by more than half of the participants are listed below with the number of times selected shown in brackets:
- Garden beds (30)
- Bioretention system (29)
- Ornamental lake (24)
- Sculptures (22)
- Public lighting (21)
- Seating area (21)
- Viewing platform (21)
Features supported by fewer than half the participants are listed below with the number of times selected shown in brackets:
- New footpaths (20)
- Decorative lighting (17)
- Picnic shelter (17)
- Jetty (17)
- BBQ (13)
- ‘Other’ (2) (frog pond; nature)
We also asked Tell us what you think of the concept plans. Is there anything else we should consider for the bioretention system and lake?
Most responses supported the protection of the local environment, or suggested new or modified design features. Some participants raised concerns about project costs and lack of nearby toilet facilities.
All comments have been shared with the project team and saved for future projects at Ballam Park.
Based on community engagement results, it is recommended that features which were selected the most often should be prioritised in the final design.
Features which were selected by fewer participants could be consider optional or delivered in later stages of the project.
Care should be taken to choose plants and design features that look like the concept images shown to participants.
Communication to nearby residents and visitors to Ballam Park should occur prior to and during construction, including project updates on Council’s website www.frankston.vic.gov.au.
Feedback that relates to other elements of Ballam Park should be saved and used to inform future projects.


Under data protection law we must tell you about how we use your personal information. This includes the personal information that we share with other organisations and why we do so. Our main GP practice privacy notice is on our website. This additional privacy notice provides details about the personal information that we are sharing with NHS Digital for its General Practice Data for Planning and Research data collection.
NHS Digital is part of the NHS. It collects, analyses, publishes and shares data to improve everyone’s health and care. Read more about NHS Digital.
We use the term patient data to refer to personal information in the rest of this notice.
The NHS needs data about the patients it treats in order to plan and deliver its services and to ensure that care and treatment provided is safe and effective. The General Practice Data for Planning and Research data collection will help the NHS to improve health and care services for everyone by collecting patient data that can be used to do this. For example patient data can help the NHS to:
- monitor the long-term safety and effectiveness of care
- plan how to deliver better health and care services
- prevent the spread of infectious diseases
- identify new treatments and medicines through health research
GP practices already share patient data for these purposes, but this new data collection will be more efficient and effective.
We have agreed to share the patient data we look after in our practice with NHS Digital who will securely store, analyse, publish and share this patient data to improve health and care services for everyone. This includes:
- informing and developing health and social care policy
- planning and commissioning health and care services
- taking steps to protect public health (including managing and monitoring the coronavirus pandemic)
- in exceptional circumstances, providing you with individual care
- enabling healthcare and scientific research
This means that we can get on with looking after our patients and NHS Digital can provide controlled access to patient data to the NHS and other organisations who need to use it to improve health and care for everyone.
Contributing to research projects will benefit us all as better and safer treatments are introduced more quickly and effectively without compromising your privacy and confidentiality.
NHS Digital has engaged with the British Medical Association (BMA), Royal College of GPs (RCGP) and the National Data Guardian (NDG) to ensure relevant safeguards are in place for patients and GP practices.


text:
UV/HEAT PROTECTION IN SUMMER: High quality spun polypropylene fabric is UV stabilized and breathable, which makes the row cover to protect plants from UV damage while allowing air and moisture to reach the plants. STRONG WIND PROTECTION: Lightweight floating row cover can also be used for pollination control. The garden cover also provides some protection from destructive winds. FREEZE PROTECTION IN WINTER: Light-weight frost blanket provides up to 28°F frost protection and 85 percent light transmission, and traps heat and moisture to speed germination and extend the growing season, therefore produce higher, better and earlier crop yields. Plant blanket fabric in various ounces helps your plant survive in cold weather. Heavier fabrics will do a better job of keeping warm. COMFORTABLE ENVIRONMENT FOR PLANTS: Frequently applied, plant freeze protection covers will definitely create a superior living environment for plants. Since row covers control the light, heat, moisture, pest, wind speed, and so on for plants, you will have a bumper harvest.
- Super heavy-weight FRCs (1.5-2.0 oz./sq. yard): are usually used to extend the growing season in spring and fall, allow 30 percent-50 percent light transmission, recommend of freeze protection and season extension, resist harsh weather such as wind, snow, hail
- Protection high quality spun polypropylene fabric is stabilized and reusable, and allows air and moisture to reach your plants
- Easy installation measured size as described, easy to cover it on the plant top personally
- Multi-application protect your vegetable such as tomato, pepper, pumpkin, strawberry rows, fruit trees, citrus and shrub, flowers as well as newly-sown grass
- Weather protection protect plants from snow, hail, frost in the winter and birds during the growing season
- Return Policy

domain: agronomy


text:
The mills can hold up to 21 percent of the sugar available with them in September, but by October, they will need to reduce the inventory level to 8 percent, Paswan said. Already, there is a stock limit of 500 tonnes for traders.
T Sarita Reddy, president of the Indian Sugar Mills Association, said factories had minimal inventories as the season drew to a close. “We urge factories not to hold stock and to continue selling to keep prices in check with the start of the holiday season,” she said.
According to the industry, the total availability of sugar in the country at the end of July was 8.29 million tonnes. Of this total, around 4.35 million tonnes are estimated to be consumed in August and September. “None of the states are expected to own more than 21% of shares by the end of September.
But there could be specific factories in the states that could hold sugar in anticipation of higher prices. They will now have to release him, ”said a sugar trader from Gurgaon. Factories in Maharashtra tend to hold stocks, he added.
Total sugar available in the 2016-17 season was 28.3 million tonnes, including carry-over stocks, domestic production and gross imports. Sugar prices in Maharashtra and Uttar Pradesh wholesale markets have remained stable at Rs 3,637 per kg over the past month. However, in southern India, prices have increased by Rs 1-2 per kg in recent days to reach Rs. 38-39.
The government has also called on states to take measures to ensure sufficient availability of onions at reasonable prices. States can impose stock limits on onions and undertake measures such as hoarding operations, actions against speculators and profiteers, the Food Ministry said in a press release. This was made necessary due to an abnormal rise in prices in recent weeks, particularly from the end of July, although the production and supply of ions is better than at the same time a year. last, he said.
The retail price of onions fell from Rs 15 per kg to Rs 28.94, the ministry said. In the subways, the increase was highest at Rs 31 per kg in Chennai, Rs 38 in Delhi, Rs 40 in Kolkata and Rs 33 in Mumbai.

domain: economics


text:
Mar. 23rd, 2005 4:54 pm
The third installment to Ubisoft's original Splinter Cell stealth action hit. Sam Fisher is back with a number of new moves and weapons to bolster an already incredible looking game.
Splinter Cell Chaos Theory will offer a completely new gameplay experience, exemplified by a totally open level design, a completely immersive and interactive environment, and advanced AI in which enemies are aware of their environment and remember past events, making them smarter and even more dangerous.
Five minutes of incredible co-op gameplay from just-gold, soon-on-the-shelves Tom Clancy's Splinter Cell Chaos Theory. Yes, five minutes. Now wipe that drool off your chin and check it out

domain: entertainment


text:
Finance a renovation
Tap into your home’s equity to fund your home renovations, big and small.
Whether it’s an emergency repair or a full home remodel, a Hometap Investment can help you access your home equity to fund home improvement projects in just a few weeks, without interest or monthly payments.
Find out if a Hometap Investment is a fitting way to handle your home renovation costs.
A home equity investment from Hometap can help you fund all kinds of renovations:
Compare your renovation financing options
|Home equity loan||HELOC||Cash-out refinance||Reverse mortgage|
|Credit score||Typically over 600 (min score of 500)||Min score of 620||Min score of 620||Min score of 620||No firm requirement|
|Average loan-to-value||Max LTV of 75%||Max LTV of 80-85%||Max LTV of 80-85%||Max LTV of 80%||Max LTV of 50%-65%|
|Other restrictions (vary by lender)||No prepayment penalties||Prepayment penalties||Minimum annual draw requirements, prepayment penalties + cancellation fees occur with some lenders||Prepayment penalties + cancellation fees||Must be 62+ years old, must own home outright or have single primary lien|
This has been a godsend for our family. We are able to pay off all of our debt, plus do some much-needed upgrades to our home.
San Diego, CA
View all resources
Helpful renovation resources
What exactly is a home equity investment?
Am I required to disclose the details of my renovation to Hometap?
View All FAQs
Do you offer renovation adjustments?
Unlock Your Home Equity, Today.
See how much equity you can unlock from your home.

domain: finance


Meeting Emissions Regs with Gasoline Filters
This year, Euro 6c emissions regulations come into effect and in 2020, China 6 regs kick in. One consequence of this is that several OEMs have decided that it is necessary to equip vehicles with particulate filters—and these are gasoline-powered, not diesel engines.
This year, Euro 6c emissions regulations come into effect and in 2020, China 6 regs kick in.
One consequence of this is that several OEMs have decided that it is necessary to equip vehicles with particulate filters—and these are gasoline-powered, not diesel engines.
One of the types of engines where these filters are particularly advantageous as regards meeting the requirements is the gasoline direct-injection engine. While these engines provide good performance and good fuel economy, comparatively speaking, they also have a consequence of producing fine particulates in their exhaust.
So enter the gasoline-particulate filter.
One supplier of filters is Dow Corning Corp. (corning.com), which produces “DuraTrap GC” filters featuring a patented cordierite-based material composition with an engineered ceramic microstructure designed to trap fine particulates while maintaining engine performance with low engine back pressure.
The demand for the filters is so high that Corning is undertaking a $100-million facility expansion program in two plants, one in Germany and one in China, to expand production of its DuraTrap filters.
In its Kaiserslautern plant, where it has been producing diesel particulate filters since 2011, it is expanding its overall footprint with new production lines and equipment for the gasoline filter production. The entire expansion will be complete early in 2018.
“In Shanghai,” says Wu Dan, general manager, China, Corning Environmental Technologies, “we are adding capacity to lead production of gasoline particulate filters for local Chinese and global automakers.”
The Shanghai plant has been producing light-duty substrates and filters since 2001, and the expansion, which is also to be complete by early 2018, adds the DuraTrap production capability.
Direct injection is the technology of the near future for both gasoline and diesel engines, say Bosch engineers. It will keep the internal combustion engine clean, powerful, and efficient during a period when hydrogen power is more dream than reality.
GM gives its mid-size pickup customers what they’ve been clamoring for, a clean and quiet, high-torque, fuel-efficient diesel.
It is a pretty good rule of thumb that automotive journalists tend to like cars that go fast.


Bringing Up Bates - Carlin Bates Opens Up About Her 15-Week-Old Daughter's Health Problems
Bringing Up Bates star Carlin Bates and her husband, Evan Stewart, welcomed their daughter Layla Rae Stewart back in January, and this past week on Instagram she told her fans that her life has been filled with “many ups and downs” since their “precious Layla was born.”
The 21-year-old posted a picture of Layla holding her finger, and she also posted a lengthy statement describing how the hospital has become their second home over the past 15 weeks.
“Since Layla was born, she has had breathing problems and episodes of turning blue where she can’t catch her breath,” wrote Bates, adding that she and Stewart first thought that Layla’s health problems were due to her premature birth.
According to People magazine, Bates was due to give birth in mid-February, but doctors induced her a few weeks early after diagnosing her with two blood-clotting disorders, just like her big sister, Erin.
Bates explained that after giving birth she got sick with meningitis and ended up in the hospital, and Layla stayed with Erin. She says that during her hospital stay, she got a call telling her that Layla was having rapid breathing and turning blue. This caused her to panic “pretty hard.”
“She was rushed to Children’s Hospital, and I was overcome with fear of the unknown, along with feeling guilty that I couldn’t be there with her. Evan went back and forth from hospital to hospital, checking on us both. I felt so alone,” wrote Bates.
After doctors told Bates and Stewart that their daughter’s EKG levels “weren’t reading right,” they recommended that Layla see a heart specialist. Bates says that they found out Layla had a small hole in her heart, and that could be causing some of her breathing issues.
Bates says that the doctors encouraged her and Stewart not to worry because they would watch Layla closely, and their prayer is that the hole will close itself, as they often do. The new mom revealed that they ordered Layla a special sock that monitors her heart rate and O2 levels because Bates was so nervous she couldn’t sleep at night.
Bates also revealed that Layla gave her another health scare recently when she turned white and her O2 levels dropped to 80 percent. Bates said that her world felt once again like it was turned upside down, and she felt helpless as she watched her daughter struggle for oxygen.
Fortunately, after ten minutes, Layla’s color returned and her oxygen levels went back to normal. Now, Bates says that Layla is on medication and the doctor believes her recent episode might have been caused by acid reflux.
Carlin Bates says that she and her husband are still nervous about the outcomes of everything, but they know God is in control and he’s writing their story. She added that becoming a mom has made her grow in many ways, and she is beyond blessed that God gave her this little girl.


Jul 29, 2015 10:09 PM
Three Glenn County residents have tested positive for West Nile Virus, and Glenn County officials are warning that people of all ages are at risk.
The cases, are the first of 2015 for Glenn County, are all adults and range in age from late twenties to seventies. Cases are not located in a specific city but lie in the valley at multiple points along the I-5 corridor within the county.
Two of the people have been hospitalized, and both are now home recovering.
On Monday, Butte County reported that residents are at an increased risk for the virus in 2015. Two human cases of West Nile Virus have been reported in Butte County this year.
Although mild for most, this disease can become very serious and even fatal for some that become ill. Symptoms, including, but not limited to fever, headaches, body aches, joint pain, vomiting, diarrhea or rash, typically develop from three to 14 days after being bitten by an infected mosquito.
North State residents should use mosquito repellents when they go outdoors, and wear long sleeves and long pants in the mornings and evenings when mosquitos are most active.
10 hours ago


text:
Adrian Willson has not received any gifts yet
Are you suffering from vein problems, or do you feel a burning, throbbing, heaviness, or pain in your legs? Keep this in mind: Neuralgia is something not to be messed with. Your nerves play an important role in your body. They pump blood back to your heart as it circulates throughout your body.
Without the ability to function properly, your nerves are…
As you get older, your body gets changed quite easily and it is noticeable. Moreover, you may notice that the veins around the particular area are prominent. These damaged blood vessels which have the name spider veins could be in purple or red. Although smaller spider veins are not dangerous for your health, these blood vessels will influence how your legs appear.
If you are just done with…Continue
If the look of unsightly veins on your legs is becoming the cause of the embarrassment, then a qualified vein doctor NY can be the best person that can help you with various things. The same can be said if you veins around the cheek area and you want to hide them.
What are the typical places to have veins?…Continue
Choosing a better health partner for your own health care is a difficult task as well as an important decision. Often you have a team of doctors as part of your health and wellness. If you have a good relationship with your general practitioner, you can get a quick appointment to see them. But even so, it's important to have a general understanding of the types of doctors and what they do.


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1. Port Chalmers Maritime Museum
This is one of the best little local museums you could hope to find – richly packed with artefacts from the town’s maritime past alongside artwork depicting the early days of Port Chalmers and other local curios. The model boats are fascinating. The museum is open daily 10am-3pm.
It’s the spot to really get a feel for what has made this town tick over the decades – chiefly piston-driven diesel engines and acres of sailcloth.
2. The Portsider
If an excellent, ever-changing selection of craft beer and top-notch pub food is just what you’re after, this is your spot in Port. Hans and Pip run a warm and welcoming establishment in this historic building.
Hans’ Dutch upbringing shapes the menu and his Bitteballen or Vegeballen are a delicious accompaniment to a glass of their fantastic beer. Wednesday night is steak night and tends to get very busy – testament to Hans’ skill with the skillet.
3. Aramoana Mole
The Mole is the long breakwater that extends out into the Pacific from the harbour mouth, its purpose to prevent sand from blocking the harbour entrance. The Mole’s construction over a century ago is something of an engineering marvel – the crumbling wooden structures on its eastern side are the remains of the railway that was constructed to carry the spill out across the water.
At least three intentionally-sunk shipwrecks lie hidden below the waves on that side as well. A walk to the very end positions you right in the belly of the sea, amid big swells and wildlife.
Shags fly past from the breeding colonies on Taiaroa Head across the harbour mouth and resting fur seals are often smelt before seen. From here you also get a sweeping view up the Otago coast. Many a visitor has fallen in love with Otago after a walk out here.
4. Orokonui Ecosanctuary
Since its inception in 2007 the Ecosanctuary has become a spot beloved by locals seeking solace from city life or showing friends and family around their home patch. Seeing takahē wandering around the lawn inside the entrance gate is just one highlight.
Walkers through this valley of remnant native forest soon meet kākā, bellbirds and tūī coming down to use the strategically placed feeding stations.
Even if the birds are quiet, the two-hour return walk to the bottom of the sanctuary is a meditative pleasure. There is also a good café and plenty of knowledge to be gleaned from the information panels and the enthusiastic staff.
5. Tunnel Beach
The track to Tunnel Beach, just south of Dunedin, descends through a tunnel cut into the rock by former landowner William Cargill for his family’s use and arrives in a spectacular setting of sandstone sculpted over the millennia by wind and rain.
If you’re going to spot a whale from the Otago shore, this may be the place to do it. Note the track is closed between August and October for lambing.

domain: geography


text:
World-renowned electronic superstar Flume has opened up about his severe anxiety, self-medication, and the fact he came close to quitting music altogether in a new interview.
Arguably one of the most popular Australian musicians of the last decade, there’s no denying that Harley Streten (otherwise known as Flume) has had something of a massive rise to fame since he was first Unearthed by triple j.
Despite his global fame and status as a highly-consistent artist and performer, Flume has opened up in a recent episode of the My Friend Podcast, hosted by his girlfriend Paige Elkington, touching upon – amongst other things – his severe anxiety and how he came close to quitting music altogether.
While noting that his infamous display of onstage anilingus was eventually a huge boost to his career (“you can’t pay for this kind of publicity,” he said), the conversation soon become far more serious, with the artist revealing he used to self-medicate with alcohol as a means to combat bouts of anxiety.
“I used a lot of alcohol,” he explained. “Like, when performing, I would definitely drink to calm nerves. I would drink to make it bearable, which sounds crazy but really it’s the truth. I’m just not a performer and I definitely have used alcohol to feel comfortable on stage in front of people.
“It’s something that’s taken a long time. Now, I don’t drink before shows because I realised it was becoming a pattern, and it was getting pretty bad doing these long tours and using booze like that.”
“The second I get to the festival I’m riddled with anxiety,” he added. “Even to this day, even after I’ve done thousands of shows, I still get anxious and I’m not really having fun until a couple of songs in.”
As he continued, Flume noted how being in music realised his “worst nightmare” of becoming a public speaker, before he drew comparisons between himself and Swedish artist Avicii, who passed away in 2018 at the age of 28.
“I got to a point where I was like, I don’t want to do this anymore,” he said. “I don’t want to have to use alcohol, I’m not having fun, I think I want to quit.”
“I went to a therapist and I was like ‘I hate my job, and it’s fucked that I can even say that because I have an incredible job that people dream of having. I feel like a bad person for saying that, but it’s true; I love making music but I hate touring. I’m not cut out for this.”
“I think people like Avicii are literally the same as me,” he continued. “And he died because he was medicating himself just like I was, with alcohol, drugs, whatever. He wasn’t happy.”
Noting he’s used therapy, anti-depressants, and medication to help manage his anxiety while on tour, Flume adds that the balance between his regular and working life has become far better, allowing him to become, as he puts it, the happiest he’s been in a long time.
In related news, Flume was announced as one of the headliners for the 20th anniversary edition of Splendour in the Grass earlier this year. Though COVID-19 has since pushed the festival back a few months, the Sydney musician is still on track to perform his only Australian show at Splendour this year.