text:
Yuri's army has mind control and genetic mutation as its central themes. While vastly inferior to other armies in terms of firepower, Yuri uses lighter units in conventional combat. His infantry dominates in urban areas, and mind control capabilities allow him to steal even the strongest units of his enemies. What he can not control, he either drives insane with chaos gas or mutates to either obedience or death. His submarines are unmatched in the sea and decent against ground targets, but his air presence leaves a lot to be desired.
Cost: $200 | Prerequisites: none
The base infantry unit of Yuri's army, Initiates use the power of their minds to deal damage. Against infantry, they are so effective that they lead literally combust them, but are not as effective against vehicles and structures. They are also capable of garrisoning civilian structures for protection and an immense firepower boost which lets no ground unit pass.
Cost: $500 | Prerequisites: none
Although unarmed, the Engineer is a very useful unit. Surgical use of engineering teams can quickly turn the tide of battle. Engineers can be used to repair destroyed bridges (by entering bridge huts), steal enemy structures, repair your own/allied structures and repair or capture neutral tech buildings, or defuse Crazy Ivan bombs by targeting the affected unit or structure. Note that when an engineer is used, the unit itself is lost, except when defusing bombs.
Cost: $500 | Prerequisites: none
Yuri's anti-armour infantry unit is the Brute, a genetically engineered monstrosity designed to crush everything that blocks its path. If a Brute reaches an infantry unit, his fists will smash the enemy infantryman to pieces. However, being one of the series' few melee units, they are ineffective against most targets in practice, as they are defenseless until they get in "range". Dogs will avoid Brutes and will not attack them.
Cost: $700 | Prerequisites: Psychic Radar
This deadly infantry unit is equipped with a sniper rifle, capable of slaughtering any infantry unit with a single shot. Worse yet, the victim is killed not with the bullet itself, but with a powerful toxin it contains which leaves a dangerous residue that damages other infantry units unfortunate enough to walk through the poisonous cloud left by a Virus' victim. The Virus sniper herself is immune to this toxin.
Yuri Clone
Cost: $800 | Prerequisites: Psychic Radar
The Yuri Clone has the ability to mentally control most organic units and vehicles. When controlled, the enemy unit becomes, effectively, your own, and you can order it to move and attack just as if you had built it yourself. If the Yuri Clone is killed, the connection with the enemy unit is broken and it returns to its original owner. The Yuri Clone cannot control ore miners, Attack Dogs, aircraft or other mind control units. If not controlling another unit, the Yuri Clone can also generate a psychic blast which instantly kills infantry that surrounds him, friend or foe. Simply double-click on him and watch surrounding infantry sizzle.
Yuri Prime
Cost: $1500 | Prerequisites: Battle Lab
Yuri's answer to Tanya and Boris is Yuri himself. Standing on a massive hovering chariot, Yuri Prime is a much more capable and deadly version of the Yuri Clone. Like the other heroes, Yuri Prime cannot be crushed by vehicles, regenerates automatically and is immune to mind control. Like his clones, Yuri Prime can control most vehicles and enemy infantry units, as well as most enemy structures, even turning enemy defences to his nefarious will. Additionally, Yuri is equipped with an improved psychic blast attack that instantly kills infantry in its area of effect and even damages units just outside of the immediate blast radius. Yuri Prime is in greater control of this effect than his clones are; when he unleashes a psychic blast, he does not damage friendly units.
Note: Only one Yuri Prime can be trained at a time per player, unless a Cloning Vat is deployed.
Cost: free | Prerequisites: Slave Miner
Miserable and malnourished, Slaves gather small amounts of ore with their shovels and return them to the Slave Miner they are assigned to. They are not directly controllable. Any Slaves killed by enemy action are automatically replaced by the Slave Miner free of charge. If the Slave Miner is destroyed, any surviving Slaves that were attached to it will join the army of their "liberators" as a weak melee unit, or will go neutral if the owner has surrendered.
Cosmonaut (campaign only)
Cost: $600 | Prerequisites: none
The Cosmonaut is only available in the sixth Soviet mission (Operation: To The Moon). It is an airborne unit like the Allied Rocketeer, and is the only infantry unit apart from the Desolator which can survive in the lunar environment. The Cosmonaut is armed with a laser that is effective against vehicles and structures.
Psi Commando
Cost: $1000 | Prerequisites: Any faction's Spy infiltrating a Yuri Battle Lab
The Psi Commando is the same as in Red Alert 2, only with different prerequisites.
Slave Miner
Cost: $1750 | Prerequisites: Bio Reactor
Rather than using a standard miner, Yuri's forces depend on the Slave Miner for their economy. The entire miner moves next to a mining site and deploys, releasing up to 5 Slaves to gather ore for processing. When mobile, damaged Slave Miners auto-repair, and when deployed, the structure can be repaired by sending an Engineer into it. Any Slaves killed by enemy action are automatically replaced by the Slave Miner free of charge. It can be built simultaneously from the Construction Yard and the War Factory. If it is destroyed, any surviving Slaves that were attached to it will join the army of their "liberators" as a weak melee unit, or will go neutral if the owner has surrendered.
Lasher Light Tank
Cost: $700 | Prerequisites: none
The Lasher Light Tank is Yuri's standard tank, comparable to the Allied Grizzly and the Soviet Rhino. Like its counterparts, it is designed to attack and defend against enemy armour, as well as crush enemy infantry. It has the weakest armour of all main battle tanks.
Gattling Tank
Cost: $600 | Prerequisites: none
The Gattling Tank is equipped with twin 50-caliber machine guns that spin rapidly, spitting out hordes of deadly shells that rip through both infantry and aerial units in just a few moments. A unique feature of Gattling weapons is that the longer they fire, the faster the barrels spin and the more damage the weapons cause, having three firing "speeds". Because of this, Gattling Tanks are most useful in prolonged firefights.
Chaos Drone
Cost: $600 | Prerequisites: none
This small drone has no conventional weaponry on its own. However, when deployed, it releases clouds of hallucinatory toxins that drive enemies berserk. Berserk units' attack power is greatly increased and they will automatically target friendly units before they attack enemies. The effect lasts for a period of time, but the "timer" resets every time the unit gets in contact with the toxins.
Cost: $1000 | Prerequisites: Psychic Radar
The Magnetron is Yuri's equivalent to artillery vehicles. When used against enemy vehicles (or ships if they can be reached), the Magnetron unleashes a powerful magnetic force that levitates the enemy vehicle, pulling it toward itself, where it can be dealt with by the units supporting the Magnetron. Additionally, the Magnetron can deal significant damage to structures by firing an intense magnetic beam at them. The main drawback of the Magnetron is that it is virtually defenceless against enemy infantry, having no effective weapon against them and no ability to crush them. Like other artillery vehicles, it is poorly armoured.
Mobile Construction Vehicle (MCV)
Cost: $3000 | Prerequisites: Grinder
As you will see in the section on Yuri's buildings, the heart of every base is the Construction Yard. When deployed, this vehicle becomes a Construction Yard, providing you with all of the benefits of that building. To deploy an MCV, select the vehicle and hold the cursor over it. If the cursor changes to a golden circle with four arrows, left-clicking on it will deploy the vehicle. If the cursor has a red circle with a line through it, there is either not enough room to deploy or something is in the way. Move the vehicle (or the offending object) to find a suitable deployment site. The MCV is poorly armoured in its mobile state and must be protected at all costs.
Master Mind
Cost: $1750 | Prerequisites: Battle Lab
Another extension of Yuri's mind control technology, the Master Mind vehicle is capable of safely controlling the minds of up to 3 enemy units at a time. However, this unit can't stop itself from mind-controlling additional enemy units. Exceeding its unit limit causes the device to break down and self-destruct, releasing all of its formerly captured units, unless enough of the controlled units are disposed of in time.
Floating Disc
Cost: $1750 | Prerequisites: Battle Lab
The Floating Disc is a multi-functional unit. Its small laser is effective against infantry units, including Allied Rocketeers, and can also cause moderate damage to both vehicles and structures. More significantly, if placed over an enemy Power Plant, the Floating Disc immediately powers down the entire base. Floating Discs can also be stationed over enemy Refineries or Slave Miners, siphoning credits to feed Yuri's war effort. A Floating Disc placed over any defensive structure that requires power effectively shuts off that structure.
Amphibious Transport
Cost: $900 | Prerequisites: none
The Amphibious Transport is used to transport units from place to place, having 12 slots available. While not invisible to radar like the Nighthawk Transport, the hovercraft is capable of carrying vehicles as well as infantry. It can cross both land and water, allowing for amphibious assaults of enemy positions. This vehicle has no armament, but has the same armour as the Soviet equivalent, meaning it is more resilient than its Allied counterpart.
Cost: $2000 | Prerequisites: Psychic Radar
Like Soviet Typhoon Subs, the Boomer is a submerged unit, capable of closing in on an enemy position without being spotted. Against other naval foes, the Boomer is capable of launching deadly torpedoes. However, it is their ballistic missiles, which are used against ground targets, that make the Boomer such a deadly foe. However, much like the rockets from V3 Launchers and Dreadnoughts, the missiles can be destroyed mid-air by anti-air weaponry. Giant Squids are unable to envelop them like other ships, so they have to pound them with tentacles instead. When attacked or badly damaged, they are visible to all other units.
Back to Command & Conquer: Red Alert 2 – Yuri's Revenge Index


text:
The view of Hidden Lake in Glacier National Park at sunset. I would have loved to have had more time to hike down to the lake. Guess I'll have to do that next time I'm in the park. :-)
Close to the Continental Divide on the Hidden Lake Trail in Glacier National Park. I made this shot as the sun was setting behind Clements Mountain behind me.

subset: commoncrawl


text:
Update your browser to view this website correctly.Update my browser now
Fly Scanner search engine allows you to save money by comparing hundreds of flight deals in seconds, finding the offer that's right for you. Filter your search according to the parameters that interest you and Fly Scanner will show you only the offers that suit your needs.
If you're looking only for direct flights to Lahore, with our search engine you can filter the offers of hundreds of companies to get only the cheapest direct flights from Manchester to Lahore. Avoid unnecessary waste of time, compare all offers in one search.
With Fly Scanner you will find all flight offers from Manchester to Lahore in one place, without wasting time. In just a few seconds you can compare all available flight offers and find the one that is most convenient for you.
The search engine Fly Scanner will show you in a few seconds airline tickets with the cheapest prices, including only results based on your preferences: the wide choice of filters will help you find the flight that best suits your needs, such as exclusively Manchester - Lahore direct flights.
The lowest price in the last 15 days for an airline ticket from Manchester to Lahore is $287.
Manchester is approximately 3980 mi from Lahore.
Lahore has one airport: Lahore.
Manchester has one airport: Manchester - Ringway.
The most searched cities in Pakistan according to our users are: Lahore, Islamabad, Sialkot, Karachi, Peshawar.
Are you looking for the cheapest price for your next flight ticket? Fly Scanner offers you the best solutions for the route Manchester - Lahore, showing you all the options for schedules and prices, depending on your needs.


text: THE LEGEND OF LONGWOOD (IFI FAMILY) Director: LISA MULCAHY 99 mins, Netherlands-Ireland-Germany, 2017, Digital Book cinema tickets This film screened 25th March 2018. This film is F-Rated. Find out more here. 12-year-old horse-loving Mickey Miller is none too happy moving to small-town Ireland from New York. Wandering near her new home she finds a wild stallion, Silver, and local boy Sean tells her the myth of the legendary Black Knight, who can be seen roaming the land on horseback. When they uncover a local woman's wicked plot to steal land, the grazing ground of a herd of wild horses, Mickey and Sean must use all of their wits and bravery to save the horses, with unexpected help from the mysterious Black Knight. Tickets: €4.80 per person, €14.40 family ticket (2 adults + 2 children, 1 adult + 3 children) Notes by Alicia McGivern Director: LISA MULCAHY 99 mins, Netherlands-Ireland-Germany, 2017, Digital


text:
Flora Crochet Hat - Black
$83 Sale • Save
Step out in style on beautiful sunny days. Brunna Co.'s Flora Hat is the perfect addition to your wardrobe for any occasion, from having a relaxing picnic on the grass to enjoying your time with friends outdoors. This gorgeous crochet hat made from 100% cotton yarn, complete with an eye-catching flower pattern, is designed to give a fun and feminine fit.
Sizing + Fit
Sustainability + Ethics
About Brunna Co
To learn more about Brunna Co, check out our brand directory.


text:
Kumerican rapper Derrick Sarfo Kantanka, stage name Amerado has released his much-anticipated Patience E.P. https://yve.fanlink.to/PatienceEP
According to Amerado, this E.P was named Patience as a story to enlighten the world on how Patience moves mountains. The 7 track project features appearances from Black Sherrif, Fameye, Shatta Wale, Benerl, Kweku Flick, YPee, and Aba Rainbow.
View this post on Instagram
Patience E.P Tracklist
- 1. Abotr3 (Patience) ft Black Sherrif
- 2. My Dairy ft Aba Rainbow
- 3. Fr3 me ft Benerl
- 4. Sing Along
- 5. Sika Dam ft Fameye & Shatta Wale
- 6. Sika Besu ft Kweku Flick & YPee
- 7. Selflessness ft Kojo Luda, 4tune, Mbee & Adomakye
Abotr3(Patience) which features Black Sherif sends the message of how necessary it is to be serene. "My Diary" talks about the things planned for the future. "Fr3 Me" in translation "Call me" expresses his wish to be called by his lover. "Sing-Along" talks about how he wants his followers to sing along with him.
"Sika Dam" meaning crazy over money also speaks about how this generation is willing to do anything for the sake of money and it features the self-acclaimed African dancehall King Shatta Wale and Fameye,
View this post on Instagram
"Sika Besu" literally meaning Money will cry also talks about how spendthrift he will be when gets money to the extreme. 'Selflessness' speaks of how much he is concerned with the needs of others than with himself. He featured four upcoming rappers; Kojo Luda, NBee, 4Tune, and Adomakye.
This E.P was released on October 26, 2021. The E.P is a mixture of Trap, Hip-hop, and Rap music. It was produced by Samsney and Apya. Stream and add this masterpiece to your Playlist.
stream "Patience" below:
Osafo Daniel
Related posts
* You will receive the latest news and updates on your favorite celebrities!
Quick Read!
Moonchild Sanelly Signs With Transgressive Records And Releases New Single
FacebookTweetPinLinkedInEmail Talented musician Moonchild Sanelly, has debuted her new single titled Bashiri. The banger ribs preachers, who use the church for capital gain. Moonchild whose career…
Nigeria's Fireboy DML releases Apple Music Session
FacebookTweetPinLinkedInEmail Nigerian musician Fireboy DML has released four newly recorded tracks as part of the Apple Music Home Session series.The Apple Music Home Session project involves…


text:
Lençóis Maranhenses National Park (Brazil)
Lençóis Maranhenses National Park is located in northeastern Brazil. The park includes 43 mi of coastline and an interior composed of rolling sand dunes. During the rainy season, the valleys among the dunes fill with freshwater lagoons, prevented from draining due to the impermeable rock beneath.
Lençóis Maranhenses National Park
Lençóis Maranhenses National Park is located in Maranhão state in northeastern Brazil, just east of the Baía de São José. The 155,000 ha (380,000 acre) park includes 70 km (43 mi) of coastline and an interior composed of rolling sand dunes.
During the rainy season, the valleys among the dunes fill with freshwater lagoons, prevented from draining due to the impermeable rock beneath.
While much of Lençóis Maranhenses National Park has the appearance of a desert, the area receives about 1,200 mm (47 in) of rain per year, while deserts, by definition, receive less than 250 mm (10 in) annually. About 70% of this rainfall occurs between the months of January and May.
The sand is carried to the park from the interior of the continent by the Parnaíba and Preguiças rivers, where it is then driven back inland up to 50 km (31 mi) by winds, creating a series of sand dunes rising as much as 40 m (130 ft) tall.
During the rainy season, between the months of January and June, the rainstorms fill the spaces among the dunes with fresh water lagoons of up to 100 m (330 ft) in length and 3 m (10 ft) in depth, and together comprising as much as 41% of the area of the park. The water in the lagoons is prevented from draining by a layer of impermeable rock located beneath the sandy surface.
The lagoons typically have a temperature between 27.5 °C (81.5 °F) and 32 °C (90 °F), pH of between 4.9 and 6.2, and low levels of dissolved nutrients. When the dry season returns, the pools quickly evaporate, losing as much as 1 m (3 ft) of depth per month.
In the interior of the park are located two oases or restingas, Queimada do Britos, covering an area of 1,100 ha (2,700 acres) and Baixa Grande, covering an area of 850 ha (2,100 acres).
The area of the park has an average annual temperature of between 26°C (79°F) and 28.5°C (83.3°F) and an annual temperature variation of about 1.1°C (2°F).
The lagoons in the park are often interconnected with one another, as well as with the rivers that run through the area. They are home to a number of fish and insect species, including the wolf fish, which burrows down into wet layers of mud and remains dormant during the dry season.
Besides the dunes that form the centerpiece of the park, the ecosystem also includes area of restinga and mangrove ecosystems.
Lençóis Maranhenses National Park is home to four species listed as endangered, the scarlet ibis (Eudocimus ruber), the neotropical otter (Lontra longicaudis), the oncilla (Leopardus tigrinus) and the West Indian manatee (Trichechus manatus). The park also includes 133 species of plants, 112 species of birds, and at least 42 species of reptiles.
In 2017, Lençóis Maranhenses National Park was added to the UNESCO World Heritage Tentative List due to its natural significance.


text:
We welcome revelant and respectful comments. Off-topic comments and spam will be removed.
While mirrors often get used for checking your physical appearance, they can also make rooms in your home appear larger and brighter. Yet, these reflective surfaces can get dirtied with dust and dirt over time. As you change clothes, comb your hair, and brush your teeth, you may spread flecks of hair, fibers, and other debris onto the exterior. As you clean these away, leftover streaks and smudges can cause your mirror to look even worse. You may put tremendous effort into getting your reflective furnishings cleaned but create a mess that is just as bad.
Even if this has cleaning issue has happened multiple times in the past, you can move past this problem. With new products and techniques, you can have shinier mirrors right away. Continue reading below to discover new ways to clean your mirrors.
Using Natural Products To Clean Your Mirrors
There are many glass cleaning products you can find at a nearby store, but you can also use natural items that you may have around your home. These can be just as effective as a store-bought cleanser and are often better for the environment and your household.
Rubbing Alcohol
Dried on toothpaste, hairspray residue, and other sticky remnants can be more challenging to remove from your mirrors. When you have a buildup like this, you can use 70% isopropyl alcohol (rubbing alcohol) to improve the look. Many people think that a higher concentration is more satisfactory, but 70% is better for disinfecting. The increased water in this percentage causes it to dissolve slowly and makes it more capable of killing bacteria. You can apply the alcohol to a cloth or cotton pad and rub away at these problem areas. Once the stuck-on dirt gets removed, wipe over the mirror with long strokes rather than circular motions.
Lemon Juice
If you have ever tasted a lemon or a tart glass of lemonade, you know how acidic it can be. This harsh characteristic is why lemon juice is great to use on your mirrors. Get started by mixing three tablespoons of lemon juice with one cup of water in a spray bottle or a bowl, this cleaning solution will sweep away any dirt with a microfiber cloth.
Vinegar is a great way to break up the grime gathered on your mirror and allow you to wipe the dirt away without leaving streaks. Not only is it helpful on your mirrors, but you can use it on your windows, photo frames, glass tables, and more. To get this done, pour 1 cup of vinegar with a cup of water into a spray bottle and spritz the site you want to clean. Avoid using a napkin that will leave behind small particles, and use a microfiber cloth instead.
Black Tea
Removing Stains From Your Mirrors
It can get hard to have the spotless facade you expect when skincare products, makeup, or fingerprints land on your mirrors. To get these removed, you may need a bit more elbow grease. Get going by making a mental note of the places you plan to address. After that, add 70% rubbing alcohol to a small cotton pad and rub the discolored areas until they are clear again.
If grime has accumulated on the corners of your mirror, use an old toothbrush to scrub those places. Add alcohol to a spray bottle and squirt the areas that need scouring. Once you get done, apply an even mist to your mirror without over spraying it and wipe it clean.
Helpful Tips To Get Improved Results With Your Mirrors
Contain the Mess
If you soak the mirror with your choice of a cleaning solution, the excess liquid may flow down to the counter or floor underneath your mirror. This approach will give you additional work to handle and make your cleaning task more difficult. You would get better results if you spritz your cleaner at the top and work down to the bottom with long horizontal motions.
Avoid Newspaper
You may have heard about older traditions that include cleaning your mirrors with a newspaper. Yet, that is not as effective today. The paper and ink currently used in these journals are different from what was used in the past. The ones available today are more likely to transfer ink onto your mirror and cause the surface to become more clouded.
Do Not Touch
While you clean your mirror, you may find yourself touching parts of it while attaining your results. But, this can ruin your work and require you to repeat your efforts. You will gain more success by folding your cloth as you clean and keeping your fingers away. Also, when you get done, you should stand back and glance at the mirror from various angles to see if you missed any stains or accidentally left your fingerprints behind.
Establish a Routine
If your mirrors get very dirty, they can diminish the look of your room and become overwhelming to manage. Yet, using a cleaning routine will help attain more enjoyment from having them in your home and provide an easier time keeping them polished. If you wipe them with a damp cloth at least once a month, you will always have sparkling mirrors in your home.
Enjoy a Superior House Cleaning Service
Scrubbing your mirrors can become a time-consuming task, particularly if your house has multiple mirrors. Getting this accomplished can take up the moments you need for more significant activities, like bonding with your family or accomplishing career goals. Often, you will be more content if you hire our professional cleaning team for help. At Cleanzen, we can provide superior cleaning services to ensure your home stays clean and healthy. Please call us today to schedule an appointment.


text:
Provide 15 pages on the selected topics (mentioned below) in a marketing plan for a new product, which is a mobile called "OnePlus 7B" which basically, a new phone for OnePlus. OnePlus competes with the high-end phones of Samsung and iPhone. Our new product is catering to compete with budget phones.
The content :
2.Swot analysis
3.Marketing Objectives and Goals
4. financial analysis (introduction, Assumptions, Break Even Analysis, Revenue Projections, Sales, Project Profit and Loss, Pro Forma Profit, and Loss, Pro Forma Cash Flow,Pro Forma Balance Sheet,Ratio Analysis,Proforma Sales Forecast)
5.financial risk assessment
6.Operational plan
7. Hr plan
8. Risk assessment plan
9. Hazard risk assessment
1. Every paper typed in this course should be in APA formatting (title page, reference page, NO abstract page, in-text citations, running head, page numbers, Times New Roman 12 font, 1-inch margins, double-spacing, etc…).
2.References (this does not count toward the required paper length).
3. use schorly articles only for the references and do not use any blog for reference. Provide at least 10 scholarly articles for the reference.


text:
Working Capital: Why Is It Important and How to Calculate It?
The general definition of working capital is the funds required to meet the regular expenses of a business. Such costs include utility bills, rent, wages, etc.
It is also sometimes known as net working capital, i.e. your gross working capital minus your current financial liabilities. Gross working capital is the total current assets of a business.
Current assets are those assets that can be converted into cash within one year. These include accounts receivable, finished goods, inventory, etc. Current liabilities are accounts payable, income tax, overdrafts, etc.
Importance of working capital
Working capital is crucial for the continuation of business operations. Hence, businesses opt for a working capital loan when faced with a deficit.
Some of the reasons working capital is important to include:
Continuous production cycle
Manufacturing companies must maintain an uninterrupted production cycle to ensure their business stays operational. They can follow some useful tips to manage their working capital efficiently. On the other hand, low working capital will decrease its liquidity.
Improves liquidity position
Liquidity is a business's ability to convert its current assets to cash. A continuous flow of working capital ensures that the liquidity and solvency position of a company is high.
Guarantees payment of regular expenses
Working capital is crucial as it ensures a business can pay off the day-to-day costs mentioned above.
Also, debtors are paid off in due time if a firm has adequate working capital. Doing so not only increases its goodwill but also may enable the company to earn discounts from suppliers.
Ability to avert a crisis
Working capital can make or break a business; it is vital to tackle situations like a financial crisis or an economic downturn.
NBFCs provide working capital loans that come to the rescue especially in such situations. Also, an adequate flow of working capital can help a firm avail a high-value business loan with ease.
Regular dividend payments
A public company is obligated to pay dividends to its shareholders regularly. Hence, it needs to have ample working capital to make sure such payments are dispersed accordingly.
Proper utilization of fixed assets
A business with a regular working capital can make use of fixed assets accurately. On the other hand, such assets will stop operating if working capital is low. Also, firms will incur depreciation and interest unnecessarily on idle fixed assists.
Hence, working capital is essential to maintain all the above. Businesses can opt for a working capital loan in case the same is low to avoid critical scenarios.
Features of working capital loans
Ample financing to meet the short-term deficit
NBFCs can provide Working Capital Loans of up to Rs. 30 Lakh that can help businesses to address their working capital deficit.
Quick approval that helps in emergencies
Customers can avail these loans within 24 hours. Hence, working capital loans can help businesses out during critical funding needs.
Convenient and flexible repayment tenors
The repayment tenors for a working capital loan ranges from 12 to 60 months. Usually, the total interest payable increases with longer tenors and vice versa.
Only a few documents required to apply
Applicants only have to provide KYC documents, proof of business, relevant financial documents, and bank account statement to apply for these loans.
Minimal eligibility criteria to fulfill
Businesses have to be at least 3 years old and file income tax returns for at least the previous year before applying for working capital loans.
Other than the above, the business loan interest rate is also competitive making it affordable for small businesses.
Working capital loans are a vital and popular financial tool for small businesses. Such advances provide the necessary financial assistance in times of need to help a business meet its short-term goals against a comparatively nominal long-term financial liability.
How To Give Your Home A Facelift: Expert Fence Modification in Katy TX
A Guide To Purchasing Artificial Grass Las Vegas What You Need To Know
Airconditioner-Technician Co in Kuwait: Providing Quality Services to Keep You Cool
Women@KD4 days ago
Expenses for a New Baby you didn't think about
Women@KD4 days ago
6 Tips to Make Baby Shower Special for Moms
Women@KD4 days ago
5 Ways on How Women Should Create Networks
Women@KD4 days ago
Parenting Tip: 6 Simple Ways a Single Parent Can Have a Work-Life Balance
Marketing4 days ago
How To Use Social Media Proxies To Grow Your Business
Marketing4 days ago
Key Moves You Can Make To Improve Your Marketing Strategy Today
Marketing4 days ago
How to Develop an Effective Digital Marketing Strategy?
Marketing4 days ago
7 Ways Successful Salespeople Prepare for Finalist Meetings


text:
|COOKIES: By using this website you agree that we can place Google Analytics Cookies on your device for performance monitoring.
University of Cambridge > Talks.cam > CUES > Seismically-Resistant Housing Design and Disaster Reconstruction in El Salvador
Seismically-Resistant Housing Design and Disaster Reconstruction in El Salvador
Add to your list(s) Download to your calendar using vCal
If you have a question about this talk, please contact Gerd Grau.
Abstract not available
This talk is part of the CUES series.
This talk is included in these lists:
Note that ex-directory lists are not shown.
Other listsChanging Health Spring School 2010 - 'Axon-Glia Biology in Health and Disease' Cambridge Centre for Political Thought
Other talksHow to Deploy Psychometrics Successfully in an Organisation Cohomology of the moduli space of curves Developmental cognitive neuroscience Babraham Lecture - Understanding how the p53 onco-suppressor gene works: hints from the P2X7 ATP receptor The Ambonese Rumphius and his inter-island information networks Social support and breastfeeding in the UK: evolutionary perspectives and implications for public health Liver Regeneration in the Damaged Liver Coin Betting for Backprop without Learning Rates and More Graph Legendrians and SL2 local systems 100 Problems around Scalar Curvature The Rise of Augmented Intelligence in Edge Networks Cambridge-Lausanne Workshop 2018 - Day 2


text:
Marcus Lusk
Licensed Professional Counselor , MA, LPC
This profile listing has not been claimed by the owner yet.
Claim this profile by updating your work details and let potential prospects reach out to you easily.
Claim this profile by updating your work details and let potential prospects reach out to you easily.
Marcus Lusk is a Licensed Professional Counselor , MA, LPC, and is based out of Cartersville, Georgia, United States. Marcus specializes in the counseling of Anxiety, Trauma and PTSD, Depression, etc. The therapist has experience in handling cases of ADHD, Addiction, Alcohol Use, Anger Management, Asperger's Syndrome, Autism, Behavioral Issues, Bipolar Disorder, Borderline Personality, Child or Adolescent, Chronic Impulsivity, Codependency, Coping Skills, Divorce, Domestic Violence, Drug Abuse, Dual Diagnosis, Emotional Disturbance, Family Conflict, Gambling, Grief, Hoarding, Infidelity, Internet Addiction, Life Coaching, Life Transitions, Medication Management, Men's Issues, Obesity, Obsessive-Compulsive (OCD), Oppositional Defiance, Parenting, Peer Relationships, Relationship Issues, School Issues, Self Esteem, Self-Harming, Sex Therapy, Sexual Abuse, Sexual Addiction, Sleep or Insomnia, Spirituality, Stress, Substance Use, Suicidal Ideation, Teen Violence, Weight Loss, and more. The types of therapies Marcus offers include, Cognitive Behavioral Therapy, Dialectical Behavior Therapy, Trauma Focused Cognitive Behavioral Therapy therapy.
- Addiction
- Anger Management
- Autism
- Behavioral Issues
- Bipolar Disorder
- Coping Skills
- Divorce
- Domestic Violence
- Drug Abuse
- Dual Diagnosis
- Family Conflict
- Grief
- Hoarding
- Infidelity
- Internet Addiction
- Life Coaching
- Life Transitions
- Obesity
- Parenting
- Relationship Issues
- Self Esteem
- Sleep or Insomnia
- Spirituality
- Teen Violence
- Weight Loss
Types of Therapy:
- Cognitive Behavioral Therapy
- Dialectical Behavior Therapy
- Trauma Focused Cognitive Behavioral Therapy
Language(s) Spoken:
- English


text:
Baby sewing patterns
Discover Pinterest's 10 best ideas and inspiration for Baby sewing patterns. Get inspired and try out new things.
Kids Pants with Free Pattern! Easy and quick to make elastic waist pull up pants in 8 sizes from 6m to 5 year old. These pants can be made in flannel, cotton, linen, denim, knit, and sweater knit.
Alex Lynn Crafts saved to Patterns & Tutorials
This is a great sewing project for beginners and perfect for using up scrap pieces of fabrics.
Ruffles add instant cuteness to a pair of plain pants and they really are easy to make! Madeline has already outgrown all the pants I made for her and if you've been following me on Facebook, you p…
Vanity Hendrix saved to Clothes
DIY TODDLER BACKPACK | Cute Bag for baby Sewing Tutorial [sewingtimes]
Mini backpack pdf sewing pattern, Kids drawstring bag tutorial, DIY animal backpack digital download
Mini backpack sewing pattern and tutorial will help to make gift for toddlers, babies, kids and children without any problem. Pattern available in ENGLISH. You will receive a PDF file. The download will be available immediately after payment confirmation. You will receive a PDF file which includes the following: ✔ a materials list; ✔ step by step instructions; ✔ pdf pattern file for printing. The file can be printed using your home printer on A4 or US Letter paper formats.
4 Free Baby Pants Sewing patterns tested out, with pictures and fit notes alongside fun fabric choices.
Swoodson Says saved to Free Sewing Patterns
Cool DIY Fabric Toy Alpaca / Llama Free Sewing Patterns Video
Joan Collins saved to sewing crochet knitting


text:
We, the team of The Job Men are pleased to inform you that there are Freshers Hiring in TIAA for Trainee for all the students passing in the 2021 batch. The Job Men is an online website developed to help talented and hardworking minds in joining the right organization. The details for the Freshers Hiring in TIAA are mentioned below:
We at The Job Men minimize the gap between opportunity and real talent. Our team posts a lot of opportunities (Jobs and internships) for you all to get you a starting kick to your career. We believe in transparency as we have mentioned all the necessary, required, and relevant details/links in every article for the ease of the candidate. We would highly recommend you to read down the Job Profile, Job description, Job Location, Bond, Pay Package and etc. from the official websites of the organizations, for your ease we have mentioned the official Websites also.
Reviews are also an important factor to determine the reputation of any organization and therefore the content table is rich with review links too. We are open to any feedback, doubt, suggestions mail us at email@example.com. Your contribution will help the entire community!
About TIAA:
The Teachers Insurance and Annuity Association of America-College Retirement Equities Fund is a Fortune 100 financial services organization that is the leading provider of financial services in the academic, research, medical, cultural and governmental fields.
Detailed Chart for Freshers Hiring in TIAA
|Published Date
|Company Name
|Job Profile
|Eligibility Criteria
|High School Preferred
|As per Company Standards
|No Information
|Job Description
|Assists with writing business requirements and technical specification documents to design and develop technical solutions that meet business needs.
Coordinates with information technology (IT) contacts and business partners to design, develop, and troubleshoot end-to-end technical solutions.
Performs basic coding to written technical specifications.
Reviews the resulting coding components in accordance with company standards and as defined in approved testing plans.
|No Information
|Registration Link
|Registration Link
|Registration Deadline
|No Information
|Company's Website
|TIAA Website Link
|Company's Reviews
|TIAA Reviews – Glassdoor
TIAA Reviews – Indeed
Skills Required for Freshers Hiring in TIAA:
- Detail-oriented.
- Leadership skills.
- Interpersonal skills.
- Reliable.
- Problem-solving skills.
- Organizational skills.
- Communication skills (both written and verbal)
- Presentation skills.
TIAA Hiring Process:
Check out the complete process of Freshers Hiring in TIAA. Click here to know.
Note: The details mentioned are correct at the time of posting this article. However, we highly recommend you to check out the Job Description on the official company's website. Job Men or any of our employees won't be responsible for any miss- happening. The details posted here are nowhere related to thejobmen. The complete content is picked from the official website of the organization and we don't own it. We are posting the same for the maximum benefits of candidates as well as organizations.
The job Process may be tough and leave you feeling nervous/helpless. But your talent and focus will win them over. Good luck for the day and may you observe the best results. Wish you the very best in the process. We would love to hear your success stories. We'll feature the same on our website.
In case you are looking for jobs or internships, we would highly recommend you to stay in touch with The Job Men, as we are posting a bunch of opportunities daily. Stay connected to The Job Men for more such updates regarding Jobs and Internships for freshers as well as experienced ones. Don't forget to share about Freshers Hiring in TIAA with your friends and colleagues.


text:
Out in HM Land Registry
"I can honestly say that I've never felt so comfortable as a gay man in any place of work." Oliver Ducker explains how HM Land Registry provides the welcoming environment every colleague deserves.
"I can honestly say that I've never felt so comfortable as a gay man in any place of work." Oliver Ducker explains how HM Land Registry provides the welcoming environment every colleague deserves.
Joining the communications team at HM Land Registry was daunting for Government Communication Service Apprentice Olivia Frost but she quickly learned her voice and ideas were valued.
Most first registrations are your typical residential properties, such as flats, garden land and houses. So it's interesting when we receive applications to register property that are not the norm.
The Stonewall riots in 1969 were a landmark in the civil rights movement for lesbian, gay, bisexual and transgender people. Rory Nicholls explains what Stonewall means to him and why he's proud to represent HM Land Registry.
Our Workflow system helps manage the 20,000 applications we receive each day. Charlotte Fretwell explains its transformational impact, now recognised by an award from our IT industry peers.
Rebecca shares her experience of working at HM Land Registry to show how autism can be different for girls.
When Erin Tregunna started her IT apprenticeship at HM Land Registry, she was looking for a career change and an opportunity to work in a fast-paced environment. The experience has been both inspiring and extremely rewarding.
How did a job as a climate change researcher lead to the role of Head of IT Operations at HM Land Registry? Rachel Jones, newly nominated for a Women in IT Award, takes us on the journey.
At HM Land Registry we enjoy a huge amount of health and wellbeing support and a thriving Disabled Employee Network. We're celebrating the current Disability History Month and this year's theme of Disability and Music.
From Tomb Raider to software development, Heather Poole talks about her interesting and fulfilling IT career so far.


text:
It's been a March Madness kind of week!
To be honest, I'm not #winning my bracket right now. I chose teams based on my love for the school, or the coach, or if they've been an underdog. It's not driven by stats or critic choices, I choose with emotion and I love March Madness season!
What really inspires me during March Madness is watching teams play with great finesse and character. An orchestrated team that doesn't give up.
So why am I talking about March Madness in this blog? Well, one it is March, clearly; and two, thinking about the components of a great team made me think of all the great teams I know at senior communities.
Stick with me.
Let me compare the make up of a basketball team in this senior community break down:
The Head Coach - The Administrator
The Administrator calls the plays and leads the team. Everyone looks to the Administrator in a senior community for guidance, procedure, and proper protocol. They lead their team and their team is vast: Residents, Families, Staff, and Community. Administrators stand strong when celebrated and unwavered when times are difficult. We definitely saw this during the last few years of the pandemic. #automatic
Power Forward - Activities
Activities play both offense and defense every single day. Activities move swiftly on their feet around the community engaging residents in physical, social, and mental activities designed to keep residents happy and healthy. #onit
The Center - Director of Nursing
The Center is responsible for standing strong in the middle. In comes the Director of Nursing. They are responsible for maintaining excellence in care, while going the extra mile for residents at times when health issues arise, or even more trying, when the resident transitions to a higher place. They make call the shots that change the course of the game of life. Every day. There are no easy #layups.
Forward - Social Services
The small forward roams all over the court, just like Social Services does in a senior community. This teammate ensures the safety of the residents, managing families needs and expectation, all the while keeping staff up to date on policies and procedures within the community. #droppingdimes
Point Guard - Marketing
Marketing would play the point guard position on a dream team. Always charged with building census and boosting online reviews, Marketing connects with referral sources to secure a safe and caring place for future residents to call home. #makingitrain
Shooting Guard - Admissions
Making shots and stealth dribbling is what makes the shooting guard a key part of the dream team. Meet the Admissions Director. Navigating through the admissions process can be cumbersome but completing a packet with a resident/responsible party and family is crucial and requires confidence, compassion, and willfulness to get the job done right. #swish
There are definitely others staff members that are essential to the overall success of a senior community. The last couple years of playing in a pandemic bracket have been insanely challenging. Congrats to all the dream teams out there! #dreamteam
Katie, Client Success


text:
Running on Empty
If Mental Fatigue is draining your battery, it's time to shut down the computer of your mind and reboot.
Recently, I asked a client if she would rather think about her job for twelve hours or go run a marathon. Without missing a beat, she said "Oh, the marathon would be way easier."
Almost everyone I talk to lately is experiencing some sort of mental fatigue: COVID fatigue, social media fatigue, politics fatigue, homeschool fatigue, parenting fatigue, or worst yet, the I-already-watched-everything-on-Netflix-fatigue. Which means, in a nutshell, that we are exhausted because we are over-thinking.
Don't get me wrong, our intellect is amazing. It is like a supercomputer allowing us to access all of the things that we know in order to retrieve stored data and utilize it in our daily lives. We use our intellect to memorize a work presentation or a yoga routine, to know all the lyrics to the latest Lizzo tune, and to recite the second law of thermodynamics.
The key about the intellect is that it is best used for what is "known", quickly retrieving what we have already stored in our mental vault. Just like a computer with massive amounts of data but no internet connection, if the data isn't saved in the files, it cannot be located. We cannot retrieve what we don't know.
With an unprecedented amount of "unknown" happening in our 2020 world, it's no wonder that our batteries are drained trying to figure out the unfigure-out-able. There are the unknowns of the pandemic, the American election, social and environmental issues, just to name the obvious large ones. With the onslaught of larger unknowns the safety and security of our individual lives seem untenable and unhinged.
There are the more personal unknowns being excavated and moved to the surface. Am I in the right job, relationship, house? What will happen if I get Covid? How can I help my kids with school when I'm so busy? What will happen if my political opponent doesn't win? Why is it so warm this winter? Why can't I stop checking Instagram?
Unlike a marathon, there is no finish line in sight. It's worrisome. Not knowing sucks and is uncomfortable. Our intellect is turned on and ready to go. Like the best in class, it really wants to do a good job, to receive its gold star for finding the known.
Since most of these topics are actually unknown, our intellect just circles in a never-ending loop, like a dog chasing its tail, never finding the answer it seeks. It keeps searching over and over for the data that just isn't there. And as a result, we experience fatigue, burnout, and mental exhaustion. Like my client mentioned, this mental fatigue feels way worse than physical exhaustion and can often lead to real health concerns.
What many people don't realize is that the intellect is not our only mental tool. We also possess something I like to call the deeper mind. You might call it intuition, wisdom, inner knowing, presence, or peace. It is found in the quiet space before thought is formed. We often feel it in moments throughout the day, usually when our mind is distracted by rote tasks like chopping vegetables or walking the dog.
The tricky thing is that the deeper mind has a hard time operating while the intellect is running at full speed. It tends to turn on once the intellect turns off. If our intellect is like a computer with a large hard drive but no internet, then our deeper mind is like a tablet that has high speed internet but no storage. It can only retrieve information for the present moment, because it is a real-time responsive intelligence. But it requires your presence.
Many of us have been living with our intellect on full blast for our whole lives. We forget what the connection to our deeper mind feels like — like a vacation on a white sandy beach, toes dug in the sand, and an extra-large Cadillac margarita in your hand. Once we become more familiar with the deeper mind, we begin to trust it more. We gain a confidence in navigating the "unknown" knowing that we will know when we will know. We can begin to press pause on the over-processing of our intellect.
It may come as a surprise but the feeling of fatigue is helping us to wake up to our current state of mind. We can recognize when we're stuck in an intellectual loop of thinking by the exhausting, draining feeling. If a computer begins to run more slowly, make funny noises, or the image gets pixelated — those are signs that it's overheating. Similarly, our feeling of mental exhaustion helps us to know that our minds are running too hot.
What do we do? STOP!
Really. The more important or hurried that our thinking feels is the signal that we're going in the wrong direction. It is the 404 error of our mind. That mentally draining feeling is helping us to know that we're stuck in a loop. And the only way out of the loop is to stop, shut down the computer, take a reboot.
Don't worry, I'm not talking about stopping our life and all of the tasks that are required to live it. I'm talking about slowing the internal setting of the mind. Simply notice that we're over-using our intellect and trust that we'll be OK if we set it down for awhile. In other words, relax our mind.
We often think of relaxing as a doing. It requires a vacation to Mexico or going to a yoga class, or drinking a glass (or seven) of wine. The truth is, relaxing is an un-doing. If our thoughts are like the snow swirling in a snow globe, set down the snow globe and allow it to settle at the bottom in between the plastic trees. Even if just for a few moments.
Just as with the snow globe, when the thinking settles we can see the scene more clearly. Once we relax into a slower mind, it allows access to the deeper mind where creative ideas, clarity, wisdom, and intuition reside.
The deeper mind responds to what you need in the moment. So if there's a resurgence of the pandemic and we need to lock down our country again, we will pivot and know what to do in the moment. We don't have to spend countless hours exhausting ourselves with endless worry, running an unknown calculation into our intellect over and over again. Instead, we wait and we trust that as soon as we know, we will know.
And until then, we can relax in the not knowing and hopefully enjoy a more restful state of mind, even if for just a few peaceful minutes.


text:
PyrofORM - Python Object Relational Mapping (ORM)
Over the past week I've been working on an ORM and have been talking about it in its various stages of development on this blog. In this post I will detail its API and follow that with some sexy code examples of the ORM in action.
If you're wondering about the name—PyrofORM—I was trying to think of how to use "Py" and "ORM" together. My thought process followed this rationale: styrofoam, pyrofoam, pyroform, PyrofORM.
A definition is everything. It describes how specific data is stored, it deals with the basic read/write/delete/etc functions, it has subclasses to deal with individual rows of data (records), sets of data (record sets), and fields, and it deals with loading and storing the pickled data. The following is a description of the API to the ORM.
- install() - If the cache file is empty, this installs default data.
- setUp() - This tells the definition which fields to support, their types and their relations.
- tearDown() - This is a hook that is called in Definition.__del__() Methods
- read(row_id) - Reads a single row into a Record object, which is similar to a dictionary.
- write(data={}) - Inserts/updates a row in the cache.
- delete(row_ids=[]) - Deletes one or more rows from the cache.
- filter(**filter_fns) - Filters data out of the data set given either values or lambda functions. Returns a new Definition.RecordSet object.
- __iter__() - Lets the programmer put the definition instance directly into a loop. __iter__ calls Definition.filter() with no filtering functiosn—thus filtering all rows.
- store() - Stores the data in the cache file.
- create() - Returns a new empty Definition.Record object. Classes
Field - Represents a single allowed field in the data (like a SQL table column)
- default(val) - Allows the programmer to change the default value of a field. Otherwise, the default value of a field is None
- hasOne(cls, alias, **filter_fns)
- ownsOne(cls, alias=None, **filter_fns) - Allows one to specify a one-to-one relationship with the definition whose class is cls. If the relation is not aliases then it will be called by cls.__name__. Relations are accessible through Definition.Record.__getattr__ (see below). Ownership means that if a row in the owner definition is deleted, then all related rows in owned definition will also be deleted (cascade delete). The filters are optional to automatically apply filtering functions in the same way that Definition.filter() works.
- hasMany(cls, alias, **filter_fns)
- ownsMany(cls, alias, **filter_fns) - Allows one to specify a one-to-many relationship with another definition. See Field.ownsOne for more details.
Record - Represents a single row from the data set (like a dictionary / associative array)
- __getitem__(item) - Allows one to access the fields as record["field"] or also access them in numeric order, eg: record[0].
- __getattr__(attr) - Allows one to access any table relations as record.attr(). See Definition.Field.ownsOne.
- save() - Saves any data in this record to the definition's data set.
- delete() - Deletes any data related to this record from the definition's data set.
- id() - Returns the value of the record's implied primary key if it is saved. Otherwise it raises an IndexError.
RecordSet - Represents one or more rows from the data set.
- __len__() - Returns the number of records in the record set, for example: len(recordset)
- __getslice__(start, end) - Allows the programmer to slice a record set as if it were a list. This can be used to limit the number of results, for example: record_set[:limit].
- __getitem__(item) - Allows the programmer to access an individual row by its numeric position in the record set. Position 0 will be the first row, etc.
- next() - Returns the current record in the record set and moves the internal pointer to the next one.
- delete() - Deletes all records in the record set from the definition's data set.
- sort(**filter_fns) - Sort the rows in the record set by specific filters. To sort by a single field in ascending or descending order, do the following: recordset.sort(field=-1) (descending order).
Example: Basic Usage
Extending the Definition class is easy. In general all one would overwrite are the hook functions; however, anything can be overwritten. For example, I wrote a nested sets (modified pre-order tree traversal algorithm) implementation using this ORM that required overwriting several of the non-hook methods such as write, save, and delete.
Here is a simple demonstration of how to extend the definition class. A People class will be defined. When that class is instantiated People.setUp() will be called. It describes how data is stored in the rows of the data set of that definition. It also happens to be the place where relations to other definitions are defined. After that, if a cache file doesn't exist for it then the People.install() method will be called to create the initial data set.
#!/usr/local/bin/python import PyrofORM import types class People(PyrofORM.Definition): def setUp(self): """Set up the fields that this definition recognizes and the types that it expects their data to be in.""" self["name"] = types.StringType self["age"] = types.IntType def install(self): """Install the default data if the cache is empty.""" peter = self.create() peter["name"] = "Peter Goodman" peter["age"] = 19 peter.save() # now lets instantiate the people class and filter out the people! for person in People(): print person["name"], "is", person["age"], "years old" # output: # Peter Goodman is 19 years old
As you can see it's very straightforward. One thing that might throw you off is how fields work. Above, we set fields by doing self["field"] = and then we tell it the type it expects by telling it what it equals. Behind the scenes this actually sets self["field"] to be a new Definition.Field() object. To use the Definition.Field.default() function one would do: self["field"].default(val).
Example - Relations
There are several ways that definition relations be accomplished. The first was is by using the built in functions that were described under Definition.Field in the above API (hasOne, ownsOne, hasMany, ownsMany). Another way to describe definition relations would be to make custom filtering functions in the Definiton.Record class (or if in the above case, define a People.Record class which extends Definition.Record) and use those.
It is important to get one point across before describing the relations system: all rows in all data sets have implied primary keys. This means that all rows will automatically have a primary key set to them. There are two ways to access the value of the primary key: record.id() and record["pk"]. By design, the relations system will match a field in the current definition to the primary key field in another definition. However, this behavior can be easily changed.
#!/usr/local/bin/python import PyrofORM import types class People(PyrofORM.Definition): def setUp(self): """Set up the fields that this definition recognizes and the types that it expects their data to be in.""" self["name"] = types.StringType self["age"] = types.IntType self["job_id"] = types.IntType self["job_id"].hasOne(Jobs, alias="job") def install(self): """Install the default data if the cache is empty.""" jobs = Jobs() job = jobs.create() job["name"] = "Programmer" job.save() jobs.store() # __del__ is finicky so we will make sure the job is stored peter = self.create() peter["name"] = "Peter Goodman" peter["age"] = 19 peter["job_id"] = job.id() peter.save() class Jobs(PyrofORM.Definition): def setUp(self): self["name"] = types.StringType # now lets instantiate the people class and filter out the people! for person in People(): print person["name"], "is a", person.job()["name"] # output: # Peter Goodman is a Programmer
In the above example I have added a job_id field onto the People definition and also gave it a relation. The relation maps People.job_id to Jobs.pk (primary key). However, assuming we wanted to change the default behavior of mapping one field to the primary key of another definition then we could use one of the following:
# related self.key to ForeignDefinition.pk self["key"].hasOne(ForeignDefinition, alias="foreign") # implied other primary key, equivalent to the above self["key":].hasOne(ForeignDefinition, alias="foreign") # map self.key to ForeignDefinition.foreign_key self["key":"foreign_key"].hasOne(ForeignDefinition, alias="foreign") # implied self primary key, this table. Maps self.pk to ForeignDefinition.foreign_key self[:"foreign_key"].hasOne(ForeignDefinition, alias="foreign")
Another thing to keep in mind is that named filters can be passed as a third parameter to the has/ownsOne/Many functions.
With nifty slicing functions, lambdas, and method chaining, Python has allowed me to make a pretty spiffy system with some neat syntax. In my next post I will show the code implementation of nested sets for a category system and release the code. Until then, tell me what you think of the API to the ORM.


text:
Genetic screen identifies suppressor of morphogenesis in genitalia-1 (SMG-1) as a modulator of sorafenib resistance in hepatocellular carcinoma cell lines
- Authors:
Affiliations: Hepatobiliary Unit, Division of Gastroenterology, Department of Internal Medicine, Incheon St. Mary's Hospital, Medical School of the Catholic University of Korea, Incheon, Republic of Korea, Clinical Medicine Research Institute, Daejeon St. Mary's Hospital, Daejeon, Republic of Korea, Southern Alberta Cancer Research Institute, Departments of Biochemistry and Molecular Biology, University of Calgary, AB, Canada
- Published online on: July 10, 2014 https://doi.org/10.3892/ijo.2014.2540
- Pages: 1450-1456
This article is mentioned in:
Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms in humans and is more prevalent among Asian and African populations (1,2). Molecular analyses have shown that HCC pathogenesis is a multifactorial and multistep process reflecting alterations derived from epigenetic instability, chromosomal instability and deregulated transcription (3). Risk factors for HCC development include viral infections such as hepatitis B or C, exposure to aflatoxin B, chronic alcohol ingestion and cirrhosis from variable causes (4–6). This advanced or relapsing disease has a poor prognosis due to underlying liver disease and lack of effective systemic treatment. Moreover, conventional chemotherapy has not been demonstrated to prolong survival of patients with advanced HCC (7,8). However, recent advances in our knowledge of HCC biology have led to the development of efficient agents to treat HCC (9).
Sorafenib (Nexavar, BAY 43-9006), an orally active multikinase inhibitor, has been used to treat several malignant neoplasms such as HCC and renal cell carcinoma (10). Although monotherapy with sorafenib has been shown to significantly prolong overall survival and delay time to progression in patients with advanced HCC, the recent reports have disappointingly been unable to substantiate a reduction of tumor burden in patients with advanced HCC (11–13). Sorafenib is currently the only accepted systemic chemotherapeutic used in the treatment of HCC, and as such, there is an urgent need to elucidate the genes that diminish its effectiveness.
RNA interference (RNAi) is a powerful new tool for performing loss-of-function genetic screens in lower organisms and can greatly facilitate the identification of components of cellular signaling pathways (14,15). By suppressing gene expression and therefore, protein function to a certain extent, RNAi models the pharmacological inhibition of a target protein and can be an effective tool for proof-of-principle experiments to identify and validate cancer drug targets (16).
We performed an unbiased genetic screen on Hep3B human HCC cancer cell lines using a short hairpin RNA (shRNA) library that identified SMG-1 as a modulator of sorafenib sensitivity in vitro and executed the validation procedures to confirm whether the resultant sequenced target gene can be a significant molecular target for resistance to sorafenib treatment of HCC.
Materials and methods
Cell culture
Hep3B, HepG2 and Huh7 cells (American Tissue Culture Collection) were seeded at a density of 1×106 cm2 and routinely cultured in Dulbecco's modified Eagle's medium (DMEM, Invitrogen Life Technology Inc.) supplemented with 10% fetal bovine serum plus penicillin-streptomycin (10 IU/ml) and fungizone (2.5 μg/ml). Cultures were maintained at 37°C in a humidified 5% CO2 atmosphere.
Establishment of the retroviral vector (pRS)- and pRS shRNA-Hep3B cell line
For viral production, 2 μg of retroviral vector pRS and pRS shRNA library were transfected into 293 Ampho cell lines (1×106). After 4 days of transfection their supernatants were infected into Hep3B cell lines and selected with 1.0 μg/ml puromycin as previously described (17).
siRNA transfection
Three Stealth™ RNAi duplexes were synthesized commercially by Invitrogen Life Technologies Inc. with the help of tools available online (http://www.invitrogen.com). Stealth RNAi lines (HSS118096, HSS118097, HSS11808) were designed to target different coding regions of the human SMG-1 mRNA sequence (NCBI Reference Sequence: NM_015092.3). Hep3B, HepG2 and Huh7 cells were seeded at 4×105 cells per well in a 60-mm dish in DMEM (Invitrogen Life Technology Inc.) containing 10% fetal bovine serum (Invitrogen Life Technology Inc.). On the following day, cells were transfected with the three Stealth RNAi duplexes as directed by the manufacturer's protocol for the Hiperfect transfection reagent (Qiagen). The final concentration of Stealth RNAi was 50 nM. A control also contained siRNA Negative Control Med GC (Invitrogen Life Technology Inc.).
Reverse transcription and real-time qPCR
Total RNA was extracted from Hep3B using NucleoSpin RNA II (Macherey-Nagel, Düren, Germany). The 1 μg of total RNA was reverse-transcribed using Reverse Transcriptase Premix (Elpis Biotech, Daejeon, Korea) according to the manufacturer's instructions. The probe for TaqMan PCR was purchased from Invitrogen and real-time PCR was performed using the 7500 Fast Real-Time PCR System (Applied Biosystems, Foster City, CA). Glyceraldehyde-3-phosphate dehydrogenase was used as an internal standard and used to normalize the Ct values.
Western blot analysis
Cells were washed with PBS and harvested in lysis buffer. Proteins were separated using NuPAGE Novex 3–8% Tri-Acetate (Invitrogen Life Technology Inc.). All primary antibodies were diluted in 3% BSA in Tris-buffered saline with 0.1% Tween (TBS-T) at the following dilutions: anti-β-actin (1:1,000, Cell Signaling Technology), anti-SMG-1 (1:500, Cell Signaling Technology) and secondary HRP conjugated antibodies (Cell Signaling Technology). HRP was detected using an Immunobilon Western Chemiluminescent HRP substrate kit (Millipore). Images were scanned using a Bio-Rad ChemiDoc XRS System.
Cell proliferation assay
The cells were treated with 0–10 μmol of sorafenib. Following a 48-h incubation period, cellular proliferation was assessed using the EZ-CyTox cell viability assay kit (Daeillab, Korea). EZ-CyTox solution (10 μl) was added to each cell cultured 96-well, and the mixtures were incubated for 2 h at 37°C. Absorbance was then measured using an ELISA reader at 450 nm (microplate reader, Bio-Rad). Cellular proliferation was expressed as a percentage of vehicle-treated cells, which were defined as 100% viable.
Immunohistochemical staining
To investigate the expression of SMG-1 in 20 human hepatocellular carcinoma tissue samples, we performed immunohistochemical staining by using anti-SMG-1 (1:200, Cell Signaling Technology) to tissues that had been surgically resected or biopsied after informed consents. Enrolled patients had no previous sorafenib treatment. We designated the expression strengths as 1 (weakest staining), 2, 3 and 4 (strongest staining) after meticulous investigation of tissue slides and then compared the expression strengths of the cancer region with non-cancerous regions of resected tissue samples.
Statistical analysis
Single group comparisons were done with two-tailed Student's t-tests and one-way Anova.
Establishment of Hep3B cell lines containing the shRNA screening library
A schematic diagram shows the screening strategy employed to identify sorafenib-resistant genes from the stage of puromycin selection to sequencing of target genes (Fig. 1A). Hep3B cells known to have high sorafenib sensitivity (18) were infected with the empty retrovirus-based pRS vector or the pRS-shRNA library that can suppress 8,000 human genes (19) and selected with puromycin (1.0 μg/ml) for 2 weeks. During puromycin selection, mock cells were all dead, whereas more than 80% of the cells containing pRS vector and pRS-shRNA library survived (Fig. 1B).
Figure 1
Schematic strategy of shRNA library screening. (A) A schematic diagram shows the establishment of Hep3B cell lines containing shRNA screening library and the strategy from puromycin selection to target gene identification. (B) Viability of mock, pRS, pRS-shRNA infected cells after puromycin selection.
shRNA screen identifies genes involved in sorafenib resistance
To determine the optimal dose for shRNA library selection, Hep3B mock or Hep3B-pRS cells were treated with sorafenib (0 to 10 μM) for 4 days. The effect of sorafenib on cell viability was measured by the WST-1 assay. Sorafenib inhibited cell viability dose-dependently (Fig. 2A). The maximal effect of sorafenib on the viability of Hep3B or Hep3B-pRS cells was shown at the concentration of 10 μM. This dose was also shown to be the highest concentration producing acquired resistance to sorafenib in HCC (20). Based on these findings, the pRS-shRNA library or pRS vector-infected Hep3B cells were cultured in the presence of sorafenib (10 μM) for 1 to 4 days. An increase in viability of shRNA library-infected cells was observed with 3- and 4-day sorafenib treatments after the third screening using the WST assay (Fig. 2B). Three successive rounds of screening led to the identification of shRNA for SMG-1 (shSMG-1) which was present in sorafenib-resistant third screened shRNA library-infected cells after each round (Fig. 2C) and also identified five other genes for investigation.
Figure 2
Genetic screening identifies knockdown of SMG-1 in development of sorafenib resistance. (A) Hep3B cells were treated with sorafenib (4 days) and viability was assessed with WST1 assays. (B) After each round of screening, viability of survived cells after sorafenib treatment (10 μM) was assessed using WST1. (C) Hep3B cells were subjected to genetic screening for sorafenib resistance with pRS-shRNA library, genomic DNA was isolated, shRNA insert was amplified by PCR and products were resolved on agarose gels.
Suppression of SMG-1 leads to sorafenib resistance in HCC cell lines
To confirm the effect of suppressed SMG-1 expression on sorafenib resistance, three specific RNAi oligonucleotides of SMG-1 were transfected into the Hep3B cell line. Among them, the cells transfected with si-SMG-1 #6 effectively suppressed the SMG-1 mRNA transcripts (Fig. 3A) and proteins (Fig. 3B) at the concentration of 50 nM. After the transfection with si-SMG-1 #6, the cells were treated with sorafenib at the indicated doses for 24 and 48 h and assayed for cell viability. Significantly higher viability at day 1 (p<0.05) and day 2 (p<0.01) was shown in the si-SMG-1-transfected cells compared to the control at the 5 and 10 μM concentrations of sorafenib treatment in Hep3B cells.
Figure 3
SMG-1 suppression induces sorafenib resistance in Hep3B cells. (A) The cells were transfected with 50 μM of si-scramble, 20 or 50 μM of three specific si-SMG-1 oligonucleotides named si-SMG-1 #6, #7 and #8 for 2 days. Reverse transcription-PCR was measured by SMG-1 specific primers. (B) The cells were transfected with 50 μM of si-scramble or si-SMG-1 #6 for 2 days. Protein expression of SMG-1 was analyzed by anti-SMG-1 antibody. Primary antibody was diluted at 1:500 and secondary antibody was diluted at 1:2,000. (C) Cell viability was measured by EZ-cytox assays after 24 and 48 h in the presence of the indicated sorafenib treatments. *p<0.05; **p<0.01 for comparison between the control and si-SMG-1 transfected cells treated with sorafenib at the indicated doses.
To investigate these results in other HCC cell lines, HepG2 and Huh7 cell lines were transfected with either si-SMG-1 #6 or si-scramble. SMG-1 RNAi suppressed the SMG-1 mRNA level to 80 and 70% at the 100 μM concentration, as seen in the HepG2 and Huh7 cell lines, respectively (Fig. 4A). Similarly, suppression of the SMG-1 resulted in significantly higher cell viability at the 10 μM (p<0.05) and 20 μM (p<0.01) concentrations of sorafenib in both cell lines (Fig. 4B). Our data suggest that the suppression of SMG-1 may increase sorafenib resistance in HCC.
Figure 4
SMG-1 suppression induces sorafenib resistance in other HCC cell lines. (A) HepG2 and Huh7 cell lines were transfected with 100 μM of si-scramble, 20, 50 or 100 nM of si-SMG-1 #6 for 2 days. Reverse transcription-PCR were measured as described in Fig. 3. *p<0.05; **p<0.01 for comparison between the control and si-SMG-1 transfected cells treated with sorafenib at the indicated doses. (B) si-SMG-1 or negative control si-RNA transfected HepG2 cells (left panel) and Huh7 (right panel) were treated with sorafenib (0, 5, 10 and 20 μM) for 24 h. Thereafter, cell viability was measured by EZ-cytox assay and compared. Mean ± SD. *p<0.05; **p<0.01 for comparison between the control and si-SMG-1 transfected cells treated with sorafenib at the indicated doses.
Immunohistochemical staining results show reduced SMG-1 expression in cancerous regions
Immunohistochemical staining of SMG-1 in cancerous and non-cancerous regions of surgically resected tissues (Fig. 5A and B) showed reduced expression in cancerous regions compared to non-cancerous regions and controls. On the other hand, there was stronger cytoplasmic granular staining in non-cancerous regions (p<0.01).
Figure 5
Immunohistochemical staining of resected cancer tissue. (A and B) Strong and diffuse cytoplasmic granular staining in non-cancerous cirrhotic hepatocytes (arrow) compared to cancer region. ×100, magnification (representative data).
We applied the shRNA library-based genetic approach to identify genes related to the sorafenib resistance of human HCC cell lines. As expected, an increase in the viability of shRNA library-infected cells was observed with 3- and 4-day sorafenib treatments after the third screening compared to controls. The value of this approach is that it allows the least biased identification of new and unanticipated tumor suppressors. In this regard, our study provides significant evidence for the identification of the novel tumor suppressor SMG-1. Successive validation experiments using commercial siRNA of SMG-1 have revealed sorafenib resistance in siRNA-transfected hepatocellular cell lines compared to controls.
Hepatocarcinogenesis is a multistep process often initiated by external insults that lead to genetic aberrations in hepatocytes or stem cells, resulting in proliferation, apoptosis, dysplasia and neoplasia (4,21,22). Significant progress in cancer molecular research technology has led to the development of various molecular approaches for the treatment of HCC. The identification of molecular targets involved in HCC pathogenesis and drug response continues to be an important area of active research.
Sorafenib is a potent antitumor agent that displays clinical activity against several solid tumors and is licensed for the treatment of patients with unresectable HCC. Its cytotoxic mode of action in HCC is mediated by inhibition of the RAS/MEK/ERK pathway, inhibition of tumor angiogenesis and induction of tumor cell apoptosis (10,23). The effect of sorafenib on tumor size reduction was lower than anticipated, and it has shown only a minimal effect on survival and reduced disease progression in patients with advanced HCC (11,12,24). Hence, the importance of discovering genes related to resistance or non-responsiveness to sorafenib treatment in the hope of developing novel means of potentiating the drug's antitumor properties.
RNA interference (RNAi) is a naturally occurring mechanism that modulates gene expression at the post-transcriptional level and is a powerful tool to perform loss-of-function genetic screens for the identification of components of cellular signaling pathways (25–27). In eukaryotes, double-stranded interfering RNAs target complementary mRNAs for degradation, which results in the selective silencing of specific proteins. This characteristic of RNAi makes it an important laboratory work tool and has led to the characterization of novel oncogenes (28,29). With the development of genome-wide RNA interference (RNAi) approaches, the cost and time that are involved in target identification, validation and other aspects of drug discovery have been significantly reduced.
SMG-1 is a serine-threonine kinase which plays a conserved role in nonsense-mediated mRNA decay (NMD) in worms and mammals, and human SMG-1 has also been implicated in the p53-mediated response to genotoxic stress (30,31). In addition, SMG-1 negatively regulates hypoxia-inducible factor-1 (HIF-1) (32,33) activity, which plays a central role in tumor progression by regulating genes involved in proliferation, glycolysis, angiogenesis and metastases, in hypoxia through MAPK activation (34). HIF-1 is one of the primary transcription factors responsible for increased gene expression in hypoxia, and vascular endothelial growth factor (VEGF), erythropoietin, and glycolytic enzymes are all targets of HIF-1 involved in the adaptive response of cells to hypoxia (35,36). The hypervascularized nature of HCC implies a particular reliance on factors related to angiogenesis (37,38). In several recent studies, VEGF was overexpressed in HCC, and HIF-1 played a central role in HCC progression and angiogenesis (39–41). Consequently, despite the complicated nature of tumor proliferation and the existence of multiple regulatory checkpoints, we hypothesize that knockdown of SMG-1 may potentiate angiogenesis or metastasis of HCC due to disinhibition of HIF-1.
Nenasheva et al (42) previously reported that defective SMG-1 kinase function might contribute to the process of malignant transformation in B cell lymphomas of different origins. Xia et al (43) recently reported that human SMG-1 was involved in gemcitabine-induced primary microRNA-155/BIC upregulation in a human pancreatic cancer cell line. Though little information about SMG-1 has been elucidated to date, further investigations of the precise action of SMG-1 in oncogenesis or chemotherapeutic responsiveness may be meaningful. In our present study, knockdown by RNAi of SMG-1 led to higher cell viability in sorafenib-treated Hep3B cells.
We performed RNAi knockdown on other HCC cell lines such as HepG2 and Huh7 cells, which resulted in a similarly increased cell viability. Although there were significant differences in cell viability between RNAi transfected and non-transfected cell lines, the survival rate of sorafenib-treated cancer cells was lower than anticipated. This may be due to the short reaction time and lower transfection efficiency of commercial RNAi itself, which is less of a consideration in the stable shRNA platform.
Immunohistochemical staining of SMG-1 in HCC tissues showed strong and diffuse cytoplasmic expression in non-cancerous cirrhotic region compared with cancerous region. These results suggest that SMG-1 expression is reduced during neoplastic transformation and also implies its role as a tumor suppressor gene. Loss of SMG-1 function may accelerate or convert malignant transformation potential to neoplasmic formation from uncertain causes. Therefore, we can postulate that SMG-1 modulates the response of HCC to sorafenib through effects on the RAS/MEK/ERK pathway, PI3K/Akt/mTOR pathway or HIF-1 (34,44,45).
There are several limitations to consider in our experiment. Firstly, we could not determine anything about the underlying mechanisms or related signal transduction of SMG-1. Secondly, we could not show whether the potential regulation of SMG-1 by sorafenib is indirect or direct. Thirdly, we could not perform apoptotic analysis or other experiments to evaluate the role of SMG-1. Further molecular studies will be needed to investigate these properties.
In conclusion, this is the first report that utilizes the unbiased genetic approach of shRNA library screening to identify genes related to sorafenib resistance in HCC. These results show that using such a screening method is successful in identifying targets that have biological relevance to the pathogenesis and disease progressions of HCC. A potential regulator, SMG-1, was validated, and future studies can investigate its potential as an adjunctive clinical target to improve sorafenib therapy in patients with HCC.
This study was supported in part by grants from the Alberta Cancer Research Institute (23123), Canada Research Chair Program (95-203751), CIHR (MOP97962) and a fund (CMCDJ-2011-P-007) of the Clinical Medical Research Institute from Daejeon St. Mary's Hospital, the Medical School of the Catholic University of Korea.
Parkin DM, Bray F, Ferlay J and Pisani P: Estimating the world cancer burden: Globocan 2000. Int J Cancer. 94:153–156. 2001. View Article : Google Scholar : PubMed/NCBI
El-Serag HB: Hepatocellular carcinoma. N Engl J Med. 365:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI
El-Serag HB and Rudolph KL: Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
Farazi PA and DePinho RA: Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 6:674–687. 2006. View Article : Google Scholar : PubMed/NCBI
Fattovich G, Stroffolini T, Zagni I and Donato F: Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology. 127:S35–S50. 2004. View Article : Google Scholar : PubMed/NCBI
Chen CJ, Yang HI and Iloeje UH: Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology. 49:S72–S84. 2009. View Article : Google Scholar : PubMed/NCBI
Forner A, Reig ME, de Lope CR and Bruix J: Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis. 30:61–74. 2010. View Article : Google Scholar : PubMed/NCBI
El-Serag HB, Marrero JA, Rudolph L and Reddy KR: Diagnosis and treatment of hepatocellular carcinoma. Gastroenterology. 134:1752–1763. 2008. View Article : Google Scholar : PubMed/NCBI
Wysocki PJ: Targeted therapy of hepatocellular cancer. Expert Opin Investig Drugs. 19:265–274. 2010. View Article : Google Scholar : PubMed/NCBI
Liu L, Cao Y, Chen C, et al: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 66:11851–11858. 2006. View Article : Google Scholar : PubMed/NCBI
Llovet JM, Ricci S, Mazzaferro V, et al: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
Cheng AL, Kang YK, Chen Z, et al: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 10:25–34. 2009. View Article : Google Scholar : PubMed/NCBI
Trojniak MP, Palozzo AC, Mazurek M and Jirillo A: Sorafenib in hepatocellular carcinoma - a post marketing evaluation. Immunopharmacol Immunotoxicol. 34:419–422. 2012. View Article : Google Scholar : PubMed/NCBI
Lum L, Yao S, Mozer B, et al: Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science. 299:2039–2045. 2003. View Article : Google Scholar : PubMed/NCBI
Ashrafi K, Chang FY, Watts JL, et al: Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature. 421:268–272. 2003. View Article : Google Scholar : PubMed/NCBI
Iorns E, Lord CJ, Turner N and Ashworth A: Utilizing RNA interference to enhance cancer drug discovery. Nat Rev Drug Discov. 6:556–568. 2007. View Article : Google Scholar : PubMed/NCBI
Ahn BY, Elwi AN, Lee B, et al: Genetic screen identifies insulin-like growth factor binding protein 5 as a modulator of tamoxifen resistance in breast cancer. Cancer Res. 70:3013–3019. 2010. View Article : Google Scholar : PubMed/NCBI
Tang TC, Man S, Xu P, et al: Development of a resistance-like phenotype to sorafenib by human hepatocellular carcinoma cells is reversible and can be delayed by metronomic UFT chemotherapy. Neoplasia. 12:928–940. 2010.PubMed/NCBI
Berns K, Hijmans EM, Mullenders J, et al: A large-scale RNAi screen in human cells identifies new components of the p53 pathway. Nature. 428:431–437. 2004. View Article : Google Scholar : PubMed/NCBI
Chen KF, Chen HL, Tai WT, et al: Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J Pharmacol Exp Ther. 337:155–161. 2011. View Article : Google Scholar : PubMed/NCBI
Thorgeirsson SS and Grisham JW: Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 31:339–346. 2002. View Article : Google Scholar : PubMed/NCBI
Villanueva A, Newell P, Chiang DY, Friedman SL and Llovet JM: Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 27:55–76. 2007. View Article : Google Scholar : PubMed/NCBI
Wilhelm SM, Carter C, Tang L, et al: BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64:7099–7109. 2004. View Article : Google Scholar : PubMed/NCBI
Kim JE, Ryoo BY, Ryu MH, et al: Sorafenib for hepatocellular carcinoma according to Child-Pugh class of liver function. Cancer Chemother Pharmacol. 68:1285–1290. 2011. View Article : Google Scholar : PubMed/NCBI
Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE and Mello CC: Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 391:806–811. 1998. View Article : Google Scholar : PubMed/NCBI
Chapman EJ and Carrington JC: Specialization and evolution of endogenous small RNA pathways. Nat Rev Genet. 8:884–896. 2007. View Article : Google Scholar : PubMed/NCBI
Kamath RS, Fraser AG, Dong Y, et al: Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature. 421:231–237. 2003. View Article : Google Scholar : PubMed/NCBI
Pan Q, Bao LW, Kleer CG, et al: Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Res. 65:8366–8371. 2005. View Article : Google Scholar : PubMed/NCBI
Zhang Z, Jiang G, Yang F and Wang J: Knockdown of mutant K-ras expression by adenovirus-mediated siRNA inhibits the in vitro and in vivo growth of lung cancer cells. Cancer Biol Ther. 5:1481–1486. 2006. View Article : Google Scholar : PubMed/NCBI
Yamashita A, Ohnishi T, Kashima I, Taya Y and Ohno S: Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay. Genes Dev. 15:2215–2228. 2001. View Article : Google Scholar
Masse I, Molin L, Mouchiroud L, et al: A novel role for the SMG-1 kinase in lifespan and oxidative stress resistance in Caenorhabditis elegans. PLoS One. 3:e33542008. View Article : Google Scholar : PubMed/NCBI
Keith B and Simon MC: Hypoxia-inducible factors, stem cells, and cancer. Cell. 129:465–472. 2007. View Article : Google Scholar : PubMed/NCBI
Kaelin WG Jr and Ratcliffe PJ: Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 30:393–402. 2008. View Article : Google Scholar : PubMed/NCBI
Chen RQ, Yang QK, Chen YL, et al: Kinome siRNA screen identifies SMG-1 as a negative regulator of hypoxia-inducible factor-1alpha in hypoxia. J Biol Chem. 284:16752–16758. 2009. View Article : Google Scholar : PubMed/NCBI
Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar : PubMed/NCBI
Mottet D, Michel G, Renard P, Ninane N, Raes M and Michiels C: ERK and calcium in activation of HIF-1. Ann NY Acad Sci. 973:448–453. 2002. View Article : Google Scholar : PubMed/NCBI
Pang R and Poon RT: Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett. 242:151–167. 2006. View Article : Google Scholar : PubMed/NCBI
Kuboki S, Shimizu H, Mitsuhashi N, et al: Angiopoietin-2 levels in the hepatic vein as a useful predictor of tumor invasiveness and prognosis in human hepatocellular carcinoma. J Gastroenterol Hepatol. 23:e157–e164. 2008. View Article : Google Scholar : PubMed/NCBI
Torimura T, Sata M, Ueno T, et al: Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol. 29:986–991. 1998. View Article : Google Scholar : PubMed/NCBI
Nakamura K, Zen Y, Sato Y, et al: Vascular endothelial growth factor, its receptor Flk-1, and hypoxia inducible factor-1alpha are involved in malignant transformation in dysplastic nodules of the liver. Hum Pathol. 38:1532–1546. 2007. View Article : Google Scholar : PubMed/NCBI
Wu XZ, Xie GR and Chen D: Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J Gastroenterol Hepatol. 22:1178–1182. 2007. View Article : Google Scholar : PubMed/NCBI
Nenasheva VV, Nikolaev AI, Martynenko AV, et al: Differential gene expression in HIV/SIV-associated and spontaneous lymphomas. Int J Med Sci. 2:122–128. 2005. View Article : Google Scholar : PubMed/NCBI
Xia QS, Ishigaki Y, Zhao X, et al: Human SMG-1 is involved in gemcitabine-induced primary microRNA-155/BIC up-regulation in human pancreatic cancer PANC-1 cells. Pancreas. 40:55–60. 2011. View Article : Google Scholar : PubMed/NCBI
Vivanco I and Sawyers CL: The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer. 2:489–501. 2002. View Article : Google Scholar : PubMed/NCBI
Fang JY and Richardson BC: The MAPK signalling pathways and colorectal cancer. Lancet Oncol. 6:322–327. 2005. View Article : Google Scholar : PubMed/NCBI


text:
Swans to open city centre store
The Swans are set to move into the heart of the city to meet the growing demands of the club's passionate and proud Jack Army.
Having seen a huge growth in merchandise sales over recent years, the club has agreed to open a new Swans store in the city centre.
Situated in Union Street, close to the main entrance of the Quadrant Shopping Centre and Swansea Market, the new double-fronted store will house the complete Swans range over 1400 square feet of modern floor space.
It will also provide a customer services point and interactive screens, plus a sales outlet for tickets and hospitality.
With the opening targeted for mid-October, just in time for the busy Christmas sales period, the club's chief operating officer, Chris Pearlman, believes it will prove a popular move for fans.
"As the club is an important part of the community, we felt we needed to have a more visible presence in the heart of Swansea," he explained.
"The continued prosperity of the city will benefit us all, and we believe this is a meaningful step in helping that growth.
"The busy club shop at the Liberty Stadium will remain, but the new city centre store will also provide another connection point for the club with our supporters."
Further details on the store will follow prior to the grand opening.


text:
Blueberry Oatmeal
As low as USD 10.18
Experience easy, on-the-go meals with premium freeze dried ingredients. No need to compromise convenience for nutrition or taste. You can have it all! Our meal pouches are perfect for camping trips, vacations, or getting quick, healthy food in a pinch. Milk and blueberries that melt in your mouth and crunchy oats that give you the feeling you're home again. Turn on your taste buds and jump into sweet paradise.


text:
salopp 9 – 12 | magazine & exhibition
salopp is an independent magazine for young photography. It provides a space for unknown new work. Founded by a graphic designer and four photographers, salopp presents a wide range of artists, each showing their unique visual world. salopp is published as often as possible. In german and in english. salopp 9 – 12 is the third issue.
salopp 9 – 12
Exhibition at Färberei, Claude-Lorrain-Straße 25, Munich
Opening: May 28th 2014, 6pm Continue Reading →


text:
Editors' note: This story has been updated to clarify that Tony's is helping make the chocolate industry 100% slave free. An earlier version stated Tony's produced 100% slave free chocolate based on incorrect information supplied by a source.
A stay-at home mom's desire to help friends by giving food demos on their behalf at Whole Foods Market turned out to be the push Kari Pedriana needed to launch Green Spoon Sales with her husband, Matt Bauman.
Boulder-based Green Spoon provides sales and marketing support to brands in the natural and organic food and beverage industry. It helps them gain access to retail stores, shelf space and help drive sales through promotions.
The whole brokerage business was run in an old-fashioned way, and was dominated by a few big players, Pedriana said. Smaller brands were getting lost, because brokerage companies were too large.
"We wanted to change that. We realized the brokerage side of the industry needed a facelift," she said.
Since its start in 2010, Green Spoon has focused on smaller brands craving attention, she said. Her husband's background as a food industry professional helped open many doors, she admits. But building a client base with a lineup of disruptive startups and established brands wasn't a cakewalk, she said. At times getting access to the right people in the industry was difficult given the company's smaller size.
"There were a lot of roadblocks, but I'm not the one to give up," she said.
In less than a decade, Green Spoon has expanded from the Rocky Mountain region, to theSouthwest, the Midwest, the Mid-Atlantic and the Northeast. Recently, the company expanded to the West Coast in southern California, northern California and the Pacific Northwest to complete its national expansion.
"It will help us support our brand in those places," Pedriana said.
Tony's Chocolonely (a Dutch chocolate maker) has grown in the United States in tandem with the expansion of Green Spoon, said Peter Zandee, business development manager for Tony's, which is working to make the chocolate industry 100% slave-free.
"We started selling chocolates in Portland, Ore., about four years ago. Since we began working with Green Spoon in 2016, we have had a very solid presence in the channels we were targeting," he said.
Green Spoon's relationships with buyers, both at the corporate and the store level, has helped Tony's as a brand.
"It's not just about selling chocolates, but creating awareness of child slave labor in the chocolate industry," Zandee said.
Green Spoon is a true advocate of the brand, he said.
Kristy Lewis, founder and CEO of Louisville-based Quinn, makers of a variety of pretzels and microwave popcorn, vouches for the company's increased sales and widened brand exposure since it began working Pedriana's company.
"I completely trust the Green Spoon team is representing our brand as its own," she said.
Team members work with retail stores to get Quinn products better shelf space and secondary store displays, she said.
"It has helped. We are excited to be a part of its ongoing growth," Lewis said.
Green Spoon boasts 75 employees and is in line to hire an additional 25 to support its expansion by early next year, Pedriana said. For business reasons, she didn't want to divulge the number of clients or the sectors they represent.
"We are supporting a lot of brands in paleo and keto space," she said.
One of Green Spoon's clients, Primal Nutrition, L.L.C., maker of Primal Kitchen condiments, sauces, dressings and snacks, was acquired by the Kraft Heinz Company in a deal that closed in January.
Green Spoon helped Primal Kitchen gain traction nationally, which led to Kraft's interest in the company, Pedriana said.
"The brokerage business is a people business. It's based on building relationships," she said.
Join the Conversation
We invite you to use our commenting platform to engage in insightful conversations about issues in our community. We reserve the right at all times to remove any information or materials that are unlawful, threatening, abusive, libelous, defamatory, obscene, vulgar, pornographic, profane, indecent or otherwise objectionable to us, and to disclose any information necessary to satisfy the law, regulation, or government request. We might permanently block any user who abuses these conditions.