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Why buy retail when you can buy wholesale? Get the most out of your budget by purchasing 24 backpacks for one low price. Perfect for back-to-school drives or as promotional products; this multi-pack is convenient for businesses or non-profit groups such as charities, churches, schools, or government agencies. A clean timeless design that is sure to remain in style, the backpack features a main zipper compartment that is equipped with an overlapping zipper cover, and convenient front zipper pocket. This backpack’s standard frame makes it perfect for elementary or middle school students with plenty of room for textbooks, notebooks, and supplies. Adjustable padded straps accommodate a wide range of ages. Bulk case of 24 backpacks.
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Which branch of engineering would someone who is good at math take?
Any and all engineering fields require expertise in math. From my own perspective, Civil engineering is easier as the formulae such as the flow capacity of a pipe are derived emperically as opposed to theoretically. My suggestion is to take calculus in your senior year of High School if you can and take general engineering courses at college fro the first year or so. I started out in Aerospace and it was easy to switch to Civil in my sophomore year of college.
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why you need small business insurance Most small businesses need General Liability and Property Insurance at the very least. If you have employees, you’ll probably need Workers’ Compensation Insurance as well; most states require it. Commercial Auto is important if you or your employees drive for your business.
Most business owners have a good idea of what tools, equipment, materials and technology they need to run their business. But they don’t always know what types of insurance they need and how much coverage is appropriate to help protect their business.
If you’re running a small business, or plan to, you probably know about some of the common perils you may face. Accidents happen and things break every now and then. Liability lawsuits are fairly common now. And the changing climate continues to produce devastating weather events resulting in record level property damage claims. Much of a business’s success is based on its resilience through adversity. So it’s up to you to take the steps to ensure your business will prevail through the most likely perils, and especially the ones you don’t expect.
Small business insurance can help your business survive and prosper through the toughest times. It can help cover the costs of liability claims and property damage. Without it, you may have to pay those costs with your own business and personal assets. If you think you can handle the expenses on your own, just remember that the cost of an average, paid liability claim is $15,000.
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For the past couple of years, I've wanted to venture to the North Rim of Yosemite Valley. I've scoured the topo maps looking for a variety of hikes and after a buddy of mine (Mark) told me about his hike to North Dome with his brother, I knew I had to go there. I didn't want to do the normal out and back from Porcupine Creek like most hikers do. I saw an option for a perfect loop and decided I had to do it.
After several failed attempts to get out there, I finally had a weekend free (okay, one where my wife let me get away) and gathered some of my hiking buddies, Tim, Tony and Rafael and headed out to Yosemite for a 2 day 10+ mile hike. Why do this as a two day hike and not a single day? Because I can! Splitting this trip into two days, allowed for a much more relaxed trip, knowing we had no time limits to get where we were going and could stop for whatever photo opportunity came our way. With a crescent moon and clear skies forecasted, we were also hoping for some great night shots over the valley. We weren't disappointed!
To paraphrase a famous quote, "what goes down must come up"! That was the story of our journey. We arrived at the trailhead at Porcupine Creek(~8100') early and got our packs on were quickly on our way down towards North Dome. The trail near the trailhead is actually an old paved road for the first .7 miles. The road starts out nice and deteriorates the further you get into the forest. Once past the "road", the trail crosses a couple of seasonal creeks (including Porcupine Creek) and roams through a typical "Yosemite" forest, mix of pines and firs and decent underbrush and lots of dead-fall all around.
Within no time (about 1.7 miles) we were at a four-way junction (photo on the right). We almost took the wrong trail, but thank goodness I looked at the topo map a little closer. The first trail heads to the left and down to Mirror Lake and Yosemite Valley via Snow Creek Trail (okay, something I want to do, but not that day). The next trail marker, about 20 ft later was the North Nome Trail to the left. The other trail marker to the right indicated Yosemite Falls. That was going to be our trail on the way back.
Okay, we made it to the junction and now it was time to go down hill to the Dome, right, nope. Gotta go up to get down and that's what we did. As you gain elevation, the terrain also changes to more of a chaparral setting, a little more exposed, but starting to gain some nice views too.
Our main destination was North Dome, but we did have a planned stop along the way at Indian Rock. In fact, I think I was more excited about checking out Indian Rock than North Dome. Indian Rock (pictured left) is the only natural arch in Yosemite and it is spectacular! The Indian Rock trail is a .3 mile spur (.6 round trip, but the topo maps show it much further away) straight up hill to the top of Indian Ridge. The rock is a large outcropping of granite that includes a 15 ft granite arch and provides lots of exploring and photographic opportunities.
After a couple of hours hanging out at the arch, we continued on down to the Dome. It was really downhill this time. In about a half a mile, the trail splits up, to the left is the "established" trail that continues among the trees, but to the right the trail follows the granite of Indian Ridge. A more direct, but steeper route and the way we went. We followed the cairns and were soon greeted with an incredible view of Yosemite Valley and its many icons: Half Dome, Clouds Rest, Glacier Point, Illilouette Falls, etc.
We soon met back up with the "other" trail and were on a ridge above North Dome. Getting down to North Dome was more fun. The trail down drops about 200 feet very quickly and soon we were among the trees at the base of North Dome (Numerous trail camps are among these trees). The gradual slope up North Dome was rewarded with a face to face view of Half Dome. We hung out at the dome for a while and headed back up to a trail camp we found on the ridge above the dome. Still fantastic views of everything, but we didn't have to haul our packs and gear down and then back up. One word of caution to those planning an overnight trip to North Dome, there is no water within a mile. You need to pack in water.
A breezy afternoon turned into a calm and perfect evening, barely a breeze and a clear night. Shutters were clicking all around our campsite. The sunset wasn't as spectacular as I was hoping but it was special. The stars were incredible and after draining my camera battery, I hit the sleeping bag under the stars (no tent for this trip). I kept waking up that night, not because I had trouble sleeping, but because I couldn't keep my eyes off the sky. Morning was just as nice. I worked on draining another battery on the sunrise, packed the packs and then were back on the trail before 8am.
The route back quickly descended on a granite trail and into a forest filled with Red Firs. It was more lush than the route from the trailhead and I thoroughly enjoyed the stroll through that part of the forest. We crossed a dry Arch Rock Creek and made it to Lehamite creek for a needed refill of our water bottles. After the creek, the trail back takes a sharp right. The marker is easy to miss (right Tony and Rafael?), you have to look back and to the right to pick up the route. There are a number of nice established trail camps here near the creek.
Remember that paraphrased quote I mentioned? Well here is where it really came into play. The first part of the trail was a gradual climb including a section through a nice meadow filled with ferns, corn lilies and other wildflowers. After that meadow it's a steep grade and a good push back to the four way trail junction. Getting back to the trailhead seemed longer, but we eventually made it and headed back to the Bay Area.
In a little more than 24 hours we hiked a great loop trail, saw some incredible sites, had lots of laughs and experienced the best night ever sleeping under the stars. I strongly encourage you to get out to North Dome and Indian Rock. It is a popular but less crowded destination and definitely a must do hike. I would rate the difficulty level of the hike a 7 (mostly because of the last steep section and length as a day hike).
Below is the track on a Google Map. You can view my preliminary trip report on Trimble Outdoors. You can also view more photos from the trip on my SmugMug photo gallery.
I love star trails. This is a 5 minute exposure. The focal point is the North Star.
Awesome writeup Dave! I knew you would love the hike. There are lots of other hikes available up there I would like to tackle soon, too.
Thanks Mark. It was a great trip and I have you to thank for it. In fact, I did!
I just got back from Yosemite again and hiked up to Cathedral Lakes. Beautiful! Nice challenging climb up, but not too bad. 8.5 miles round trip. It may take a little time to get the trip report on line though.
Great trip report. I've been to North Dome twice but both times did not do Indian Rock! Will have to go back.
I also did Cathedral in August. You can do a great loop by crossing the low saddle just to the right of the mountain (offtrail) and then continuing down to meet the Budd Lake trail, which goes back north along Budd Creek and connects with Cathedral Trail about a half mile from Tioga Road.
I did a day trip to Tuolumne and both Cathedral lakes last month and it was great. I hope to get my trip reports up soon. I've looked at the route to budd lake and want to do it when I have more thanks day.
Awesome experience shared by you; Great quality Ultralight Camping tent, quite simple to put together. The second camp out it rains half the night pretty constant so we woke up bone fragments dry! The actual buy-ins it comes with tends to be okay at the best http://ultralighttent.info.
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Flexing into the splits during my yoga practice today, I came to realize that this exercise is not just a physical one, but a psychological and spiritual one as well. Stretching your body requires flexibility of mind and demands that you open and free all the channels within you that may be blocked with rigid beliefs.
Rigid ideas of what's possible and acceptable and okay can prevent us from not only expanding our mind to infinite dimensions, but flexing our muscles, tissues and bones in new and expansive ways. It is vital during yoga to free your mind, to relax your standards and assumptions, and to feel into novel ways of being.
In order to do the splits, to extend our limbs to the highest degree, a liberation must occur in our minds and hearts. We have to set ourselves upon a higher vantage point to allow the body to transcend barriers of space and time and fixed posture. Yes, we must in yoga lean into infinity and in so doing stretch beyond our perceived physical limitations.
In your practice today, permit your mind to wander away from its ego occupations. Just allow your body to melt into the poses. Give it no false boundaries and expectations and watch as it bends and folds with ease, splitting and opening on a cellular level to regenerate and restore the eternal nature of your being.
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Staff was great, room.was clean. Disappointed the heater in the pool was broken. We looked forward to the pool.
Hotel was very quiet, room clean and comfortable.
We were underwhelmed by this place. With all the positive reviews, I was expecting more for the money. It didn't help that they abruptly closed the pool while we were there. I think you could easily find a hotel of this same quality for 60-70% of the price elsewhere.
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Could someone brief me what describes Conventional Self Publishing?
Maybe a success story or two?
Conventional self-publishing: Rather than getting a publisher, you pay a printer to produce X copies of your book, which you then attempt to sell on your own. They literally just convert a stack of blank paper into book form- you write, edit, lay out, design the covers, market the result, register the copyright and everything else.
With POD - print on demand, which is what most of the internet sites around at the moment offer - you provide them with an electronic copy (usually PDF), which they only print up when somebody orders a copy. With the former, you get the benefits of bulk manufacture costs (if you need that many copies), while the latter costs a lot more per book, but has no startup fees (depending on who you use - www.lulu.com is one of the best, well-known ones on the net) and the printer's cut comes out of the cost of each book printed.
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Do you often hear that a daily jog is a great exercise for you to take up? You heard right! Sure, it might not look like the most intense exercise routine out there, but the health benefits of jogging are driving more and more people to try out this simple way to stay fit.
Jogging is a low-impact exercise that provides a number of health benefits. What’s more, it’s simple enough for you to make it a daily routine. It is also free, which makes it a cost-effective fitness solution. Some of the health benefits of jogging include relief from stress, improved cardiovascular health, reduced risk of stroke and heart attack, and elevated energy levels.
Weight loss and healthy bones are two of the key benefits of jogging.
Read on to find out some of the amazing benefits of jogging, an activity that can help you live a healthy life.
When it comes to dropping those extra pounds from your body, jogging can do the trick. While being easy on the joints, this form of exercise helps in burning a great number of calories, enabling you to shed all the excess flab. Before you begin any weight loss program by jogging, it is important for you to understand that 1 pound of fat is equivalent to 3500 calories, which means that you have to burn 3500 calories to shed a pound of fat.
The Heart Book, a publication by Yale University School of Medicine indicates that a person weighing 150 pounds who jogs at 5 mph burns around 8 calories in a minute, and while jogging at 7 mph burns 12 calories in a minute.
The Harvard Women’s Health Watch highlighted a certain research study, which showed that individuals who jogged for 12 miles in a week experienced no increase in body fat, while individuals who completed 20 miles in a week experienced a decrease in stomach flab as well as body fat.
Scientists firmly believe that jogging is effective in the prevention of cancer. The reason behind this claim is that cells that are not supplied with oxygen in the body often begin to mutate, and such mutations eventually leads to cancer. Jogging helps increase the supply of oxygen to the different parts of the body, which in turn helps in preventing cancer.
The Arthritis Foundation has stated that rheumatoid arthritis patients can benefit greatly from jogging.
Jogging as a form of exercise helps in increasing your strength as well as your ability to carry out everyday activities. By strengthening your joints and muscles, and reducing your weight, jogging helps reduce the risk of ailments like osteoarthritis and osteoporosis.
It is important to note that arthritis patients must seek their doctor’s approval before starting any fitness regime.
A healthy heart is one of the greatest benefits that jogging has to offer. With just half an hour of jogging, you’ll be well on your way towards a healthier heart. Jogging boosts the circulation of blood in your body and keeps you healthy.
Jogging is highly effective when it comes to dealing with stress. It provides the mind space for people to deal with their problems and helps in boosting the right attitude in them. This is due to the fact that jogging in an outdoor setting aids in the release of endorphins, which give the jogger a sense of happiness and contentment.
Jogging can be enjoyed by people of all age groups, and a reduction in stress is one of the top jogging benefits.
The benefits of jogging are many and the best part is that this exercise is ideal for people of all age groups. It’s time to put on your running shoes and jog your way towards a healthier life!
This entry was posted in Fitness and tagged health benefits of jogging, jogging benefits by Zipheal Editorial Staff. Bookmark the permalink.
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How can one possibly control one’s life when besieged with so many external controlling forces? One has to conform to bosses, neighbors, family as well as all of the body’s demands such as hormones and other inner chemical and neural forces which certainly attempt to dominate. The largest controlling force is when aging of the body and mind start to take over and not only limits activities but also raises strong doubts about what one can do in life.
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Wie viel wissen wir über unsere Emotionen?
Emotionen sind unsere ständigen Begleiter. Sie beeinflussen unsere Entscheidungen und unser Verhalten; ob wir es wollen oder nicht. Die Fähigkeit, unsere Emotionen wahrzunehmen und zu verstehen sowie zu erkennen, wie unsere Emotionen uns und andere beeinflussen, heisst Emotionales Selbstbewusstsein. Das Emotionale Selbstbewusstsein gehört zu den fundamentalen Kompetenzen der Emotionalen Intelligenz.
Emotionales Selbstbewusstsein steht in Zusammenhang mit folgenden Begriffen: Radar, Zwiebel, Spiegel und „ripple Effekt“. Überlegen Sie einmal, welchen Zusammenhang es zwischen diesen Begriffen und dem Emotionalem Selbstbewusstsein geben könnte. Die Antwort auf diese Frage finden Sie gleich in diesem Video.
Was ist der Mehrwert, über unsere Emotionen Bescheid zu wissen?
Durch die (Er-)Kenntnisse unserer Emotionen erhalten wir den Zugang zu unseren Bedürfnissen und Informationen über unsere Reaktionen in konkreten Situationen. Dies können wir dafür nutzen, bessere Entscheidungen zu treffen oder unser Verhalten bei Bedarf anzupassen. Wenn wir unsere Emotionen nicht beachten, kumuliert sich in unserem Inneren Energie, deren Macht wir uns kaum bewusst sind.
1). Was fühle ich im Moment?
2). Warum fühle ich was ich fühle?
3). Was macht das mit mir?
4). Wie beeinflussen meine Emotionen andere?
5). Möchte ich im aktuellen Emotionalen Zustand bleiben oder nicht?
Die Gewohnheit, den Blick nach innen zu kehren, ist sehr wertvoll. Sie ermöglicht Ihnen eine spanende Reise in Ihrer eigenen Welt. Diese Reise ist entdeckungsreich und unendlich. Machen Sie sich auf den Weg!
http://eqpower.ch/wp-content/uploads/2013/08/EQpower_med_rgb4-300x66.jpg 0 0 Marina Riedi http://eqpower.ch/wp-content/uploads/2013/08/EQpower_med_rgb4-300x66.jpg Marina Riedi2017-03-21 12:23:102017-03-21 12:23:10Wie viel wissen wir über unsere Emotionen?
Reality Testing – are you sugarcoating reality or fearing the worst?
Reality Testing is the capacity to remain objective by seeing things as they really are, rather than as we wish or fear them to be. It involves noticing when our perception of a situation is overly negative or overly positive.
Some people tend to wear rose-colored glasses. The glasses may make the world look nice, but there is a flip-side: the person might misinterpret critical information, underestimate risks or overlook a danger. For example, if a person can’t accurately assess the amount of effort needed for the task at hand, he or she might end up stressed.
The opposite of seeing the world through rose-colored glasses is coloring reality with own fears. For example, if such a person isn’t greeted warmly by a manager in the hallway, this person might think: “Oh, my manager doesn’t like me anymore. I did something wrong.” His thoughts colored by insecurity might prompt wrong assumptions, which prevent him from seeing the situation objectively.
Good Reality Testing means verifying how well our perceptions match reality. Is there an absolute reality out there? Yes, no, and maybe. We probably wouldn’t be able to answer this question. However, people with a good sense of reality are able to tune into a situation and assess the correlation between what’s experienced and what objectively exists. They remain on the same page as everyone who is involved in this situation. Reality Testing enables us to focus on ways to cope with what we discover and keep our emotions in check, untainted by illusions.
• Do you tend to sugarcoat reality?
• Do you fear the worst?
• Which emotions influence your sense of reality?
Be Emotionally Smart by “Being Realistic”!
http://eqpower.ch/wp-content/uploads/2013/08/EQpower_med_rgb4-300x66.jpg 0 0 Marina Riedi http://eqpower.ch/wp-content/uploads/2013/08/EQpower_med_rgb4-300x66.jpg Marina Riedi2015-01-22 10:20:032015-01-22 10:21:04Reality Testing - are you sugarcoating reality or fearing the worst?
To be a Social Samaritan means to demonstrate your social conscience and be compelled to help society and social groups. This competency is called “Social Responsibility”. Social Responsibility is that moral compass directing your behavior toward promoting the greater good of others.
A good example of Social Responsibility is to do fund raising projects for charities or to help out at social events as a volunteer. To me, being on the organizing committee of an annual neighborhood get-together is also a sign of Social Responsibility, though on the local level.
Whether for one person or for all of mankind, your contribution matters! Not only for others but also for yourself. If you are one of those who thrive while contributing, your social activity will bring you a deep sense of fulfillment and inner worth. I have had this experience helping out my son with his projects for WWF. Being engaged in social activities allows you to train different skills. For example, being the president of a tennis club will give you a chance to practice your leadership skills. Another advantage is to build relationships with people who are involved in the same social activity. Maybe these relationships will help you in the future.
As with all competencies of Emotional Intelligence, finding the golden mean is the key!
– Check in with yourself to ensure that you are not avoiding your current emotional state by focusing solely on helping others.
– Ask someone close to you (e.g., family or close friends) to describe what your intentions to help look like from their perspective. Others may be able to see the real motives behind even the best intentions.
– If you are overly involved to the point that your personal well-being is neglected or you are placing unrealistic expectations on your friends, family, or colleagues for their social or corporate involvement, it may be time to reflect on the motives behind your desire to help others.
– Identify two or three charities, nonprofit organizations, or causes to which you feel a connection.
– While brainstorming, record several activities that you can engage in to help at least one of these organizations. Write down what outcomes you expect to see from engaging in each activity. Ensure that these outcomes benefit the organizations or people and aren’t just about making yourself feel good.
– Create a plan and a time frame and if possible, share these details with someone who can hold you accountable to follow through on them.
Be Emotionally Smart by Being a Social Samaritan!
Empathy – are you able to step into another person’s shoes?
Empathy is best described as the ability to step into another person’s shoes and to recognize, understand, and appreciate how other people feel. It involves being able to articulate your understanding of another’s perspective and behaving in a way that respects others’ feelings.
The most important demonstration of empathy comes when the consideration of the other person’s position is followed by an action. The action may vary from just actively listening to helping a person on the task at hand. The support should be genuine and not of a “transactional” nature, in other words, not intended as a way to get something in return.
The empathic nature makes a person approachable, someone with whom people feel safe sharing thoughts and ideas. It provides a foundation for all other interpersonal skills.
People who have difficulty empathizing can’t articulate another’s perspective and are more focused on facts than on others’ feelings and reactions. For instance, if a person fails to take into account colleagues’ feelings when resolving conflict, managing change, or making tough decisions, he or she leaves them feeling alienated and undervalued. Additionally, you cannot predict how others will accept change if you cannot address the emotions they are experiencing (e.g., fear or excitement).
– In general, listen more than you speak. Try it in your next interaction and note the approximate amount of time you spend listening versus speaking.
– When you find yourself jumping in to speak, stop, listen, and reflect back what you have heard before offering your own opinions.
Being too empathic has a negative side. When colleagues trust you with their issues and feel comfortable coming to you for advice, you, being very concerned with their feelings, run the risk of taking on their problems, becoming the victim of your empathy. Being over-empathic can lead you to avoid making tough decisions or to act in some way at the expense of your own interest or needs.
– Need more preparation time in order to express the right amount of empathy. Write down what you want to say and rehearse it.
– Be respectful of people’s reactions, but don’t let them derail you.
– Keep in mind that if you mirror someone’s emotion, you will likely intensify that person’s reaction. For example, if the news you are bringing someone makes them angry, by becoming angry yourself you are likely to make the situation more heated.
Be able to step into the other person’s shoes but don’t lose your own.
http://eqpower.ch/wp-content/uploads/2013/08/EQpower_med_rgb4-300x66.jpg 0 0 Marina Riedi http://eqpower.ch/wp-content/uploads/2013/08/EQpower_med_rgb4-300x66.jpg Marina Riedi2014-07-09 10:19:112015-01-22 10:23:57Empathy – are you able to step into another person’s shoes?
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Radio frequency identification, or RFID, is a generic term for technologies that use radio waves to automatically identify people or objects. There are several methods of identification, but the most common is to store a serial number that identifies a person or object, and perhaps other information, on a microchip that is attached to an antenna (the chip and the antenna together are called an RFID transponder or an RFID inlay). The antenna enables the chip to transmit the identification information to a reader. The reader converts the radio waves reflected back from the RFID tag into digital information that can then be passed on to computers that can make use of it.
An RFID system may consist of several components including tags, tag readers, edge servers, middleware, and application software.
The purpose of an RFID system is to enable data to be transmitted by a mobile device, called a Tag, which is read by an RFID reader and processed according to the needs of a particular application. The data transmitted by the tag may provide identification or location information, or specifics about the product tagged, such as price, color, date of purchase, etc.
In a typical RFID system, individual objects are equipped with a small, inexpensive tag. The tag contains a transponder with a digital memory chip that is given a unique electronic product code . The interrogator, an antenna packaged with a transceiver and decoder, emits a signal activating the RFID tag so it can read and write data to it. When an RFID tag passes through the electromagnetic zone, it detects the reader’s activation signal. The reader decodes the data encoded in the tag’s microchips and the data is passed to the host computer. The application software on the host processes the data, often employing Physical Markup Language (PML).
Radio frequency identification, or RFID for short, is a term describing technologies that use radio frequencies to identify objects.
Is RFID technology better than using barcode technology?
Radio frequency identification technology is not necessarily better than bar codes. It can work in conjunction with bar codes to help manage inventory. The main difference is the fact that bar codes have to be in the line of site for the scanner to read it, whereas RFID tags can be read in multiple quantities as long as they’re in close proximity of the reader (usually 2-5 ft). Another benefit of using RFID technology is where barcodes can only identify a type of good; Radio Frequency Identification technology can narrow the information down to the single product itself. RFID technology furthermore allows for data to be encoded onto the tag allowing multiple reads to occur at the same time. For example, in one application inventories could be counted in seconds rather than hours, thus utilizing employees at hand more efficiently and productively.
Will RFID technology replace barcodes?
That is not very likely since bar codes are inexpensive and are effective for certain tasks. RFID will grow and work with the information on the bar code to help inventory management and tracking costs low.
RFID has been around since the 1970’s, but has been too expensive to operate. Today, companies are finding cheaper ways to produce the RFID tags now making the whole RFID system more affordable than ever.
Why is RFID technology only starting to catch on now in the supply chain industry?
The main problem has been the standards for RFID. Most companies request frequency ranges to be Ultra High Frequency (UHF), which offers a longer read range. UHF is a relatively new technology, and has only started to become affordable recently. Also, a conversion to RFID is a major step that just one company in the supply chain might not want to do until other companies in the supply chain are ready for RFID.
Are there companies out there today using RFID technology?
Yes, there are many companies around the world using this new technology. Companies such as Wal-Mart have started the trend by requiring all suppliers to use RFID technology.
What are some of the common applications for RFID?
RFID can be used to track inventory in retail businesses from cereal to toothpaste, can even be used to locate parts needed for equipment repair, as well as collect payments at tolls. RFID is also being used today at local hospitals in multiple applications. These are just a few applications; the use of RFID is limitless in its possibilities.
How will RFID benefit my company?
RFID can be used to track work in progress and can speed up the flow of goods in a warehouse. The main objective of RFID technology is to reduce the cost of labor used in tracking goods, reduce errors in shipping and overall inventory levels, and to increase the overall efficiency in any field.
The basic parts of an RFID system include an RFID tag that consists of a microchip with a small antenna. That antenna enables the microchip to receive and respond to Radio-Frequency (RF) queries from an RFID reader or interrogator. The reader sends out waves to the Tag, after that the Tag responds back to the reader with the information given. These again are just the basics of an RFID system.
RFID Tags and Readers need to be on the same frequency in order to function. The differences of the frequencies are similar to those in radio. Different channels have different information. Finding the right frequency is critical because radio waves can only function at their own frequency level.
How do I know which frequency to use?
Low end frequencies (LF) require less energy and are less costly. They work well exceptionally well on non-metallic items. They do work well around items with high water content, but the read range is limited to just a few feet. An ultra-high frequency (UHF) is effective at reading tags at further locations. Also, UHF can transfer the data faster than low end frequencies. The downfall of UHF is the fact that it cannot read through certain materials, in that case the product would have to be directed at the reader.
Are all countries going to use the same frequency?
The answer is no. Governments will decide what frequencies to use; they will also regulate the power of the readers to limit the interference with other devices.
What are some common types of RFID equipment being used today?
RFID equipment can be broken into 3 main categories: there are RFID readers, RFID tags, and RFID antennas which are the essentials of RFID equipment and are vital in running an RFID supply chain. There are other RFID products being used that can add more efficiency to the supply chain, such as RFID printers and RFID smart labels.
Why RFID technology is so important in today’s industry?
Many top end retailers and companies are using RFID technology in today’s market and are requiring suppliers to do the same. This technology helps any supply chain or business flow much more efficiently with less time spent on tracking.
Why should I use RFID technology?
With growing inventory costs and the down time of lost products, RFID technology can help decrease the extra costs caused by leaks in the supply chain. RFID technology has been around for many years now, and the use of this technology in supply chains around the world has shown tremendous success in the efficiency and overall flow of the business.
How much information can a tag store?
That depends on the vendor and the application of the tag. Most tags will use a 96-bit serial number. These are the simple tags that will be used in most throw away packaging. The tags can hold up to 2KB of data, however these are not to be just used once and thrown away.
What’s the difference of between read-only and read-write RFID tags?
The Read-Only tags have all the original information the manufacturer placed on them, but have no capability of adding additional information to them. While Read-Write tags have the ability to add additional information to the tag, it also has the capability to erase and re-write information on a particular tag and can be used again in another product.
What is a WORM tag?
WORM stands for write once, read many. This acts as a read-only tag where they have no ability to have information added to them; however Worm Tag information is added by the consumer rather the manufacturer.
What are the differences between Active and Passive RFID tags?
Active tags have a power source linked to them similar to a battery; the power is used to broadcast a signal to the reader. Passive tags draw their power from the reader using electromagnetic waves to induce the antenna on the tag to send out the information. The key difference between the two is Active tags can be read at longer distances than Passive tags, which subsequently leads to a higher cost.
There is no simple answer for this question. Low frequency tags have a range of about 1-2 ft. Ultra High Frequency (UHF) tags have a range of 20-30ft, and active tags can boost the signal to 300 ft.
This is when many tags or transponders send a signal back at the same time, the reader then becomes confused. Different vendors have come up with different ways to help singulate the tags.
Most passive RFID tags just reflect back the waves with the information on it. Energy harvesting is when the tag gathers the energy and stores it for a brief moment, the information is then sent back to the reader at a different frequency. This method will help the passive tags performance dramatically.
Chipless tags are a generic term used to describe a tag without a microchip inside. Instead of a microchip, the radio frequencies take a “picture” of the tag to identify the product; a computer then takes the wave or “picture” and uses it like a fingerprint to identify the product.
RFID doesn't’t work well on metal or water products right?
Well yes and no. Certain frequencies have a hard time with metal and water. Low end and high end frequencies have been working well around metal and water. Some low end frequencies have actually been embedded into some metal car parts without any RFID problems.
Agile readers can multitask by being able to read different frequencies or by some other method of communication between the tag and the reader.
One small problem with RFID is there can be interference between two readers. This is called reader collision. The RFID fields of the readers collide and can cause friction in the supply chain. One solution might be to have the readers operate at different times to reduce collision.
Dense reader mode is used when many readers are being used in close proximity. Each Reader will use a different channel from the other Reader in the vicinity to communicate with the tags. This prevents reader collision.
Can class 1 and class 0 Readers be upgraded to read EPC gen 2 Tags?
In most cases RFID Readers can be upgraded, it depends on the model or brand.
What is the difference between intelligent and dumb Readers?
Intelligent readers can have many different protocol functions such as storing tag data and can run applications. Dumb readers might only be able to read one type of tag, one frequency, and the ability to operate one protocol.
Will governments be able to track people with RFID?
Only if they are willing to place RFID tags in every piece of our clothing or put a tag in our skin. Then the government would have to understand all the information in the database, in other words not likely.
Why do companies want to use RFID if not keep track of the consumers?
RFID will help improve the supply chain to its maximum efficiency. This means less money spent on tracking, and more money in profits.
What kind of data does a company want to collect?
The RFID is used to help keep items on the shelves for consumers to buy. RFID wants every product to be accounted for so it can continue to improve the supply chain.
Can RFID tags in consumer products be deactivated?
Yes, there is a kill command that can be used when the item has been purchased. EPC standards are pushing to have a kill command placed in all Tags so they can never be reactivated.
UPC stands for Universal Product Code, which has been used to auto-identify items via machine-readable barcodes for a number of years.
A UPC only identifies object classes or generic categories of product — such as a pack of Wrigley’s Spearmint gum. An EPC uses a unique serial number to identify each individual pack of gum and makes it possible to automatically track products from manufacturer to store shelf.
An inlay is the functional portion of the RFID label. It is made up of the antenna to which a chip (the brains of the inlay) is attached. The inlay is typically supplied on a substrate or carrier and is called a dry inlay, or if adhesive is added, it is called a wet inlay. In both cases the inlay is supplied to a converter where it is inserted into a label or tag or whatever type of construction is required for the application.
What benefits does RFID have over barcodes?
The most obvious benefit is that RFID does not have to be seen to be read. Bar codes must be placed on the outside of the product and the product must be orientated so the bar code is inline with the scanner. On the other hand, with RFID, you could have (multiple) products inside a sealed carton (for example) and each product can still be identified. Another important difference is that RFID is a read/write technology. So if desired the data can be written (or programmed) after it has been attached to the product. This offers a higher level of flexibility to track and update the data as the product goes through the supply chain, into the end use application or beyond.
What are the components of an RFID tag?
An RFID tag has a protective/printable face-stock then a layer of adhesive.then the RFID inlay.then another layer of adhesive.and finally a removable liner.
The RF inlay provides the RFID functionality. The inlay consists of a carrier sheet that holds an RF antenna, to which is bonded a tiny microchip. The liner and face stock are typically made of paper, but may also be made from other materials such as plastic films.
The selection of materials determines how well the tag will survive and whether it will be compatible with printers, applicators and other system hardware. Material selection may also have to accommodate FDA regulations. In addition, there are mechanical considerations, such as selecting an adhesive that will ensure the tag will remain adhered to the carton.
Functionally, an inlay consists of an antenna and a microchip.
The antenna drives tag performance and governs how well the tag will work in a particular application. Precision-designed to receive and broadcast RF signals, the antenna is made from a conductive material (such as silver, copper or aluminum). The antenna makes contact with an RF reader over a distance determined in large part by the amount of metal and size of the antenna. Contacts attached to the microchip make the circuit between the microchip and antenna.
The chip design determines the protocol or class of the tag’s operation. Different microchips have different features that can also affect performance. RFID microchips contain circuitry capable of handling a variety of functions from power conversion to data storage and retrieval.
What does an RFID strap consist of?
A strap consists of a microchip with two over-sized contact pads on a carrier sheet to facilitate high-speed roll-to-roll manufacturing. In conventional flip-chip manufacturing, the microchip is a very small component.less than 1mm square.with tiny contact pads that must be placed very precisely on the antenna. This is a relatively slow process. To overcome this problem, Avery Dennison RFID Division has developed an innovative high-speed strap attach process that substantially improves yield rates.
What are RFID inlay antennas made of?
Traditionally, RFID antennas were etched from copper — a relatively slow, relatively wasteful process. Today’s antennas tend to be produced with more efficient methods such as etching or stamping.
Why are quality and testing important?
RFID testing provides necessary data on both component quality and expected performance in real-world conditions. Avery Dennison RFID employs an “end-to-end” testing approach, challenging the quality of our inlays from prototype to delivery. Our Atlanta Technical Center simulates the real-world of the supply chain with conveyor, portal and RFID printer and printer/applicator hardware.
Component testing assures that the inlay’s electronic portions will perform as expected. Different test protocols must be followed for different classes of microchips to evaluate near-field performance. This testing protocol includes a “writing to chip” test performed on Class 0+ and Class 1 inlays (including Gen 2).
Another component of the testing protocol is the read sensitivity test. This is performed on all inlays to make sure they meet far-field requirements.
What is "free space" testing?
Tests performed in free space (i.e. performance tests of unattached tags conducted in a controlled environment) are the starting point for performance tests. Although these tests provide good baseline information, they provide insufficient information on which to select tags for specific applications. Carton contents.the orientation of the tag toward the reader antenna. and other environmental issues such as radio frequency noise and physical object interference can impact performance.
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0.999256 |
Is a singer a musician?
I should start by saying that everything I'm about to say is just my thought process and opinion on this question, the crowd might be divided on this but I could be completely off base, maybe I'm wrong (it wouldn't be the first time).
For years I was a singer/vocalist in different bands and I really don't know how I feel about this question, there are so many different factors to consider and to draw definite lines is near impossible to me.
Personally, I would define myself as a musician, even though I may not have been playing an instrument in these bands, I could/can play, and I'm more than capable of writing a half decent song (although that could be subjective). So of course, I can confidently say I am a musician.
Within the setting of a band, I think even if you are instrument-less, you can still be a musician, after all, mosts bands write music together and as a singer, you're always listening to sounds, making writing notes, creating melodies and moulding something from nothing alongside and equal to other members. So it would stand to reason that just because you're writing music without playing an instrument doesn't mean you aren't making music as a musician.
Then there is the question, what is a musical instrument? Well, to me it's anything that produces a sound that you can create music and/or songs with, computers fall into that category for me, and so I THINK my opinion is that even if you're programming and sequencing music, you're still a musician, surely? Maybe not in the 'traditional' sense, but then times do change, and so things like this have to change too I guess.
So far I'm pretty sure that if you are a singer in a band, someone who makes music electronically, or just a singer that can and does contribute to the musical aspect of songwriting in any environment then I'm pretty sure I'd class you as a musician, but let's say you are a singer and just that. You don't write songs or melodies, you just perform the song as it's presented to you and don't hold any ability to play a musical instrument, wait a minute... Isn't your voice a 'musical instrument? For the sake of this point, let's say it's not.
There is a difference between a performer and a musician, but they are both 'artists' I wouldn't call someone who takes a song, as it's given to them, performing it as it's already been written - without changing any of the musicality in the track - a musician. I would, however, call them a performer and an artist. My view of the music world is that two industries have accidentally occupied the same space. Those industries are the musician's industry and the musical performer's industry, together they're just called 'the music industry' but they are vastly different worlds. One appeals to the art of making music and the other appeals to the art of performance, they occupy the same space and so to the average listener they are taken away as the same thing. That's just my view and how I see music on a broader scale.
So, I guess to summarize, yes I think a singer is a musician given that the circumstances are that there is musical input when creating the music/song. Equally, you can be a singer but not a musician if you are simply performing what has already been written. However, in both scenarios, you're still an artist just two different types of artists occupying the same space. I don't think the two are mutually exclusive.
Like I said in the start I could be wrong. What do you think the answer is? is there even one out there?
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0.956887 |
Read the following information and answer the questions based on it.
If A + B ✕ C, then which of the following is true?
If A + B - C, then which of the following is true?
If A ✕ B + C, then which of the following is true?
In a certain code language 687 means 'all the best'; 579 means 'best of luck'; 853 means 'all luck good'; Which of the following is the code for 'the'?
In a certain language HEARTBEAT is written as HETAAERBT. Then, how is ABSENCE written in that language?
Answer the questions based on the information given below.
Six friends namely Anu, Gauri, Mehar, Sushma, Tanu and Vimala, each one likes a different clothing brand like Aaika, Biba, Belle, Calaso, Libas Vero Moda. They also have a different taste for ice cream flavours like, Black forest, Butterscotch, Chocolate, Mango, Pineapple and Strawberry.
Anu likes Pineapple but doesn't like either Biba or Aaika. Sushma likes Belle, but doesn't like Butterscotch. Mehar likes Vero Moda, but doesn't like Mango or Strawberry. Gauri likes Chocolate, but doesn't like Libas or Aaika. The person who likes Calaso likes Mango. Tanu likes Black Forest.
Which ice dream flavour does Sushma likes?
What is the correct combination for Gauri?
Which brand does Vimala likes?
Which of the following statements cannot be true?
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0.950896 |
A theoretical model is presented which describes selection in a genetic algorithm (GA) under a stochastic fitness measure and correctly accounts for finite population effects. Although this model describes a number of selection schemes, we only consider Boltzmann selection in detail here as results for this form of selection are particularly transparent when fitness is corrupted by additive Gaussian noise. Finite population effects are shown to be of fundamental importance in this case, as the noise has no effect in the infinite population limit. In the limit of weak selection we show how the effects of any Gaussian noise can be removed by increasing the population size appropriately. The theory is tested on two closely related problems: the one-max problem corrupted by Gaussian noise and generalization in a perceptron with binary weights. The averaged dynamics can be accurately modelled for both problems using a formalism which describes the dynamics of the GA using methods from statistical mechanics. The second problem is a simple example of a learning problem and by considering this problem we show how the accurate characterization of noise in the fitness evaluation may be relevant in machine learning. The training error (negative fitness) is the number of misclassified training examples in a batch and can be considered as a noisy version of the generalization error if an independent batch is used for each evaluation. The noise is due to the finite batch size and in the limit of large problem size and weak selection we show how the effect of this noise can be removed by increasing the population size. This allows the optimal batch size to be determined, which minimizes computation time as well as the total number of training examples required.
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0.999617 |
Why do some car parks / hotels say can't amend, can't cancel?
These types of packages are usually slightly cheaper but can't be changed or cancelled*.
Packages with extra flexibility cost slightly more but give you the option to amend or cancel the arrangements 24 hours before your package start date.
These packages may also be known as being 'non-flexible', 'flexible' or SuperSaver.
*personal details, including car registration and flight numbers can be changed free of charge.
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0.964124 |
Is it true...blondes have more fun?
If I've only one life...let me live it as a blonde!
Do these phrases sound familiar? They should: these ads were penned back in the '50s by a trail-blazing female copywriter named Shirley Polykoff, and changed the American hair care industry forever. Let me put it this way: before Shirley Polykoff penned that first slogan, just 7% of American women dyed their hair, most of whom were actresses and models. When Shirley's stewardship of the Clairol account ended in the 1970s, that number had skyrocketed to 40%, and included women of all walks of life.
Shirley Polykoff's words were so effective, they even inspired me to pursue a book length project on the topic, 50 years later. But who was Shirley Polykoff? I scoured the Internet to find out, and in the process learned: she was a delightful paradox.
She was born in Brooklyn in 1908 into a poor, Ukrainian Jewish family. She went on to became one of the most successful, well-compensated advertising professionals of the 20th century, despite the obstacles presented by industry bias against her gender and her religion.
She was a natural brunette, but always dyed her hair blonde, even when she was still just a teenager, "even in the days when the only women who went blond were chorus girls and hookers."
Shirley's attitude was decidedly unfeminist: "Miss Polykoff was cut from a pre-feminist mold, never forgetting, as she often put it, that she was 'a girl first and an advertising woman second,' (NYT Obituary, 1998.) Polykoff went by a different name at home, as Polly Halperin, always kept the two lives separate, and put her family first before her career. She even insisted that her employers cap her salary at a measly $25,000/year, as she believed it inappropriate for a woman to make more money than her husband (her advertising firm, Foote, Cone & Belding, doubled her salary twice within a few years of her husband's death.) But Shirley's actions spoke louder than her words, and Ms. Polykoff was incredibly ambitious: she lied about her age so as to obtain a job in advertising while still in her early teens, worked her way up in the ad world and held a copy-writing job (as opposed to a secretarial or administrative position) in the '30s when the Depression found many American men out of work, and already had an established advertising career by the '50s, while most of her peers were at home managing the cult of domesticity.
Now, I truly believe that advertising and marketing in this day & age have a terribly deteriorating and damaging impact upon women's self esteem. More specifically, upon my self-esteem. I struggle every day with notions that I am not skinny enough, blonde enough, made-up well enough, dressed well-enough, and on and on. And I am not alone: as Naomi Wolf wrote in The Beauty Myth, "Recent research consistently shows that inside the majority of the West's controlled, attractive, successful working women there is a secret 'underlife' poisoning our freedom; infused with notions of beauty, it is a dark vein of self-hatred, physical obsessions, terror of aging, and dread of lost control." Wolf argues that we may be worse off than our un-liberated grandmothers, that the beauty myths that bind us now may be more stringent than our great grandmother's corsets.
And then there's Shirley Polykoff, a woman who, according to her daughter Alix Nelson Frick, believed "you could acquire all the accouterments of the established affluent class, which included a certain breeding and a certain kind of look. Her idea was that you should be whatever you want to be, including being a blonde." And thanks to her brilliant copy-writing, that's exactly what I've done.
What do you think, readers? Is it a delightful paradox? Or a vicious cycle? Are we liberated by the ads? Or oppressed by them?
Oh Miss Kitty, it's quite a dangerous line. It's one thing to feel empowered to be whoever you are inclined to be...whether it is becoming a blond or becoming a steel worker. It is another thing when advertisements bombard us with the ideas that we MUST be something in order to be beautiful. The most frightening to me was when ad copy essentially told us we needed to be heroin skinny in order to be beautiful. So not my idea of beautiful and not what I wanted my teenage niece to be seeing. Essentially, I'm sad any time I feel like I can't decide what makes me happy. Just to let the rest of you know...I LOVE my jet black hair and I think my curves are deliciously voluptuous. I also love my svelte and beautifully undercover blond friend! We are strong, powerful, women who are individuals. That is what makes us beautiful.
"Blondes Make Men Act Dumb"
how many blondes does it take to break a blender?
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0.914661 |
Completed in 1903, for John A. McCall (1849-1906) and his wife Mary Ignatius Horan (d.1935). This 52-room mansion - the first of two built on the same site - had a short and chequered history. It was home to two convicted Wall Street crooks and a President. One critic described the architecture as "all design and no rhetoric" while others enthusiastically hailed it as "a palace". In 1916, it was used by Woodrow Wilson (1856-1924), 28th President of the United States, as his Summer White House. But, it burned down in 1927 and was replaced with an even larger mansion - Shadow Lawn (1929) - that for several years retained it's predecessors name until it was purchased by Monmouth University and renamed Woodrow Wilson Hall.
McCall was the President of the New York Life Insurance Company. Nearing retirement in 1902, he purchased the Hulick farm of 27-acres on Cedar and Norwood Avenues. He added to the estate until it encompassed 65-acres, buying neighbouring land from archeologist Charles Conrad Abbott (1843-1919) and actress/playwright, Ettie Henderson. McCall then employed architect Henry E. Cregier (son of the Mayor of Chicago) to build a house, "suggestive of the grandeur of the Alhambra, the Petit Trianon, and Sanssouci".
Situated on a grassy knoll some 50-feet above the ocean, McCall's modified colonial summer home was complete by August 1903. The 52-room mansion of three stories was dominated by two vast porticos and named for the clusters of great trees that threw shadows over the lawn. On top of the third floor was an atrium and two pillared lookout towers from which to enjoy the view over the estate and down to the sea.
The semi-circular front portico towered over the formal gardens and terraces, descending to a long lawn that ran down to Whale Pond Brook at the end of Norwood Avenue. The brook itself had been dammed to create a lake on which two gazebos were built. The mansion boasted gold-plated plumbing and three conservatories that produced grapes, peaches and pears. The original old farmhouse was converted into a carriage house - with it's own windmill and water tower.
McCall did not get long to enjoy his new home. In 1905, the same year that Murry Guggenheim (1858-1939) moved in across the street to the Guggenheim Cottage, McCall was found guilty of bribing state legislators with $275,000 of company money. He resigned his position and was ordered to repay the amount, which meant he had to sell Shadow Lawn after having enjoyed it for barely three summers.
Shortly before his death the following year, McCall sold the mansion for $350,000 to New York attorney Myron H. Oppenheim. His intention make Shadow Lawn the center-piece of what he hoped would become the Brook Lawn Country Club. But, within a year (1906) his plans had failed to come to fruition and this time for $500,000 it was sold once again. The new buyer was the early 20th century's answer to the "Wolf of Wall Street", Abraham White, more favorably known as "the postage stamp capitalist" whose ego couldn't resist the urge of immediately renaming the estate White Park.
A crook he was, but a romantic he might have been: White had claimed that he purchased Shadow Lawn for his wife who he reckoned to have the most beautiful voice in America. However, despite her highly touted talent, she refused to sing in public. White therefore hoped that the beauty of the mezzanine floor would result in her breaking out of her shell and performing - at the very least - to her friends.
As quickly as White had made his money, so he lost the house in equal style. In the same year that he bought Shadow Lawn, his realty company that was to pay the $100,000 mortgage was foreclosed. Nonetheless, White still managed to strip out and sell off all the McCall's silver chandeliers and doorknobs, as well as not paying any of the tradesman for works throughout the year. He snuck out of town to run back to Texas before finally being convicted in 1910 for larceny - when the records on him go quiet.
Once again, the mansion came back to Oppenheim when re-purchased it at the ensuing sheriff's auction, for $125,000. Due to poor credit, Oppenheim put it in the name of his business partner, Robert L. Smith, and for a brief period his dream was realised as it became the Brook Lawn Country Club. It didn't last, and in 1909 it was sold to the fifth owner in seven years - Colonel Joseph Benedict Greenhut (1843-1918).
Very large, with a staircase, wide enough for an army abreast, opposite the front door. This staircase ended in a big platform on which rested a grand piano. Then the stairs parted to run in opposite directions as if each was ashamed of the other... When we got settled, we were happy and comfortable at Shadow Lawn.
Two flights of stone steps run up the terraces to the top of the rise of ground on which the house is built. The entrance is guarded by a large dome, level with the roof of the second floor, supported by eight columns. A porch of about 250 feet in length runs about the north, east and south sides of the house, commanding a view of the ocean and beautiful country. The building is of wood painted white and of stone.
In 1918, Greenhut died, and his heirs sold Shadow Lawn for $800,000 to Hubert Templeton Parson (1872-1940). On taking ownership, he increased the estate to 108-acres; instructed a $1 million renovation of the house; and, spent a further $1.25 million furnishing his summer home. Shadow Lawn's brief and chequered history was brought to an end by a fire on January 27, 1927. Parson replaced it with the 130-room mansion found there today - the 5th largest house in the United States - Shadow Lawn (1929).
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0.999826 |
Chicago (CNN)Two law enforcement sources with knowledge of the investigation told CNN that Chicago Police believe Jussie Smollett paid two men to orchestrate the assault.
The brothers, who were arrested Wednesday, were released without charges Friday after Chicago police cited the discovery of "new evidence." The sources told CNN that the two men are now cooperating fully with law enforcement.
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0.990926 |
Country labor market predictions: Alex Bryson on the UK labor market.
Okay so, I’m from Britain, so the greatest labor market challenge facing my country is probably, a two-fold one actually.
One, that everybody will expect me to say, which is Brexit, and boy is that true because we rely on international talent to remain globally competitive in Britain. We are still a small nation state, and it’s extremely important that we show that we’re open to business and can attract and retain the best talent in the world.
The second one is perhaps something that people will have less, paid less attention to and that’s this long term stagnation in real wages. It’s been going on for some time, in fact it slightly predates the recession, and this means that there are real problems in the labor market. We do very well on employment and employment rates, but workers are finding it very very difficult, and find, struggle to maintain standards of living when wages have been stagnate for so long.
The government’s been doing a little bit about that, in particular increasing the national minimum wage, but it’s a challenge for all of us to ensure that labor gets its fair share of increasing wealth in the country.
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0.997195 |
I live in Minnesota and am afraid I don’t receive enough vitamin D throughout the year.
A. Dear Ethel, Vitamin D is incredibly important to virtually every cellular process within our body. When our skin is exposed to sunlight, there are certain cells that undergo changes and convert a special kind of cholesterol into usable, vitamin D. There are many factors that can impact how efficient this process is: including age, latitude, cholesterol status, ethnicity, and many others.
While the recent increase of the RDA for vitamin D is promising, I think the level may still be too low for most people to receive many of the therapeutic benefits of vitamin D. This is especially important for the people living in areas of the world where receiving vitamin D from the sun may not be available year-round.
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0.960501 |
Choose the correct option to complete the sentences below.
1Mum, where is -thea dog? I want to take it to a-the park.
2I like -thea cake, but I don't like thea- cake you make.
3It's obvious that athe- students should listen to their teacher, but -thea students in my class never listen.
4Can you pick up a-the kids today? I'm going to be at -thea work until late.
5A: "Shall we go on a picnic today? TheA- sun is very warm." B: "I don't like -thea picnics."
6A: "Have you tried the-a tea Tim brought?" B: "No, I never drink a-the tea.
7A: "He's thea- fan of Manchester United." B: "I don't understand how he can like thea- football so much."
8My favourite day is a-the Friday, and -thea 2010 was my favourite year.
9I don't like athe- French. Well, I don't like thea- languages in general.
10We are going to fly from athe- USA to -athe Cairo.
When we mention something for the first time.
I saw an old woman with a dog.
To say what kind of person or thing something/somebody is.
When I was a teenager, I enjoyed sleeping.
Can I have an orange?
For frequency, rates and speeds etc.
I work 6 hours a day, and I go to English classes three times a week.
The rent is €500 a month.
We were driving at 70 km an hour.
In the expressions what a/such a + singular countable noun.
Yesterday was such a horrible day!
This is such a difficult problem!
Thanks, you are such a good friend.
With things or people already mentioned, or when we know which things or people we are talking about.
A man and a woman sat in front me. The man was British, but I think the woman wasn’t.
‘Where are the kids?’ ‘They’re in the garden.’ (=Both speakers know which kids and which garden).
When a noun is made specific by details we give after it.
I sat on a chair (maybe one of many).
I sat on the chair in the corner.
I saw the man who tried to rob me.
When there is only one of something: the earth, the moon, the planet, the internet, the universe, the sky, the city (=not the country), the country (=not the city), etc.
I’d like to live in this country, but not in the capital.
The moon looks beautiful today.
I’m going to the bank.
I found Peter at the station.
This is the best restaurant in town.
With the names of oceans, seas, rivers and canals (the Mediterranean, the Amazon, the Panama canal, etc.).
To describe something in general (with plural or uncountable nouns).
Love and health are more important than money.
Women drive more cautiously than men.
But we use the article if we refer to these places just as places, or buildings; when they are not used for their main purpose.
I found the keys under the bed.
I’m going to the school to pick up my children.
Yesterday I went to the hospital to visit my grandmother.
Dinner is served at 8.
I always have breakfast with my children.
With names of years, months and days of the week.
Friday is my favourite day of the week.
I think 2020 will be an excellent year.
He is in room 15.
But Turn off the TV. I’ve bought a new TV.
The meeting is next Thursday.
But names of countries that are plural or that include words such as State or Republic, or Kingdom are used with the: the US (the United States), the UK (the United Kingdom), the Philippines, the Netherlands, the Czech Republic.
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0.966974 |
What are the best Music Colleges in Manchester, CT?
Manchester's largest music school is Manchester Community College. In 2010, Manchester Community College graduated approximately 3 students with credentials in music.
In 2010, 3 students graduated with a music degree from one of Manchester's music schools. In 2009 tuition at music schools in Manchester was $3,200 per year, on average.
In addition to tuition costs, you should plan on spending an average of $1,000 for books and supplies each year, while enrolled in a music program in Manchester.
Many music graduates choose to work as musicians after graduation. If you choose to follow that path and remain in Manchester, your job prospects are not very good. There were 1,170 musicians working in Connecticut and 220 working in the greater Manchester area in 2010. Manchester's musician workforce is projected to increase by 1% by the year 2018. This projected change is slower than the projected nationwide trend for musicians.
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0.947559 |
Mainland Chinese or Mainlanders are Chinese people who live in a region considered a "mainland". It is frequently used in the context of areas ruled by the People's Republic of China, referring to people from mainland China as opposed to other areas controlled by the state such as Hong Kong or Macau. The word is also often used by Taiwan people to distinguish the Chinese from Mainland China from themselves, if not calling the mainlanders and themselves as Chinese and Taiwanese directly respectively.
Ma Ying-jeou, the former President of the Republic of China (Taiwan).
1949 immigrants or Waishengren (Chinese: 外省人; pinyin: wàishěngrén; literally: 'extraprovincial person') are people who moved to Taiwan from mainland China after 1945 until the late 40s and early 50s. This group also includes all of their descendants born in Taiwan.
Daluren (大陸人; dàlùrén; 'mainland people') are residents of mainland China, especially citizens of the People's Republic of China (PRC) who live in mainland China.
In the context of demographics of Taiwan, the term mainlander when applied to a Taiwan resident most likely refers to daluren.
The translations of waishengren (Chinese: 外省人; pinyin: wàishěngrén; Pe̍h-ōe-jī: gōa-séng-lâng) and benshengren (本省人; běnshěngrén; pún-séng-lâng) into English poses some interesting difficulties. The usual English translation of waishengren is Mainlander, although many waishengren find this translation uncomfortable since it implies that waishengren are residents of mainland China, when they are all residents of Taiwan. Benshengren, which literally translates to "this province's person" and is sometimes translated as "native Taiwanese", refers to the people native to Taiwan before the Republic of China took over rule of Taiwan in 1945 and the mass exodus of mainlanders following the Chinese Civil War, but this translation could be confused with the indigenous Austronesian people. Most academic literature uses the terms waishengren and benshengren directly. The terms rarely come up in the English-speaking media.
Many supporters of Taiwan independence object to the term "extra-provincial people", because it implies that Taiwan is a province of China, and prefer the name Taiwanese new immigrant [zh], (新住民; Pe̍h-ōe-jī: sin-chū-bîn). The latter phrase has not become popular in Taiwan and is extremely unpopular among waishengren themselves.
Chinese Civil War veterans especially are called "old taro" (老芋仔; lāu-ō·-á) in Taiwanese Hokkien, due to the similarity between the shape of mainland China and taro leaves), or waisheng laobing (Chinese: 外省老兵; literally: 'external-province veteran', in Mandarin. In government publications and the media, they are also called "honorable citizens" (榮民; róngmín; êng-bîn).
Mainlanders make up about 10% of the population of Taiwan and are heavily concentrated in northern Taiwan especially in the Taipei area. Although no longer dominating the government, waishengren still make up a large fraction of bureaucrats and military officers.
The formal definition of a mainlander is someone living in Taiwan whose "native province" is not Taiwan. Native province does not mean the province in which one is born, but rather the province where one's father's "ancestral home" is. Until 1996, identity cards and passports in Taiwan contained an entry for native province. The removal of native province from identity cards and replacement with place of birth was motivated in large part to reduce the mainlander/local distinction. This is especially true given that virtually all "mainlanders" born after 1949 were born in Taiwan, not in their "native provinces".
Because of the "native province" definition, someone who is born on Taiwan, but whose father's family roots are not in Taiwan, is generally considered a waishengren. By contrast, someone who is not born in Taiwan, but whose native province is Taiwan (most notably Lien Chan) is generally not considered a waishengren. Similarly, a child that is born to a Taiwanese businessman residing in the PRC would generally not be considered a waishengren.
Furthermore, recent immigrants to Taiwan from Mainland China, mostly from marriages and undocumented migrants, are not considered waishengren, but make up a separate social category. Although the numbers of these people are thought of as small and insignificant by most Taiwanese, it has been pointed out that recent immigrants from Mainland China and their children actually make up a larger population in Taiwan than Taiwanese aborigines.
The distinctions get even fuzzier with mixed marriages and the fact that provincial identity sometimes does not correlate in obvious ways to characteristics such as political orientation or ability to speak Taiwanese. For example, although Mainlanders are often stereotyped as supporting Chinese reunification and opposing Taiwan independence, there are numerous examples where this formula does not hold. Similarly, it is common to find younger waishengren who speak fluent Taiwanese and younger benshengren who cannot speak it at all.
The number of the original waishengren generation who migrated to Taiwan sixty years ago has been dwindling as they age and die. Thus, the great majority of today's waishengren are their descendants born in Taiwan, and they do not speak the dialect of their "native province".
Waishengren are descended from the people who followed Chiang Kai-shek to Taiwan after the Kuomintang lost the Chinese Civil War in 1949. These people included Kuomintang officials, soldiers, merchants, bankers, executives, scientists, intellectuals, refugees, and anyone else who feared Communist rule. Until the 1970s, these people controlled the political systems of Taiwan; this, along with the looting and corruption that occurred under Chen Yi's military government immediately following the Japanese surrender in 1945, generated resentment among benshengren and was one of the main causes of the Taiwan independence movement.
Starting in the 1970s, Chinese nationalist dominance of the government began to recede. This was due to a lack of a political or social theory that would justify continued Chinese nationalist dominance, meritocratic policies which allowed local Taiwanese to move up in the political establishment, and economic prosperity which allowed for social mobility for those outside of the political establishment.
Intermarriage and a new generation raised under the same environment has largely blurred the distinction between waishengren and benshengren.
In the late 1990s, the concept of "the New Taiwanese" became popular both among supporters of Taiwan independence and Chinese reunification in order to advocate a more tolerant proposition that waishengren, who sided with the Allies against the reluctant Japanese colony in Taiwan during World War II, are no less Taiwanese than benshengren. However it quickly became apparent that the notion of New Taiwanese meant different things to supporters of independence and unification. To supporters of independence, the concept of New Taiwanese implied that waishengren should assimilate into a Taiwanese identity which was separate from the Chinese one. By contrast, the supporters of Chinese reunification seemed to believe that all Taiwanese (not just waishengren) should restore a previously marginalized Taiwanese identity without antagonizing a larger pan-Chinese identity.
As of the early 21st century, more and more waishengren see themselves as Taiwanese and as socially distinct from current residents of Mainland China. Unlike those belonging to groups such as the Hakka or Taiwanese aboriginals, waishengren are not encouraged to find their root, and their relationship with anti-China organizations suffers further as a result. Most of them, especially those of the younger generation, make extensive efforts to establish themselves as Taiwanese, sometimes by manifesting good interest in Hoklo Taiwanese culture. At the same time, right-wing discourse alleging that pro-unification waishengren are a fifth column for the PRC agonizes those mainlanders who regard Taiwan as their new homeland.
Now, the term "mainlander" is used to describe a person, Chinese by race, born and raised in mainland China, thereby avoiding confusion with waishengren.
Lien Chan has been sometimes denoted a waishengren, often by his political opponents, although the general perception on Taiwan is that he is not. Although he was born in mainland China and his mother was of mainland ancestry, his father's ancestral home was in Tainan, Taiwan.
Since the mid-1990s, there has been a small amount of mainland Chinese immigration into Taiwan. These immigrants are predominantly female and are often colloquially known as dàlù mèi (大陸妹), which means "mainland girls" (literally: mainland sister). These consist of two categories: female brides of businessmen who work in the mainland; and women who have married rural Taiwanese, mainly through a marriage broker. This population is distinct from waishengren.
Tung Chee Hwa, former Chief Executive of Hong Kong.
In Hong Kong and Macau, "mainlander" (also "inlander"[dubious – discuss]) refers to residents of mainland China, or recent immigrants from mainland China.
Residents of mainland China are usually referred to as 大陸人 (jyutping: daai6 luk6 jan4, literally "mainlanders"), 內地人 (jyutping: noi6 dei6 jan4, literally "people from the inland"). Officials in China, as well as a few leftist institutions in Hong Kong, refer to themselves as 內地同胞 (jyutping: noi6 dei6 tung4 baau1, literally "inland compatriot"). The second term is neutral, and the first term is commonly used by local Hong Kong Chinese but also used by government issued statements to refer to people from mainland China.
Mainlanders are sometimes called 表叔 (jyutping: biu2 suk1, literally "father's male cousin"), 表姐 (jyutping: biu2 ze2, literally "female cousin"), and 阿燦 (jyutping: aa3 chaan3), which were coined by various characters in movies and television series. These terms are considered derogatory and are politically incorrect. Recent immigrants are more politically correctly called 新移民 (jyutping: san1 ji4 man4, literally "new immigrants"). 阿燦 is especially rude.
At the time when Hong Kong was colonised by Great Britain, the colony first covered only Hong Kong Island, with a population of only around 6,000, most of whom were fishermen. Other than the indigenous population on Hong Kong Island, Kowloon and New Territories who had lived in the area before the British arrived, most people in Hong Kong either immigrated from somewhere in mainland China, or were descendants of those immigrants.
The largest influx of population from the mainland was during the Taiping Rebellion (late 19th century) and the Chinese Civil War (1945–1949). The British colonial government maintained a touch-base policy until the early 1980s, allowing people from Mainland China to apply to be Hong Kong residents if they manage to arrive in the territory.
Some of these early immigrants, especially those who moved from Shanghai in the 1940s and early 1950s to escape the Communist government, some came to dominate the business world in Hong Kong. In the 1980s and 1990s, Shanghai-born immigrants also occupied some of the prominent roles in the government, including former Chief Executive Tung Chee-hwa and former Chief Secretary Anson Chan.
After decades of wars, internal conflicts and the Cultural Revolution, there was a large gap in the level of development between Hong Kong and the mainland. Many new immigrants arriving in the late 1970s and early 1980s were thought to be less sophisticated, and preserved many habits from the rural way of living. A very popular TVB series in 1979, 網中人, "the Good, the Bad, and the Ugly", starring Chow Yun Fat as a good-hearted and handsome Hong Kong university graduate, Carol "Dodo" Cheng as a rich and charismatic HK-and-UK-educated university graduate, and Liu Wai Hung (廖偉雄) as 阿燦 (jyutping: aa3 chaan3), Chow's long-lost good-hearted but unsophisticated rural-bred mainland brother arriving in Hong Kong as a new immigrant.
Starting from the early 1990s many new immigrants to Hong Kong are the spouses of residents and their children. Many of them are not rich, and some have to rely on money from Comprehensive Social Security Assistance to survive. Although only a few do so, new immigrants of this time were held in a negative view.
Since the Handover in 1997, academic exchanges between Hong Kong and Mainland China have become much more common. In 2004, a policy was passed that allowed mainland high school students to apply to Hong Kong universities. The Chinese government encouraged more Hong Kong students to study in mainland universities by offering scholarships.
Since 1 July 1997, the day when Hong Kong became a Special Administrative Region of the People's Republic of China, the immigration policies have changed. It is stated that "[a] person of Chinese nationality born outside Hong Kong before or after the establishment of the HKSAR [Hong Kong Special Administrative Region] to a parent who, at the time of birth of that person, was a Chinese citizen who is a permanent resident, is a permanent resident of the HKSAR and enjoys the right of abode in Hong Kong".
But in 1999, the Supreme Court of the HKSAR made a judgment that as long as the person is born in Hong Kong, they will be regarded as a permanent resident and will get the right of abode, even though their parents are not permanent residents of Hong Kong at the time they are born.
Since then, a lot of Mainlanders have come to live in Hong Kong. Every day there is a quota of 150 immigrants.
A daily sub-quota of 60 is given to children of all ages who are eligible for the right of abode in Hong Kong.
A sub-quota of 30 is for long-separated spouses.
those entering Hong Kong for the inheritance of property.
In 2003, the mainland authorities loosened control on mainland residents over visiting Hong Kong and Macau. Before this change, residents from the mainland could only visit Hong Kong and Macau for sightseeing as part of tour groups. The Individual Visit Scheme allows mainland residents of selected cities to visit Hong Kong and Macau for sightseeing on their own. It has boosted tourism in the two special administrative regions.
On 28 June 2006, the HKSAR imposed the Quality Migrant Admission Scheme. It is a scheme which aims at attracting highly skilled or talented persons who are fresh immigrants not having the right to enter and remain in Hong Kong to settle in Hong Kong in order to enhance Hong Kong's economic competitiveness in the global market. Successful applicants are not required to secure an offer of local employment before their entry to Hong Kong for settlement. Many Mainland artists and former national sportsmen/sportswomen have applied for the right of abode via this way, such as Li Yundi and Lang Lang.
The following are some notable people who were born in the mainland and moved to Hong Kong.
Anson Chan, politician, born in Shanghai.
Wong Jim (aka. James Wong), musician, born in Guangdong.
Lau Chin Shek, politician, born in Guangdong.
Tang Hsiang Chien, businessman, born in Shanghai.
Tung Chee Hwa, politician, born in Shanghai.
Wong Kar-wai, filmmaker, born in Shanghai.
^ "Hong Kong 2006 - Population and Immigration". Yearbook.gov.hk. Retrieved 2013-10-19.
Ku, A. 2001. “Hegemonic Construction, Negotiation, and Displacement: The Struggle over Right of Abode in Hong Kong.” International Journal of Cultural Studies, no.4(3): 259-278.
Kuah, K.E.; and Wong, S.L. 2001. “Dialect and Territory-Based Associations: Cultural and Identity Brokers in Hong Kong.” in P.T. Lee (eds). Hong Kong Reintegrating with China:P, Cultural and Social Dimensions. Hong Kong: Hong Kong University Press.
Siu, Y.M. 1996. “Population and Immigration.” in M.K. Nyaw and S.M. Li (eds.) The Other Hong Kong Report 1996. Hong Kong: The Chinese University Press. pp. 326–347.
So, A.Y. 2002. Social Relations between Pearl River Delta and Hong Kong : A Study of Cross-border Families. Hong Kong: Centre for China Urban and Regional Studies, Hong Kong Baptist University.
Tang, H.H. 2002. New Arrival Students in Hong Kong: Adaptation and School Performance. M.Phil thesis, Department of Sociology, University of Hong Kong.
Tzeng, Shih-jung, 2009. From Honto Jin to Bensheng Ren- the Origin and Development of the Taiwanese National Consciousness, University Press of America. ISBN 0-7618-4471-6.
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While corporate events can run the gamut from casual staff parties to more formal luncheons, they all have one thing in common. They can be better attended and loads of fun if you come up with a slate of exciting giveaways for attendees. Cool giveaways for corporate events not only add interest and enjoyment to the event, but they let people go home with extra perks that show how much they’re appreciated.
Need some ideas about fun giveaways to offer at your next event? Here are four prizes the crowd is sure to love, and tips on how to get them excited about the giveaway.
Gift certificates: Whether you pick a gift card from a nearby favorite restaurant or a popular store, gift certificates never go out of style. They let employees select a purchase or meal that suits their exact tastes.
Spa days: Check out what kind of vouchers for services your local spas offer for a perk that benefits employees as well as your overall company. Employees get a chance to kick back, relax, and rejuvenate, and then return to work with a revitalized body and mind.
Company swag: Notebooks, tote bags, tumblers, lanyards, and other swag sporting the company logo make for cool giveaways at corporate events for their versatility. Go for smaller swag, and you can make sure everyone in attendance goes home with a gift. Go for more substantial items if you want to include a few as grand prizes.
Goodie Baskets: Baskets packed with goodies are another idea for cool giveaways at corporate events, again for their versatility. Stick with traditional baskets cascading with fruit, candies, and snacks, or create themed baskets stocked with any variety of different items. Themes can include office and work-related goodies, games and puzzles, or health and fitness items.
While the smaller company swag can go to everyone in attendance, you can come up with exciting ways to choose the recipients of the more substantial gifts.
Raffle: Raffles can be a blast, with raffle tickets handed out to people as they enter the event. Raffles are quite good at holding people’s attention, so schedule them near the end of the event to ensure everyone sticks around.
Other Games of Chance: Raffles are fun because recipients are left up to chance, and there are a few other ideas in that same category. Contestants can be asked to draw straws, pick cards, or even engage in a round of tabletop Wheel of Fortune with your own set of prizes inserted as options on the wheel.
Games of Skill: Competitions are another way to dole out your corporate event prizes, and you have a wide range of options. Trivia games, company fact games, and spelling bees are a few ways to pick out your top winners.
Whether you’re raffling off a spa day or answering trivia questions to win a gift basket, employees will appreciate the extra show of appreciation that cool giveaways for corporate events can bring. Shop PaperDirect for your office giveaway, gift, and stationery needs.
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What is the life expectancy of your pipes?
It is important for you to know what type of pipes you have in your home. This knowledge can help you not only know what their life expectancy is, but also, help you know how to properly take care of and maintain them. Depending on the type of pipes you have, their life expectancy can vary from 20 to up to 100 years.
Copper, brass, and galvanized steel pipes, are typically used as supply pipes. Supply pipes are under a constant amount of pressure, and are the most likely pipe to burst, leak, and cause water damage in the home. The life expectancy for these supply pipes are typically 40 to 70 years for brass, 20 to 50 years for galvanized steel, and at least 50 years for copper.
For pipes that are used as drain lines, their life expectancy is somewhat longer because they are not under a constant amount of pressure. This type of piping is generally constructed with either cast iron or pvc. If the drain line is made with pvc, the life expectancy is indefinite. However, if the line is made with cast iron, the life expectancy ranges from 75 to 100 years.
Along with taking care of your pipes, it is important to use pipe thread protectors. These products are used to prevent any type of damage to pipes, and they extend the life of the pipe. Most protectors are made from either plastic or metal.
The most effective pipe thread protectors are made from plastic. This is because they are made from a combination of resin and plastic. This design, compared with the natural durability and stability of plastic, makes it one of the toughest protectors available. These protectors provide the pipes with volume resistance, tensile strength, a low rate of water absorption, and an inability to corrode, unlike the metal protectors.
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The two past tenses and their usage To talk about past events, German has two tenses that are almost entirely interchangable, in terms of their meaning. These are the simple past (das Präteritum) and the perfect (or present perfect, das Perfekt).
These have equivalents in English, of course, but it is very important to understand that, while in English “I was hungry” (simple past) does not mean the same thing as “I have been hungry” (present perfect), in German there is essentially no difference in meaning between the two tenses. The difference is almost entirely one of usage.
In written German, one tends to use the simple past; in spoken German, one tends to use the perfect. However, for some very common verbs, the simple past is more common than the perfect in spoken German.
This usage varies by region, education level, social situation, even personal preference. But it’s a pretty accurate generalization to say that in everyday spoken German, most people most of the time use the simple past for sein, haben, werden, and the modals; the perfect for all other verbs. Therefore, it makes sense that beginners who are being introduced to the German past tenses for the first time should learn the simple past of sein, haben, werden, and the modals, along with the perfect tense of all the verbs in their vocabulary.
Haben, sein, and werden are highly irregular in the simple past, and their forms should be memorized.
The modals form their simple past by adding the following endings to the verb stem.
Those modals that have umlaut in the infinitive lose it in the simple past. This is quite regular, so that it should not be necessary to memorize all the forms of each modal. The full conjugation of each modal verb is given here, for your reference, however.
Mögen when used as modal verb has the forms möchte, möchtest, etc. These have no exact equivalent in the simple past or perfect tense. If you want to say that you wanted to do something, use the simple past of wollen.
The perfect is a compound tense; that is, it is formed from two parts–an auxilliary verb and a past participle.
The creation of the perfect from an auxilliary and a past participle is identical in German and English. But there are two important differences. First, in German, the auxilliary appears in the usual position of the conjugated verb (it is the second sentence elelement), while the past participle is placed at the end of the sentence. Ich bin gestern Nachmittag aus Wien angekommen.
Second, while the auxilliary in English is always a form of to have, in German you have to learn rules for choosing between haben and sein as the auxilliary.
The participles of irregular verbs must be memorized; those of regular verbs are formed by rule. Irregular verbs may be classified as “strong” (ending in -(e)n, by far the largest group of irregulars) or “mixed” (ending in -t). German has somewhere around two hundred irregular verbs, but many of these are uncommon. A much larger number of verbs are regular. However, many of the most common verbs are irregular.
Again, the participles of irregular verbs must be memorized, but there are at least four things that can help with the memorization.
German does not have an infinite or even an immensely large variety of possible changes in the stem. Certain patterns of change are common to several verbs. As children, native speakers use these patterns to help them learn the irregular verbs; adult learners can do it, too.
Some of the patterns of change in German irregular verbs are identical or very similiar to patterns of change in English irregular verbs: singen-gesungen, for example, is very similar to sing – sung.
You have already learned certain verbs that have a stem change in the second and third person singular present. These are all strong verbs.
Regular (or “weak”) verbs form their participles by adding the prefix ge- and the suffix –t to the stem. For example, the stem of machen is mach-. The participle is gemacht. Many hundreds of verbs form their participles this way.
Verbs with separable prefixes add the ge-between the separable prefix and the stem; for example: aufgemacht, ausgegangen.
Verbs with inseparable prefixes do not add the ge-; for example: vergessen, befragt.
The choice between haben and sein is made according to very simple rules. If you ask yourself the following questions in this order, you will make the correct choice between haben and sein.
Is the verb sein or bleiben? If yes, use sein. If no, go to question #2.
Does the verb have a direct object? If yes, use haben. If no, go to question #3.
Does the verb indicate a change of location or condition? If yes, use sein. If no, use haben.
There may be a very small number of verbs to which these rules to do not apply, but none of them are learned in the first semester.
You may approach the haben/sein choice through memorization if you prefer.
However, it is not necessary, and ultimately it does not work, since a fair number of verbs can be conjugated with either haben or sein in the perfect, depending on their meaning in a particular context.
Page last updated by World Languages and Cultures at 1:42 pm February 8, 2017 .
This page was printed from http://foreignlanguages.camden.rutgers.edu/german/german-help/help-with-verbs/ at 12:30 AM Monday, April 22, 2019.
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I want to develop a python script that takes as input a video recording from a dashcam and estimates the speed of the cars in the video.
as I put you will also have the second by second speed, gps coordinates, and gyroscope measurements of the dashcam (mounted inside my car as I'm driving).
- retrain YOLOv3 to also detect licence plates in image. there are many open source licnese plate datasets out there. Yolo is already implelemeted in tensor flow in many open source github repos. you can use any of them.
- draw a bounding bos around each license plate.
- use edge detector to detect 4 edges of license palte.
- you will get real licnese plate dimensions (width and height in cm) as well as focal length of camera as input as well.
- use geometry to figure out coordinates of target license plate in 3d space for each frame. then detect centered of licnese plate.
- you will get frame rate of input video also. you can use this information to calculate speed of licnese plate from frame to frame.
- output in Csv or json format saying coordinates of 4 corners of each license plate, frame number, and estimated speed.
Hi there, I have read the details I am experienced with Machine Learning, Mathematics, OpenCV, Python. I can help you with this job, Please come to chat so we can discuss this job.
dear Sir, I can do this project. I am a researcher in deep learning, I can assure you that if you work with me once, you will always work with me for these kinds of projects.
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Want to feel happier? Then it might be time to contemplate a change of scenery because one Scandinavian country has just been named the happiest in the world.
According to the results of the UN's 2018 World Happiness Report – an annual ranking of countries, based on a range of factors, including self-reported wellbeing, life expectancy and social support – Finland is now the happiest place in the world to live.
And even though Finland has leaped up the list from fifth place in 2017, it's perhaps not surprising that a Scandinavian country has come out on top, as they have dominated the top of the rankings since the Report first launched in 2012.
Indeed, last year's number one, Norway, came in at number two, while Denmark and Iceland also made the top five.
The author reports wrote: 'There is a new top ranking country, Finland, but the top 10 positions are held by the same countries as in the last two years, although with some swapping of places.
'Four different countries have held top spot since 2015 – Switzerland, Denmark, Norway and now Finland.
The UK, on the other hand, only just managed to make it into the top 20, coming in at number 19 – the same position it held in 2017 – with the US just ahead at number 18.
This is despite the fact that the Office of National Statistics announced last month that happiness levels in the UK are on the rise.
Meanwhile, Burundi in east Africa – which has been affected by civil wars and coup attempts for decades – was named the unhappiest country, joined by the Central African Republic and South Sudan in the bottom three.
Is this the best city in the world?
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In 1144 the Christian world was shocked by the news of the fall of Edessa. Taking advantage of Count Josceline's absence, the Turkish ruler of Mosul - Zengi - was able to besiege the city, which was stormed after twenty eight days. This represented the first major victory by a Muslim power in the course of the Crusades. Indeed, it was a particular setback for the Franks as the County of Edessa had been the first Crusader State to be established and was one of the oldest cities in Christendom. Appeals for help from the Latin states following from this led to the creation of the Second Crusade, with Pope Eugenius III issuing the crusade bull on 1st December 1145.
This Crusade was notable for being an almost total failure despite the scale of the effort - with the king of France and the Holy Roman Emperor having taken part. It was a major setback for the position of the Franks in the East and damaged their reputation of military superiority. Conversely it was a significant Muslim victory that allowed Nur al-din (the son and heir of Zengi) to gain the initiative against the Franks. The Second Crusade also led to the development of the crusading movement, which included campaigns in Iberia against the Moors and in Eastern Europe against the pagan Wends.
This Crusade was primarily comprised of two major French and German contingents led by their respective sovereigns. Louis VII of France had already been eager to taken part in an expedition to the Holy Land and so embarked on it with gusto. Conrad III of Germany and Holy Roman Emperor Elect and the German nobility were originally unenthusiastic about the crusade until they were swayed by the powerful oratory of Bernard of Clairvaux one of the most respected clergymen in Christendom.
In June 1147 both armies set off for the East following the land route to the Holy Land. This choice seems influenced in part by the proven success of the route in the First Crusade but also due to the conflict between the Holy Roman Empire and the Normans of Sicily - thereby making a voyage by sea potentially more dangerous. An additional factor was due to sheer logistical difficulties, which indeed were to cause problems throughout the course of the Crusade. A smaller contingent from northern regions such as the Lowlands and England travelled by sea and on-route assisted the recently independent ruler of Portugal - King Afonso - in capturing Lisbon.
The German army marched ahead of the French army through Hungary into the Byzantine Empire. Though there were some clashes between the Germans and the Byzantines, the Emperor Manuel agreed to provide assistance to the Crusade whilst they travelled through his territory in Anatolia. Despite this, in Asia Minor the German army was much harassed by the Turks and their army was all but destroyed, with Conrad and the remnants of his army barely able to escape to join the French. The French were initially more successful than the Germans and managed to win a clear victory over the Turks in December 1147. However, the army became disorganised whilst crossing the Cadmus Mountains in Central Anatolia and falling victim to an ambush suffered heavy losses. After a further difficult march to the south coast the leaders of the Crusade and the cavalry embarked at the Byzantine city of Attalia for Syria, leaving the unfortunate infantry to continue on foot.
The French army regrouped at Antioch and were originally well received by its ruler - Prince Raymond - who hoped to benefit from being the uncle of Louis's wife - Eleanor of Aquitaine - to assist him in a northern campaign However, Louis's unwillingness to do so and rumours of him being to familiar with his niece led to the French moving on southwards to Acre.
At Acre a great council of war was convened by the leaders of the Crusade together with the local Frankish nobility led by King Baldwin of Jerusalem. With the city of Edessa all but destroyed - after Nur al-din had crushed a rebellion there - the decision was taken to attack Damascus. William of Tyre explains that the decision was taken because it was "A city that presented a great threat to us". This was a city which after a period of truce with the Latin states had become hostile to the Franks - due to a rapprochement between its ruler Umar and the ruler of Aleppo, Nur al-din.
In July 1148 the Christian armies reached the city and initially besieged it on the western side through the dense orchards; however after the course of a few days the decision was taken (supposedly on the advice of the native Franks) to attack the eastern part of the city, which was allegedly less well defended. After a few days the lack of provisions, the continued resistance of the defenders and the eminent arrival of the army of Nur al-din led to the collapse of the attack and the end of the crusade.
Why did the crusade fail?
Contemporaries at the time gave a number of explanations to explain why a crusade sanctioned by God had ended in disaster. Louis VII blamed the disastrous losses on the march through Anatolia due to the treachery of the Greeks - a view, which seems to have some justification considering the minimal assistance the crusaders received from the Byzantines. Others such as William of Tyre blamed it on the treachery and cupidity of some of the Franks who persuaded their leaders to make the error of moving their camp (bribed by the defenders) so that they "Deserted the place which they had previously occupied with great effort and loss of men". The Damascene chronicler, Ibn al-Qalanisi attributes the Muslim victory to the prowess of the defenders in defeating the attack and also as "News was reaching the Franks of the rapid approach of the Muslim armies" (Nur al-din).
These factors are all likely to have played a role in the collapse of the crusade before the walls of Damascus. Additionally historians such as Jonathan Philips have argued that it was lack of men and money that played a crucial role - the former undoubtedly as a result of the losses sustained on the journey to the Holy Land. A lesson that Richard I on the Third Crusade was careful to avoid with his well prepared and financed expedition. A further factor was the disunity of the leaders of the crusade as well as that of the native Franks some of who - as mentioned - were accused of sabotaging the crusade and whose refusal to take part in an expedition against Ascalon (following the debacle of Damascus) led to the westerners returning home. This was also a factor in the Third Crusade and led to Pope Innocent III's decision to recruit an army with leadership from the nobility for the Fourth Crusade - as was the case with the First Crusade.
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How to improve innovation in the treatment of hepatitis C.
The conundrum of hepatitis C is well known. The virus kills more than 20,000 Americans each year, more, according to Centers for Disease Control and Prevention, than the other 60 infectious causes of death combined. A cure is in hand, but is out of reach for many because it costs tens of thousands of dollars per patient. The problem is most acute in state Medicaid programs and prisons, where 700,000 people need treatment but only 20,000 a year will get it. The price controls some have asked for would make treatment affordable, but would also be likely to chill innovation in pharmaceutical companies, the very innovation that benefits society by producing such remarkable drugs.
A recent consensus committee of the National Academies of Sciences, Engineering, and Medicine proposed a novel strategy to improve access to hepatitis C medicines. Their report recommends that the firms producing the hepatitis C treatments compete to license their patent to the federal government for use in neglected patients, such as Medicaid beneficiaries and prisoners. Such a deal would protect the innovator companies’ market share in the lucrative private markets, while allowing the government to save billions of taxpayer dollars and reach more poor patients.
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0.990036 |
Non-fused switch disconnectors are a safety device designed to power down or isolate a part of a circuit while it is being serviced or maintained. Unlike fused switch disconnectors, they do not use a fuse to break the circuit, instead using either a rotary or knife-blade disconnect. Rotary switches break the circuit by rotation of a lever, while knife-blade switches use a hinge to lift a lever off its slot.
What are non-fused switch disconnectors used for?
Non-fused switch disconnectors are used to isolate circuit breakers, transmission lines and transformers as part of their maintenance process. They are a safety measure and are not intended for use as a regular part of the circuit.
Non-fused switch disconnectors vary in the method of disconnecting that they use, whether rotary or knife-blade. Beyond that, they have differing power, voltage and switch ratings, as well as different maximum current capabilities, which will determine which non-fused switch disconnector you choose.
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0.999958 |
Construction sites are dangerous places for smartphones, unless you pick the best and most durable model.
Based on the number of smartphones you see with spiderweb-cracked screens, you might think every model out there was an expensive and fragile waste of money, particularly if youre active on a jobsite. Drops and bumps, water sprays, dust, extreme temperatures, and vibrations are all threats to an otherwise essential technology tool.
Luckily, not all smartphones are delicate flowers. There are strong options available for construction contractors, engineers and skilled tradespeople who cannot afford to compromise on ruggedness. Whether you need something weatherproof, impact-resistant, optimized for multimedia, ready for collaborative projects or all of the above, you just need to know where to look.
What makes a smartphone rugged?
To call a phone rugged, not to mention waterproof or water-resistant, it should have a variety of certifications to its name. That means a third party has conducted tests to prove whether the device can withstand some pretty serious abuse. There are generally two types of these certifications: IP and MIL-STD.
The IP (Ingress Protection) rating on a smartphone is published by the International Electrotechnical Commission, which determines if a device performs after exposure to dirt, dust and water. The ratings for dirt range from 1 to 6, and 1 to 8 for water. The max rating for particulates would be IP6, and a max rating for liquid would be IP8. That would mean an IP68 phone is completely resistant to dirt damage and can be left underwater indefinitely, at a depth determined by the manufacturer.
The MIL-STD (Military Standard) specs are set by various arms of the U.S. Military and Department of Defense. The numbers associated with MIL-STD indicate far more than just protection from water and dust. For instance, MIL-STD-810Gs certifies that something can withstand nuclear radiation, drops onto concrete, and exposure to rapid freezing or heat. These certifications can be much more nuanced, but most commonly in rugged smartphones, youll note they are listed under an umbrella designation of MIL-STD-810G, which has a number of subcategories.
It is worth noting that a smartphone lacking one of these certifications may still be able to take a beating. For instance, companies such as Panasonic and Xplore are more focused on making sure their devices can be dropped than they are on them being able to handle really cold weather.
The ioutdoor X (about 229$ Aliexpress) is IP68 certified to offer protection against dust, shock from a 6-foot fall onto concrete, vibration, temperature extremes, blowing rain, low pressure, solar radiation, salt fog, humidity and water immersion. The Android phone sports a big storage 6GB+128 GB, and 18:9 full screen, NFC, which is is a state-of-the-art smartphone with fashion design suit for daily use.
The Sonim XP7 ($579) is another smartphone to consider for jobsites. Its more tank than entertainment center, and it comes with a three-year, no-questions-asked warranty. Its Gorilla Glass 2 screen doesnt match the Brigadiers for imperviousness, but it runs Android and is IP69 rated.
The Crosscall Trekker-X3 was built to live outside. It is IP67 rated, meaning it can survive a full range of outdoor conditions. It does far more than deliver your email and apps, too. It comes with a built-in thermometer, hygrometer, barometer and magnetometer. The box it comes in doubles as a wireless charger.
If you want to buy our ruggedphone,please get it on our official Alistopre.
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0.977323 |
Is there a way to export a map in HTML?
I've created several maps with photos in bubbles attached to places, but after a few photo bubbles, the map gets hard to read.
I'd like to be able to export the base map with markers and hyperlink those markers to the appropriate photos.
This would be especially useful for mapping a cemetery.
You can export to a graphics file to use in an html page. Zoom to whatever you want on the site, then go into publisher. You can customize the map there and then under the file menu you can export to a graphics file of various formats.
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0.996324 |
Prerequisite: Math 7200 or the equivalent.
Text: Algebraic Number Theory by A. Froehlich and M. Taylor, Cambridge University Press, 1991.
This course is intended to be a bridge between undergraduate and graduate-level number theory and should appeal to a broad audience. Due to time constraints during the summer term, this is not intended to be a full-fledged research-level number theory course , but rather a complete introduction to the standard algebraic and analytic techniques that are used in more advanced courses.
We will develop in some detail algebraic tools such as the theory of Dedekind domains, discrete valuation rings, p-adic numbers, completions, etc., and also some analytic tools such as zeta functions. We will also discuss applications of analytic methods to classical results such as the prime number theorem and Dirichlet's theorem on primes in arithmetic progressions.
The "official" textbook is "Algebraic Number Theory" by A. Froehlich and M. Taylor (Cambridge University Press 1991), but we will also use other sources for some parts of the course.
This course provides practical training in the teaching of mathematics at the pre-calculus level, how to write mathematics for publication, and treats other issues relating to mathematical exposition.
Communicating Mathematics I and II are designed to provide training in all aspects of communicating mathematics. Their overall goal is to teach the students how to successfully teach, write, and talk about mathematics to a wide variety of audiences. In particular, the students will receive training in teaching both pre-calculus and calculus courses. They will also receive training in issues that relate to the presentation of research results by a professional mathematician. Classes tend to be structured to maximize discussion of the relevant issues. In particular, each student presentation is analyzed and evaluated by the class.
Prerequisite: Math 4200 or the equivalent.
This course will cover the basic material on groups, rings, fields and modules with special emphasis on linear algebra.
This course is designed to give an introduction to the representation theory of finite and compact groups. It will start with the representations of finite groups over the complex numbers. In particular, we will discuss how finite-dimensional representations break up into sums of irreducible representations, Schur's lemma, the group algebra, character theory, induced representation and Frobenius reciprocity. We will give many examples, culminating in the representation theory of the symmetric groups and the remarkable combinatorics associated with it. We will then turn to the representation theory of compact groups, which is formally very similar to the finite group situation. The course will end with a discussion of the representation theory of the unitary groups and its close relationship with the representation theory of the symmetric groups.
Prerequisites: Math 7200 or the equivalent.
Homological Algebra is a tool that appears in almost all branches of mathematics, ranging from mathematical physics, PDEs, Lie groups and representation theory, through topology (where it originiated) and on to number theory and combinatorics. We will cover the basics of homology of chain complexes, elementary category language, derived functors, Ext and Tor, spectral sequences, simplicial methods. There are various further topics and directions which will depend on the available time and interests of the class. Each student will have a project to do - these can be chosen from an application of homological methods in the student's area of interest.
Text: Real Analysis, Measure Theory, Integration, and Hilbert Spaces by E. M. Stein and Rami Shakarchi, Princeton University Press, 2005.
This course deals with Lebesgue measure on Euclidean space and its analog in the more general setting of measure spaces. We will obtain all the basic properties of measure and integration, including convergence theorems, Fubini's Theorem, the Radon-Nikodymn Theorem, and the Caratheodory extension process. Banach spaces, particulary the Lp spaces will be discussed.
Time permitting, we will cover other topics important in real analysis, for which useful references may include Real Analysis by Royden and Real Analysis by Rudin.
Prerequisites: Math 4031, Math 4032, and Math 3355.
The aim of the course is to provide a mathematical account of the arbitrage theory of financial derivatives. A short treatment of stochastic differential equations and the It\^o calculus will be presented, and will include the Feynman-Kac formula, and the Kolmogorov equations. Risk neutral valuation formulas and martingale measures will be introduced through Feynman-Kac representations. The course will cover pricing and hedging problems in complete as well as incomplete markets. Barrier options, options on dividend-paying assets, as well as currency markets will be studied. Interest rate theory will include short rate models and the Heath-Jarrow-Morton approach to forward rate models. A self-contained treatment of stochastic optimal control theory will be used to study optimal consumption/investment problems.
Systems and control theory is one of the most central and fast growing areas of applied mathematics and engineering. This course provides a basic introduction to the mathematics of finite-dimensional, continuous-time, deterministic control systems at the beginning graduate student level. The course is intended for PhD students in applied mathematics, and for engineering graduate students with a background in real analysis and nonlinear ordinary differential equations. It is designed to help students prepare for interdisciplinary research at the interface of applied mathematics and control engineering. This is a rigorous, proof-oriented systems theory course that goes beyond classical frequency-domain or more applied engineering courses. Emphasis will be placed on controllability and stabilization.
Prerequisite: Math 7311 (Real Analysis-I) or equivalent.
Text: Dr. Rubin will use his own notes for this course.
This is an introductory course in the theory of the Radon transform, one of the main objects in integral geometry and modern analysis. Topics to be studied include fractional integration and differentiation of functions of one and several variables, Radon transforms in the n-dimensional Euclidean space and on the unit sphere, some aspects of the Fourier analysis in the context of its application to integral geometry.
Prerequisite: Basic concepts of numerical analysis, basic knowledge of linear algebra, and basic programming skills in C, Matlab or other computer language. Preferably Math 4065, 4066 or equivalents.
This course serves as a foundation for analysis, design, and implementation of numerical methods. In particular, it provides an in-depth view of practical algorithms for solving large-scale linear systems of equations arising in the numerical implementation of various problems in mathematics, engineering and other applications.
Linear algebra and numerical linear algebra refresher, in particular, solutions to system of linear equations.
Multilevel methods such as multigrid.
The course will focus on both the theoretical aspects and the numerical implementation of these methods. Evaluation will be based upon both theoretical and numerical projects.
Prerequisite: Some functional analysis and basic PDE and ODE is necessary. Some of the background will be reviewed in class.
Text: A list of articles for reading will be provided. The background material will be taught from: L. C. Evans - Partial Differential Equations and L. Nirenberg - Topics in nonlinear functional analysis.
At first I'll provide an introduction to the theory of Sobolev spaces, to elliptic regularity to direct methods of the calculus of variations, and to linear bifurcation theory. This should include about two thirds of the course. Then, I'll present the Ginzburg-Landau energy functional, prove existence of minimizers and discuss some general properties of the minimizer. I'll then cover some topics from the theory of superconductivity, including: Surface superconductivity, Abrikosov's lattices, radial vortices, self-duality and the Jaffe-Taubes assumption, thin rings, and if time allow the Bethuel-Brezis-Helein theorem and the weak field limit. (I probably won't be able to do that much so you can have influence on the material to be covered).
Text: J.G. Oxley, Matroid Theory, Oxford, 1992, reprinted in paperback with corrections, July, 2006.
Prerequisite: MATH 2057 or equivalent.
Text: James R. Munkres, Topology, 2nd edition, Prentice Hall, 2000.
Topology contains at least three (overlapping) subbranches: general (or point-set) topology, geometric topology and algebraic topology. General topology grew out of the successful attempt to generalize some basic ideas and theorems (e.g., continuity, open and closed sets, the Intermediate Value and Bolzano-Weierstrass Theorems) from Euclidean spaces to more general spaces. The core of this course will be a thorough introduction to the central ideas of general topology (Chapters 2 - 5 of Munkres). This material is fundamental in much of modern mathematics. Time permitting, we will also look briefly at the ideas of homotopy and the fundamental group (Chapter 9), subjects that belong to the algebraic-geometric side of topology, and will be covered in greater depth in 7512.
Prerequisite: MATH 7512 (Topology II) or equivalent.
If time permits we will cover related topics in Geometric Topology.
Prerequisite: Math 7510 (Topology I) or the equivalent.
References: Carmo, Riemannian Geometry (Birkhauser, ISBN: 0-8176-3490-8) and Introduction to Symplectic Geometry by Dusa McDuff and Dietmar Salamon (Oxford University Press, ISBN: 0-1985-0451-9 ) will be useful.
Riemannian Geometry (connections and Gauge theory). This course is an introduction to Riemannian geometry: manifolds, metrics, Levi-Civita connections, and curvature. Riemannian geometry is key to understanding Einstein′s general relativity and plays an important role in gauge theory and invariants of smooth 4-manifolds. We will use this technology to introduce and investigate symplectic geometry, another important topic in mathematics that also comes from physics.
Students do not need to be enrolled in the Spring 2006 differential geometry course (Math 7550) to take Math 7590-2 in the fall.
Readings to be selected after discussion with the students.
This reading seminar will meet weekly at at a time to be announced. If you are interested in this seminar, please contact Prof. Vertigan before you register.
This course provides practical training in the teaching of calculus, how to write mathematics for publication, how to give a mathematical talk, and treats other issues relating to mathematical exposition.
Prerequisite: Math 7200: Geometric and Abstract Algebra.
Text: A Course in Galois Theory by D. J. H. Garling (Cambridge University Press) and Fields and Galois Theory - notes by J. S. Milne, available on-line.
This is primarily a course on Theory of Fields. Topics include: review of results from Group and Ring Theory, algebraic field extensions, ruler and compass constructions, separability, Galois Theory, algebraic equations, finite fields, transcendental extensions. If time permits, some applications to Algebraic geometry and /or Number Theory will be discussed.
Prerequisite: Some knowledge of homological algebra, such as Prof. Hoffman's Fall 2006 Math 7280 course on homological algebra.
Text: no required text; notes will be made available as appropriate, and references will be given during the semester to books, such as M. Kashiwara and P. Schapira, Sheaves on manifolds or A. Beilinson, J. Bernstein, and P. Deligne, Faisceaux pervers in Asterisque.
The theory of "perverse sheaves" was introduced around 1980 as a tool in algebraic topology for constructing a particular kind of homology theory. Since then, it has turned out to be an incredibly powerful framework with far-reaching consequences, especially in representation theory. A number of major results since then (e.g., the proof of the Kazhdan-Lusztig conjectures, the whole theory of character sheaves, and much work related to the geometric Langlands program) could not have gotten off the ground without perverse sheaves.
The goal of this course will be to develop the basics of the theory of perverse sheaves and look at a couple of applications. Perverse sheaves are defined in terms of the derived category of ordinary sheaves. No prior knowledge of sheaves or derived categories is necessary; these topics will be covered in the course. However, it is a good idea to have some familiarity with abelian categories and derived functors. The applications will likely come from representation theory, but no prior knowledge of representation theory will be assumed.
classical algebraic number theory would be helpful but is not indispensable. Please feel free to contact Prof. Morales if you have any questions.
Text: Number Theory in Function Fields by Michael Rosen, Springer-Verlag 2002.
Classically, number theory is concerned with properties of the ring of integers Z, its field of fractions Q and its finite extensions (number fields). In this course we will do number theory over the ring A = F[t], instead of Z, where F is a finite field, and study the arithmetic properties of finite extensions of F(t) (function fields).
We will discuss function field analogues of the Riemann zeta function and prove analogues of classical theorems such as quadratic reciprocity, Dirichlet’s theorem on primes in arithmetic progressions, etc. We will also discuss the relation with algebraic curves over F and the Riemann-Roch Theorem. We will see how the Riemann Conjecture (which is a theorem in the function field case) yields estimates of the number of rational points on algebraic curves. This course can be seen as an introduction to both number theory and the theory of algebraic curves.
Text: Functional Analysis by George Bachman and Lawrence Narici, (1966, 2000) now published by Dover.
Banach spaces and their generalizations; Baire category, Banach-Steinhaus, open mapping, closed graph, and Hahn-Banach theorems; duality in Banach spaces, weak topologies; Hilbert Spaces, other topics such as commutative Banach algebras, spectral theory, and Gelfand theory.
MATH 7350: Complex Analysis. This course will serve as a Core-2 course for the current year.
Text: Function Theory of One Complex Variable (3rd Edition): Robert E. Greene, Steven G. Krantz, AMS Publication, 2006.
This is a first rigorous course in the theory of functions of one complex variable. Topics include holomorphic (or complex analytic) functions; power series; complex line integrals; Cauchy's integral formula, and some of its applications; singularities of holomorphic functions; Laurent series, and computation of definite integrals by residues; the maximum principle and Schwarz's lemma; conformal mapping; and harmonic functions (if time permits). The text and the course emphasize connections with multidimensional calculus.
Note: Math 7350 is being offered this year as a Core-2 Course. Students taking this course will have the option of taking a Complex Analysis Core-2 PhD Qualifying Examination.
Text: Non-Abelian Harmonic Analysis, Howe, Roger and Tan, Eng Chye. Springer Verlag Universitext Series, 1992. Softcover ISBN-10: 0-387-97768-6 or ISBN-13: 978-0-387-97768-3.
Optional Reference: SL(2,R) by Serge Lang, Addison-Wesley, 1975. ISBN: 0201042487.
Topics will include Lie groups and Lie Algebras, Linear Semisimple Groups, Finite and Infinite Dimensional Representations, Unitary dual, Character formula,Matrix coefficients and applications. The emphasis will be on the very important example of SL(2,R) and its representations.
Prerequisites: Math 4032 or Math 4340 or Math 4038.
Text: Partial Differential Equations by Lawrence C. Evans.
This course will be suitable to mathematics graduate students with good backgrounds in analysis but with no previous course on PDEs. It will also be suitable to Physics and Engineering students who are minoring in mathematics but have taken either Math 4340 or Math 4038. The course will concentrate on representation formulas for solutions of various partial differential equations. Topics that will be covered include the transport equation, Laplace equation, the heat equation, the wave equation, nonlinear first order PDEs, other ways to represent solutions; similarity solutions, Fourier and Laplace transforms, converting nonlinear PDEs into linear PDEs Hopf-Cole transformation, etc.
For more information, contact Michael M. Tom at 310 Lockett Hall or call Prof. Tom at 578-1613 or email Prof. Tom.
Prerequisites: Math 7311 (Real Analysis I) or the equivalent.
In this course we will develop the basic mathematical theory of the finite element method for elliptic boundary value problems, which provides a foundation for further study and research in the area of finite elements. Topics include background material for Hilbert spaces and Sobolev spaces, variational formulations, constructions of finite element spaces, interpolation error estimates, and discretization error estimates. We will cover Chapters 0--5 of the text. Additional material will be covered if time permits.
Prerequisite: The prerequisites for the course are very modest---all graduate students in Mathematics should be able to follow the lectures.
Recommended References: Graph Theory by Reinhard Diestel, Third Edition, Springer, 2006, which is available both as a paperback (for about $43 + shipping from various online stores), or as a free download at http://www.math.uni-hamburg.de/home/diestel/books/graph.theory/GraphTheoryIII.pdf.
Another good book on the subject is Introduction to Graph Theory by Douglas B. West, Prentice Hall, 1996.
The main theme of this course will be graph theory. We will discuss a wide range of topics, including spanning trees, Eulerian trails, matching theory, connectivity, hamiltonian cycles, coloring, planarity, integer flows, and graph minors.
There are many books on graph theory. Prof. Oporowski recommends the references listed above, but they are not absolutely necessaary. He will present the lectures with his own notes, which will be available for download, and which should make good study material. However, the amount of detail in the lecture notes is less than that of either of the mentioned books. If your interest in the subject is anything more than superficial, you would be well advised to get at least one of those books - especially the first one listed.
Grades for the course will be based 60% on homework and 40% on two exams (midterm and final). Decisions in borderline cases will be made on the basis of class participation. There will be the total of over twenty problems given as homework, and the two lowest problem scores will be dropped.
If you have any questions about the course, do not hesitate to contact Prof. Oporowski.
This is an introduction to algebraic topology. In algebraic topology, topological questions are related to algebraic questions. Sometimes this allows one to answer the topological questions using algebra. We will discuss homotopy, homotopy type, the fundamental group, the Jordan curve theorem, Brouwer fixed point theorem, covering spaces, and time permitting elementary aspects of higher homotopy groups. We will study chapters 0 and 1 and perhaps the elementary parts of chapter 4. Munkres's Topology will be an alternative source.
Prerequisite: Math 7200 and 7510; or equivalent.
This course is an introduction to algebraic topology, with an emphasis on homology and cohomology. The goal will be to cover as much of the material in chapters 2 and 3 of Hatcher's book as time permits. This includes simplicial, singular and cellular homology, excision, the Mayer-Vietoris sequence, cohomology groups, the Universal Coefficient Theorem, the cup product, and Poincare duality.
Prerequisites: MATH 7200 and 7510 (and undergraduate analysis).
This course provides an introduction to smooth manifolds, roughly speaking, spaces which locally resemble Euclidean space and have enough structure to support the basic concepts of calculus, as well as related constructions. These include submanifolds, tangent vectors and bundles, smooth mappings and their effect on tangent vectors, implicit and inverse function theorems, vector fields, differential forms, Stokes' theorem, etc.
This course will serve as an introduction to mapping class groups of surfaces. Mapping class groups are a fundamental object of study in topology, as the automorphism groups of 2-manifolds, but also arise naturally in many other fields, such as complex analysis and algebraic geometry. We will survey some basics such as generators and relations for the mapping class group, subgroups important in 3-manifold theory such as the Torelli group and the handlebody subgroup, and representations of mapping class groups. As time permits, and according to the interests of the class, we will also discuss related groups in geometric group theory, Teichmuller theory, and associated combinatorial structures such as the curve complex, among other topics.
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0.995486 |
Destinypedia doesn't currently have a walkthrough for this level, could you write it?
Entropy's Pinnacle is a Story mission in Destiny The Taken King. It takes place in the Ishtar Sink and the second and final mission in the The Taken War quest line on Venus.
IKORA REY: The search to root out the Taken on Venus has led us to some dark places. None are darker than the heart of the Vex. If my information is correct, the blight now curls around the heart of their Citadel. This must not stand.
IKORA: The assault on the House of Wolves gave us detailed information about the Citadel's spire. By all indications, the heart of the blight is there, at the top of the tower. Good luck, Guardian. May your path through the Darkness lead you to the Light.
The Guardian makes their way to the Citadel.
GHOST: The roots of the Citadel go deep into the heart of the planet. The spire is the metal trunk of a very, very big tree. Sort of.
The Guardian enters The Juncture, finding it overrun with Taken. The Guardian eliminates the Centurions and Goblins, and approaches the lift. More Taken enemies, including Captains, warp in, but the Guardian destroys them all. The force field surrounding the lift dissipates, and they float upward.
GHOST: Remember Skolas? Crazy Kell, angry Fallen? Can we go back to that? I prefer them to the Taken any day.
The Guardian reaches the top of the Spire, navigating their way across the disappearing platforms. Upon reaching the central structure, four Taken Phalanxes appear, and use their shield blasts to attempt to knock the Guardian to their death. The Guardian dodges or braces their impact, and quickly deals with them after their guard is down.
GHOST: They were trying to knock us off that platform! Oh, the Taken really are insufferable!
The Guardian safely makes it the rest of the way across The Terminus. Several Taken blights float in the air. Under fire from Hobgoblins, Captains, Centurions, and Minotaurs, the Guardian works through the Taken army, reaching the Vex Transfer Gates. An Echo warps in, waiting for them. A large battle occurs as the Guardian is surrounded by dozens of Taken reinforcements and relentless fire from the Echo. However, the Guardian prevails and the Echo dies, taking the seemingly endless horde with it.
IKORA: You sent Oryx screaming back to the Ascendant realm, and still his Echoes stain our system. That is why you are here, Guardian. Only you are strong enough to stand against the terrors in the night.
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0.962933 |
Can you please help me with below question.
2. According to the passage, which of the following constitutes prevailing scholarly opinion regarding the beginning of modern science?
(C) Modern science began with the widespread application of the principle of Occam's razor.
Modern science should not, however, be identified with any particular set of scientific achievements. Rather, modern science should be identified with a particular way of approaching the study of nature, and many important elements of this approach were already in place and articulated as early as the fourteenth century.
Prevailing scholarly opinion holds that (modern science began with the great achievements of the scientific revolution of the sixteenth and seventeenth centuries).
3. It can be inferred from the passage that the author would be most likely to agree with which of the following statements concerning modem science?
(A) The use of experiments is the crucial factor enabling scientists to engage in what can properly be described as modem science.
(B) A certain set of scientific achievements had to be accomplished before scientists could engage in modem science.
(C) The scientific revolution of the sixteenth and seventeenth centuries marks the beginning of what should be considered modem science.
(D) The origins of modern science can be traced back to the articulation of a particular approach to the study of nature.
Thanks for detailed explanation. I've reviewed the thread but unable to get this right.
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0.995743 |
Here’s my take on the classic sunset seascape: The Red Sun sitting on the horizon. It’s the first of the three stages of twilight. So next to this painting, I’ll paint the second stage of twilight: the red sun gone halfway down the horizon, but still spreading its radiance to the sky, the clouds, and the sea Then, I’ll paint the third stage stage of twilight: a radiant point on the horizon where the sun has gone down, just before dusk sets in. Dusk is the darkest sky, even darker than nighttime. I’ll skip painting a dusk sky, knowing that dawn break will soon brighten up the sky once more.
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0.999966 |
*Note that larger spaghetti squashes tend to yield sweeter strands. However, small ones will also work if they are all you can find. To Make: Carefully cut the spaghetti squash in half, lengthwise. green hair from pool how to fix For starters, you will of course need spaghetti squash, a bit of water, and a glass baking dish. Wash the outside of the squash, then slice it lengthwise and scrape out the seeds.
Make cuts all around the spaghetti squash with a knife. Place in microwave and microwave on medium-high in 5 minute increments. Rotate spaghetti squash every 5 minutes until soft [total time should be anywhere from 10-15 minutes depending on the size of the spaghetti squash].
Preheat the oven to 400�F. Arrange a rack in the middle of the oven and heat to 400�F. Meanwhile, prep the squash. Slice the squash in half. Use a chef's knife to cut the spaghetti squash lengthwise from stem to tail.
For starters, you will of course need spaghetti squash, a bit of water, and a glass baking dish. Wash the outside of the squash, then slice it lengthwise and scrape out the seeds.
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0.958009 |
Saxe-Coburg and Gotha (German: Sachsen-Coburg und Gotha), or Saxe-Coburg-Gotha, was an Ernestine duchy ruled by a branch of the House of Wettin, consisting of territories in the present-day states of Bavaria and Thuringia in Germany. It lasted from 1826 to 1918.
The name Saxe-Coburg-Gotha also refers to the family of the ruling House of Saxe-Coburg and Gotha, which played many varied roles in the dynastic and political history of Europe in the 19th and 20th centuries. In the early part of the 20th century, before the First World War, it was the family of the sovereigns of the United Kingdom, Belgium, Portugal, Bulgaria, and Saxe-Coburg-Gotha. In 1910, the Portuguese king was deposed, and the same thing occurred in Saxe-Coburg-Gotha in 1918 and in Bulgaria in 1946. As of 2015, branches of the family still reign in Belgium, the United Kingdom, and the other Commonwealth realms. The former Tsar of Bulgaria, Simeon II (reigned 1943–46), kept his surname while serving as the Prime Minister of Bulgaria from 2001 to 2005.
Alfred, KG, KT, KP, GCB, GCSI, GCMG, GCIE, GCVO, PC (Alfred Ernest Albert; 6 August 1844 – 30 July 1900) reigned as Duke of Saxe-Coburg and Gotha from 1893 to 1900. He was the second son and fourth child of Queen Victoria of the United Kingdom and Prince Albert of Saxe-Coburg and Gotha. He was known as the Duke of Edinburgh from 1866 until he succeeded his paternal uncle Ernest II as the reigning Duke of Saxe-Coburg and Gotha in the German Empire.
Alfred was born at Windsor Castle to the reigning British monarch, Queen Victoria, and her husband, Prince Albert of Saxe-Coburg and Gotha, the second son of Ernst I, Duke of Saxe-Coburg and Gotha. As a son of the British monarch, he was styled His Royal Highness The Prince Alfred at birth and was second in the line of succession behind his elder brother, The Prince of Wales. He was known to his family as "Affie", after a childhood mispronunciation of the name "Alfred".
Alfred was christened by the Archbishop of Canterbury, William Howley, at the Private Chapel in Windsor Castle on 6 September 1844. His godparents were his mother's first cousin, Prince George of Cambridge (represented by his father, The Duke of Cambridge); his paternal aunt, the Duchess of Saxe-Coburg and Gotha (represented by his maternal grandmother, the Duchess of Kent); and Queen Victoria's half-brother, Carl, Prince of Leiningen (represented by The Duke of Wellington, Conservative Leader in the Lords).
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Play during childhood is necessary, essential and beneficial for the little ones, especially if we do it as a family. A good idea to have fun with our children are the riddles. Do you know what the benefits of playing riddles with children?
, and it can be done both outside and inside, either inside a vehicle to make long trips, or in house during rainy afternoons that we can not play in the parks. Contribu 7- Contribute to encourage creativity in the smallest, since they can start creating new riddles by proposing their own ideas of riddles.
8- The game of riddles gives children self-confidenceand confidence when they manage to solve them or when they manage to invent some riddles.
9- Riddles also awaken in children their innate capacity for curiosity . It is necessary to adapt the riddles to the ages of the children but without doubt they become a complete and playful game in which fun is guaranteed.
10- Most of the riddles are elaborated in the form of rhyme, so they also provide the children with literary learning, helping them to form their own riddles with this type of structure.
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What? Connection reset by peer?
We are running Node.js web services behind AWS Classic Load Balancer. I noticed that many 502 errors after I migrate AWS Classic Load Balancer to Application Load Balancer. In order to understand what happened, I added Nginx in front of the Node.js web server, and then found that there are more than 100 ‘connection reset’ errors everyday in Nginx logs.
2017/11/12 06:11:15 [error] 7#7: *2904 recv() failed (104: Connection reset by peer) while reading response header from upstream, client: 172.18.0.1, server: localhost, request: "GET /_healthcheck HTTP/1.1", upstream: "http://172.18.0.2:8000/_healthcheck", host: "localhost"
2017/11/12 06:11:27 [error] 7#7: *2950 recv() failed (104: Connection reset by peer) while reading response header from upstream, client: 172.18.0.1, server: localhost, request: "GET /_healthcheck HTTP/1.1", upstream: "http://172.18.0.2:8000/_healthcheck", host: "localhost"
2017/11/12 06:11:31 [error] 7#7: *2962 upstream prematurely closed connection while reading response header from upstream, client: 172.18.0.1, server: localhost, request: "GET /_healthcheck HTTP/1.1", upstream: "http://172.18.0.2:8000/_healthcheck", host: "localhost"
2017/11/12 06:11:44 [error] 7#7: *3005 recv() failed (104: Connection reset by peer) while reading response header from upstream, client: 172.18.0.1, server: localhost, request: "GET /_healthcheck HTTP/1.1", upstream: "http://172.18.0.2:8000/_healthcheck", host: "localhost"
2017/11/12 06:11:47 [error] 7#7: *3012 recv() failed (104: Connection reset by peer) while reading response header from upstream, client: 172.18.0.1, server: localhost, request: "GET /_healthcheck HTTP/1.1", upstream: "http://172.18.0.2:8000/_healthcheck", host: "localhost"
The number of errors was increased after I migrate Classic LB to Application LB, and one of the differences between them is Classic LB is using pre-connected connections, and Application LB only using Http/1.1 Keep-Alive feature.
The load balancer received a TCP RST from the target when attempting to establish a connection.
The target closed the connection with a TCP RST or a TCP FIN while the load balancer had an outstanding request to the target.
The target response is malformed or contains HTTP headers that are not valid.
I’m working on a project which needs to fetch messages from hundreds of SQS queues. We’re using SQS long polling to reduce the number of empty responses. It was very quick to get response at first when there are only dozen queues. As we added more and more queues, the performance getting worse and worse. It takes 60 seconds to get the response when there’s 300 queues and WaitTimeSeconds set to 10 seconds.
We are using Node.js in single thread mode, and I believe that it could handle 10 thousands connections without any problem because most of the tasks are IO processing. We also created an AWS support case, but nobody clearly answered the question.
Many open source books are written in asciidoc, in order to read the book in kindle, I have to convert it to mobi file. Here’s a quick note on how to convert files.
The git branches in local repository will grow rapidly if you are using branch development, e.g. always create a new branch for any new feature/story/bug-fix.
The branch becomes useless after it merged to master, here’s some commands to clean up branches in local repository.
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I believe that television has had a mainly positive effect on society. Television is one of the best ways to convey information to many people. For example, news programs are easy to watch and allow people to effortlessly stay up-to-date with current events. Television news programs cover everything from local events to worldwide news, and are very convenient for people to watch before or after work. In addition, I think that television is good for family life. Families can often sit together and watch television, and in a time when teenagers rebel against their parents and seek independence, TV offers a nice way for family members to stay close to one another.
I believe that television has a positive influence on society. First of all, with the spread of TV, people can get to know what is happening in this world without much delay. We can know the latest news of almost every field and every country, which equips us with a better understanding of the world. The second reason is that watching television is one of the best ways to relax ourselves. After a busy day, if we can sit in the couch and watch television and just make ourselves entertained, we can soon get refreshed.
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Catholic News World : Top 5 Christmas Carols to SHARE - #Carols Video and #History - Beautiful Music to Uplift your Soul!
Top 5 Christmas Carols to SHARE - #Carols Video and #History - Beautiful Music to Uplift your Soul!
A Christmas Carol is a song or hymn dedicated to Christmas. They originated in Rome around the 4th Century AD. Here is a little history of the top 5 Christmas Carols in history.
Silent Night, originally "Stille Nacht, heilige Nacht" in German, was written by the Catholic Priest Joseph Mohr and the melody composed by Franz Xaver Gruber. The tune was written in Austria in 1818.
According to most sources the Adeste Fidelis (O Come, All Ye Faithful in Latin) was composed there by John Reading about the year 1680. It is believed that the lyrics were written by Cistercian monks much earlier.
What Child is This was written in 1865 by William Chatterton Dix. It was set to the traditional English Tune of Greensleeves which originated around 1580.
Away in a Manger was published in Philadelphia in 1885. It is uncertain who wrote the lyrics. However, the tune was called St. Kilda and attributed to J. E. Clark.
Joy To The World was written by Isaac Watts and based on Psalm 98. It was published in 1719 and was arranged to music in 1839 by Lowell Mason.
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Eco Etiquette: What's The Environmental Cost Of Cut Flowers?
Are cut flowers really bad for the environment? My wife loves them, and I know she's probably expecting a bunch this Valentine's Day.
Selfishly, I don't want to write this article, because I fear if I veto one more of my husband's romantic gestures for not being "eco" enough, he'll give up on me forever.
I seriously want to punch myself in the face just reading this. The man is a saint.
So when he surprised me last week with a bunch of magnificent calla lilies, I of course didn't have the heart to tell him what I'm about to tell you: Conventional cut flowers are just about the least natural thing you can get your sweetie this Valentine's Day.
I know, it's hard to believe: Flowers are so beautiful, so organic looking -- in the truest sense of that word. How could they possibly be bad for the planet?
To answer that question, let's take a look at the lifecycle of your run-of-the mill supermarket red roses, which most likely began their journey in a production greenhouse in South America. Seventy-eight percent of cut flowers in the US are imported from countries like Ecuador and Colombia, where warm weather makes for ideal year-round growing conditions.
The rest of the growing conditions, however, are less than optimal, at least where the environment and workers' rights are concerned. Output is key, since US demand is so high (particularly on holidays like Valentine's Day, which will see the sale of 200 million stems of roses alone), so flowers are doused with a toxic cocktail of fungicides, insecticides, and herbicides to keep disease and vermin at bay.
Twenty percent of those chemicals are so dangerous they're actually restricted in the US or Europe, according to a 2007 study by the now named International Labor Rights Forum. That's especially unfortunate for the unprotected workers (mostly women, sometimes children) who are suffering everything from respiratory distress to higher rates of miscarriage to neurological impairment as a result of exposure.
Might want to rethink that rose petal bath, huh?
Once the roses are harvested, they're stored in an energy-eating chilled warehouse, transported to the airport in a gas-guzzling refrigerated truck, flown via cargo plane to the US (sorry, no refrigerated airplanes, but I think the carbon emissions from flying are pollution enough), and then shipped yet again via refrigerated truck to their destination -- in this case, the supermarket.
There, they wait in -- you guessed it! -- a refrigerated display case, until someone snaps up a dozen to take home and surprise his honey. But the journey doesn't end there: Once the flowers fade in a week or so, they're tossed in the trash (unless you compost) and sent to the landfill, where they decay and emit methane, a potent greenhouse gas.
If you still have your heart set on fresh flowers, you don't have to forgo them entirely, though. Seeking out blooms that are certified either USDA organic or sustainably grown by the third-party Veriflora program will go a long way toward reducing your pesticide petalprint. Buying in-season flowers from a local grower (you can find one on LocalHarvest) is another eco option that can help support native bee populations threatened by colony collapse disorder.
But if you want to impress your Valentine with your romantic as well as environmental prowess, I say ditch the cheap carnations and try this sustainably suave suggestion: Give her a package of rare heirloom flower seeds along with a beautiful vintage flowerpot. Then tell her you want to plant them with her this Valentine's Day and watch the flowers grow along with your love.
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What other human genetic diseases are potentially caused by miRNA dysfunction?
microRNAs (miRNAs) are a class of small RNAs (19-25 nucleotides in length) processed from double-stranded hairpin precursors. They negatively regulate gene expression in animals, by binding, with imperfect base pairing, to target sites in messenger RNAs (usually in 3' untranslated regions) thereby either reducing translational efficiency or determining transcript degradation. Considering that each miRNA can regulate, on average, the expression of approximately several hundred target genes, the miRNA apparatus can participate in the control of the gene expression of a large quota of mammalian transcriptomes and proteomes. As a consequence, miRNAs are expected to regulate various developmental and physiological processes, such as the development and function of many tissue and organs. Due to the strong impact of miRNAs on the biological processes, it is expected that mutations affecting miRNA function have a pathogenic role in human genetic diseases, similar to protein-coding genes. In this review, we provide an overview of the evidence available to date which support the pathogenic role of miRNAs in human genetic diseases. We will first describe the main types of mutation mechanisms affecting miRNA function that can result in human genetic disorders, namely: (1) mutations affecting miRNA sequences; (2) mutations in the recognition sites for miRNAs harboured in target mRNAs; and (3) mutations in genes that participate in the general processes of miRNA processing and function. Finally, we will also describe the results of recent studies, mostly based on animal models, indicating the phenotypic consequences of miRNA alterations on the function of several tissues and organs. These studies suggest that the spectrum of genetic diseases possibly caused by mutations in miRNAs is wide and is only starting to be unravelled.
microRNAs (miRNAs) are a class of single-stranded RNAs (ssRNAs), 19-25 nucleotides (nt) in length, generated from hairpin-shaped transcripts. They control the expression levels of their target genes through an imperfect pairing with target messenger RNAs (mRNAs), mostly in their 3' untranslated regions (3' UTRs) . The biogenesis of miRNAs involves a complex protein system that includes members of the Argonaute family, Pol II-dependent transcription and the two RNase III proteins, Drosha and Dicer . miRNAs are first transcribed in the nucleus as long transcripts, known as primary miRNA transcripts (pri-miRNAs), which can sometimes contain multiple miRNAs [3, 4]. Few pri-miRNA transcripts have been studied in detail, but increasing evidence suggests that miRNAs are regulated and transcribed like protein encoding genes .
In brief, within the nucleus, Drosha first forms a micro-processor complex with the double-stranded RNA-binding protein DGCR8 . It then processes the pri-miRNAs into a smaller, stem-loop miRNA precursor of ~70 nucleotides (pre-miRNA) . pre-miRNAs are exported, in turn, across the nuclear membrane and into the cytoplasm by the Exportin-5 complex [8–10]. These pre-miRNAs are further cleaved by Dicer thus producing a 19- to 25-nucleotide RNA duplex. These duplexes are then incorporated into a ribonucleoprotein complex (RNP) called RISC-like complex [11, 12], referred to as the miRNA-induced silencing complex (miRISC). Only one strand of the miRNA-duplex, known as the mature miRNA, is incorporated into the miRISC complex, while the other strand, the miRNA-star (miRNA*), is degraded although, recently, miRNAs* have been found to play a role similar to that of their cognate miRNAs. Within the miRISC complex, miRNAs bind to the mRNA targets and regulate gene expression, either at the translational level [13, 14] or at the transcript level [15–17] or both . A crucial role in the recognition of the target mRNA by the miRNA is played by the so-called seed region, which is composed of six to seven nt, which shows a perfect complementarity between a miRNA and its target. miRNA can be localized in the intergenic (40%) or the intragenic (60%) regions . Intragenic miRNAs are located within other transcriptional units which are termed host genes. The vast majority of intragenic miRNAs is localized within the intronic regions of their host genes and only a minority (10%) lies within exonic regions, usually pertaining to the non protein-coding host genes. Interestingly, it has been demonstrated that many intronic miRNAs and their host genes are co-regulated and co-transcribed from a common promoter [20–22].
miRNAs are implicated in a wide range of basic biological processes, including development, differentiation, apoptosis and proliferation [23, 24]. Since the discovery of the strong impact of miRNAs on biological processes, it has been hypothesized that mutations affecting miRNA function may have a pathogenic role in human diseases. A large body of evidence has already shown that aberrant miRNA expression is implicated in most forms of human cancer [25–27], but fewer studies have established a clear link between miRNAs and human genetic disorders. Initially, there were two main (and contrasting) arguments against the hypothesis of miRNAs as genes responsible for human genetic diseases: (1) each miRNA is endowed with such a basic role in the regulation of gene expression and consequently in the regulation of basic cellular processes that a significant alteration of their function is not compatible with cell survival and ultimately with life; and (2) considering the great deal of redundancy in miRNA actions, a significant alteration of the function of a single miRNA may only give rise to subtle modifications in both the cellular transcriptome and proteome, which are unable to determine a significant perturbation of biological processes and ultimately lead to a diseased phenotype.
Our aim in this review is to provide an overview of the evidence available to date which support the pathogenic role of miRNAs in human genetic diseases, with a particular focus on monogenic disorders. In order to achieve this goal, we will first describe the types of mutations affecting miRNA function that can result in human monogenic disorders, giving some recently described examples. In the second part of this review, we will give a broader picture of the hypothetic involvement of miRNAs in the pathogenesis of human monogenic diseases based on the results obtained in vivo from the analysis of several animal models characterized by either the global perturbation of miRNA pathways or by the perturbation (either inactivation or overexpression) of single miRNAs.
Given the mechanisms of action of miRNAs (see above), three main types of mutation mechanisms affecting miRNA function can be envisaged (Figure 1): (1) mutations affecting primarily miRNAs, either point mutations in the mature sequence or larger mutations (that is, deletions or duplications of the entire miRNA locus); (2) mutations in the 3' UTR of mRNAs that can lead to the removal or to the de novo generation of a target recognition site for a specific miRNA; and (3) mutations in genes which participate in the general processes of miRNA processing and function and, therefore, are predicted to impact on global miRNA function.
Schematic diagram summarizing the main types of miRNA mutations with a potential aetiopathogenic role in monogenic disorders (see text for further details).
Likewise, protein-coding loci and also miRNA loci can be subjected to large mutations, such as deletions or duplications. To date, there are no examples of such mutations which are clearly associated with human mendelian diseases. However, a careful analysis of the genomic organization of miRNAs reveals that a number of intragenic miRNAs are localized within host genes (see above) whose mutations are responsible for human genetic disorders. By analysing the mutation spectrum previously described for the latter disease genes in the Human Gene Mutation Database (HGMD) , we found evidence that some mutations do, indeed, significantly affect one or more miRNAs (Table 1). This is the case, for instance, in certain intragenic deletions responsible for Duchenne muscular dystrophy, choroideraemia and Dent disease, among others, which are also predicted to encompass some miRNAs. It is of crucial importance to confirm these predictions and to determine whether or not the deletion of these miRNAs is able to play a role in the phenotype observed. Furthermore, several miRNAs loci are also either deleted or duplicated (Table 1) in some well-known human aneuploidy syndromes, and there is initial evidence of their contribution to the pathogenic mechanisms of the complex manifestations of these disorders .
Duan and colleagues, in 2007, described a single nucleotide polymorphism (SNP) within the seed region of miR-125a. Through a series of in vitro analyses, the authors demonstrated that this SNP in miR-125a, in addition to reducing miRNA-mediated translational suppression, significantly altered the processing from pri-miRNA to pre-miRNA. Although this SNP has not been associated with a disease status, these data suggest, for the first time, that SNPs that reside within miRNA genes may, indeed, impair miRNA biogenesis and alter target selection and, therefore, have a potentially profound biological effect .
The first example of point mutations in the mature sequence of a miRNA with an aetiopathogenic role in a human mendelian disease has been recently reported by Mencìa et al. . They identified two different nucleotide substitutions in the seed region of the human miR-96 in two Spanish families affected by an autosomal dominant form of deafness, namely DFNA50. In particular, both the mutations, miR-96 (+13G>A) and (+14C>A), which were not present in several unrelated normal-hearing Spanish controls, were segregated in both of the families with a hearing impairment. miR-96, together with miR-182 and miR-183, is transcribed as a single polycistronic transcript and is reported to be expressed in the inner ear. For this reason, the authors also carried out a mutation screening of miR-182 and miR-183 in the same cohort of patients, tested for miR-96. However, they did not find any potential mutation, although this does not exclude the possibility that the latter two miRNAs may be involved in the pathogenesis of other forms of deafness. The fact that both the above families manifested the hearing loss postlingually indicated that probably neither of the two miR-96 mutations resulted in impaired development of the inner ear. Instead, they could have had an impact on the regulatory role that miR-96 plays in the hair cells of the adult cochlea which maintain the gene expression profiles required for its normal function. In vitro experiments showed that both mutations impaired, but did not abrogate, the processing of miR-96 to its mature form, although an additional indirect effect on the expression of miR-182 and miR-183 due to the miR-96 mutations cannot be excluded. Furthermore, a luciferase reporter assay confirmed that both mutations were able to affect the targeting of a subset of selected miR-96 target genes, mostly expressed in the inner ear. In contrast, no significant gain of function was associated with these two mutations, at least for the potentially new acquired miR-96 targets investigated. In addition, after an ophthalmologic revision, no ocular phenotype was observed in individuals carrying mutations in miR-96 (age range between 2 and 66 years), suggesting that its specific targets in the retina, a site in which miR-96 is also strongly expressed, were not critical for its function or that the translation of these targets was not markedly affected .
The finding of a single base change (A>T) in the seed region of miR-96 in a mouse mutant (diminuendo) with a progressive hearing loss phenotype, provided additional support to the finding that a single base change in miR-96 is the causative mutation behind the hearing loss phenotype in both man and mouse . In particular, the diminuendo mutant showed progressive hearing impairment in heterozygotes and profound deafness in homozygotes associated with hair cell defects. Lewis and colleagues suggested that the degeneration observed in homozygotes could be a consequence of a prior dysfunction of the hair cells. Bioinformatic analysis indicated that the mutation has a direct effect on the expression of many genes, including transcription factor genes, that are directly required for hair cell development and survival. The large number of genes whose expression is affected by miR-96 suggests that the mechanism that explains the effects of the mutation may not be simple but, rather, may be the result of a combination of different small effects that act in concert to cause hair cell dysfunction .
In animal cells, most miRNAs form imperfect hybrids with sequences in the 3'-UTR, with the miRNA 5'-proximal 'seed' region (positions 2-8) providing most of the pairing specificity [33, 34]. However, evidence is also accumulating that miRNAs may target mRNA-coding regions . Generally, miRNAs inhibit protein synthesis either by repressing translation or by bringing about deadenylation and degradation of mRNA targets . Since more than 700 miRNAs have been identified in the human and mouse genomes , and also considering that each miRNA can regulate, on average, the expression of 100-200 target genes [38, 39], the whole miRNA apparatus seems to participate in the control of the gene expression for a significant proportion of the mammalian gene complement.
It is conceivable that some sequence variations falling within the 3'-UTR of mRNA may alter miRNA recognition sites, either by altering functional miRNA target sites or by creating aberrant miRNA target sites. Both types of sequence variations may potentially have deleterious effects in the case of either miRNA-mRNA pairs endowed with a biologically relevant (and non-redundant) role or when the formation of an illegitimate miRNA target occurs in mRNAs that are under selective pressure to avoid target sites for that particular miRNA (that is, in the case of the so-called anti-targets) .
One of the first animal disorders with a mendelian transmission reported to be caused by dysregulation of a specific miRNA-mRNA target pair was the Texel sheep model. The Texel sheep phenotype is characterized by an inherited muscular hypertrophy that is more pronounced in the hindquarters of sheep . Clop et al. demonstrated that the myostatin (GDF8) gene of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir-1 and mir-206, which are highly expressed in the skeletal muscle. This sequence change leads to a translational inhibition of the myostatin gene and, hence, is responsible for the muscular hypertrophy of Texel sheep .
There are now some examples of sequence variations in the 3'-UTR of mRNAs altering miRNA recognition sites which have been suggested to have a pathogenic role in human genetic diseases. The first was reported by Abelson et al. , who identified two independent occurrences of the identical sequence variant in the binding site for the miRNA hsa-miR-189 (now termed miR-24*) in the 3'-UTR of the SLITRK1 mRNA in familial cases of Tourette's syndrome, a developmental neuropsychiatric disorder characterized by chronic vocal and motor tics. This 3'-UTR sequence variation in SLITRK1 was proposed in order to determine an increased extent of repression of this gene by hsa-miR-189 (miR-24*). It must be underlined, however, that the involvement of SLITRK1 in Tourette's syndrome has been subsequently questioned by other reports [43–47]. The second example is represented by two different point mutations in the 3'-UTR of the REEP1 gene which have been associated with an autosomal dominant form of hereditary spastic paraplegia (SPG31) [48, 49]. These mutations, which alter the sequence of a predicted target site for miR-140, were found to segregate with the disease phenotype and were not detected in a large set of human controls. These data strongly suggest the pathogenic role of the impaired miR-140-REEP1 binding in some SPG31 families, although so far no functional data have been provided to consolidate this hypothesis.
Georges and colleagues tried to address, in a more systematic way, the potential implications of sequence variations in the 3'-UTR of mRNAs in the pathogenesis of human diseases. They demonstrated, through SNP analysis, that sequence variations creating or destroying putative miRNA target sites are abundant in the human genome and suggested that they might be important effectors of phenotypic variation . A list of additional sequence variations altering putative miRNA recognition sites, and with a potential role in human disease, can be found in a review by Sethupathy and Collins . The authors critically reviewed a number of studies that claimed that there is an association between the presence of polymorphisms/mutations in miRNA target sites (poly-miRTSs) and human diseases, giving a special emphasis on possible biases and confounding factors. They concluded that only a few presented rigorous genetic and functional evidence. The authors therefore suggested a set of concrete recommendations in order to guide future investigations of putative disease-associated poly-miRTSs .
As previously described, a number of different proteins are involved in the processing of miRNAs. Mutations altering the function of these proteins are predicted to determine a global alteration of miRNA function. This aspect is exploited, for instance, in the experimental inactivation of Dicer that is used to assess the biological consequences of the global perturbation of miRNA activity in whole organisms or specific tissues/cell types (see also below). Complete loss-of-function mutations of certain key members of the miRNA processing pathway (such as Drosha and Dicer) are expected to be incompatible with life and, therefore, are not believed to play a role in the pathogenesis of human monogenic disorders. However, there are two human diseases characterized by mutations in genes involved in miRNA processing/activity, namely DiGeorge syndrome and Fragile X syndrome. The DGCR8 gene, which maps to chromosomal region 22q11.2, is commonly deleted in DiGeorge syndrome , characterized by cardiovascular defects, craniofacial defects, immunodeficiency and neurobehavioral alterations. As previously mentioned, DGCR8 is a component of the Drosha complex and its haploinsufficiency in DiGeorge syndrome patients may have a potential impact on miRNA processing. However, also based on the results of the targeted inactivation of the corresponding gene in mouse , there are no data, thus far, which point to a functional effect of DGCR8 haploinsufficiency on miRNA biogenesis.
The second example is represented by the Fragile X syndrome. The product of the FRM1 gene, whose loss-of-function is responsible for this condition, is a selective RNA binding protein. It has been proposed that the FMRP1 protein may function as a translational repressor of its mRNA targets at synapses by recruiting the RISC complex along with miRNAs and by facilitating the recognition between miRNAs and a specific subset of their mRNA targets. This interaction is suggested to be important in the process of synaptic plasticity which, instead, is largely compromised in Fragile X syndrome patients [54, 55]. However, this hypothesis requires further investigations. In conclusion, there is no evidence so far to support a direct role of altered global miRNA processing in human hereditary disorders.
The number of cases in which mutations in miRNA and in miRNA targets have proven to be firmly associated with monogenic disorders is still limited (see above). However, we expect the contribution of miRNAs, and related pathways to the pathogenesis of these conditions, to increase in the near future, following both a better knowledge of their biological function and the advancement of high-throughput mutation detection approaches [56–58]. We will now try to make some hypotheses on the possible diseases in which miRNAs may have a pathogenic role, mainly based on the results obtained from the analysis of animal models.
The heart is the first organ to form and to function during vertebrate embryogenesis . Perturbations in normal cardiac development and function result in a variety of cardiovascular diseases, which are the leading cause of death in developed countries .
The first indication of the global involvement of miRNAs in heart development and function was derived from the analysis of conditional knockout mice carrying a cardiac-specific inactivation of the Dicer enzyme. As described above, Dicer plays a key role in miRNA biogenesis and its inactivation is predicted to cause a general deficiency of the mature forms of all miRNAs.
Chen and colleagues reported that cardiac-specific knockout of the Dicer gene led to rapidly progressive dilated cardiomyopathy, heart failure and postnatal lethality. Dicer mutant mice showed misexpression of cardiac contractile proteins and profound sarcomere disorder. Functional analyses indicated significantly reduced heart rates and a decreased fractional shortening in Dicer mutant hearts. Furthermore, this study demonstrated, for the first time, the essential role of Dicer in cardiac contraction and also indicated that miRNAs play a critical role both in normal cardiac function and under pathological conditions .
Moreover, da Costa and colleagues found that an inducible deletion of Dicer in the adult mouse heart results in a severe alteration of myocardial histopathology, suggesting a crucial role for this enzyme in ensuring the integrity of the postnatal heart. Interestingly, Dicer depletion in the juvenile heart provoked an overall tendency to arrhythmogenesis and less marked myocyte hypertrophy, but its inactivation in the adult myocardium gave rise to myocyte hypertrophy and angiogenic defects. These findings seem to imply the presence of differences in the biological role, as a whole, of miRNAs between the juvenile and the adult myocardium .
The generation of cardiac disease-like phenotypes in animal models may not only be caused by a global alteration of miRNA function but also by the dysfunction of specific miRNAs. For instance, miR-1-2 appears to be involved in the regulation of diverse cardiac and skeletal muscle functions, including cellular proliferation, differentiation, cardiomyocyte hypertrophy, cardiac conduction and arrhythmias . miR-1, together with another heart-specific miRNA (miR-133a), is known to be transcribed by a duplicated bicistronic genetic locus (miR-1-1/miR133a-2 and miR-1-2/miR133a-1) sharing identical sequences of the mature miRNAs. Mice lacking miR-1-2 present a spectrum of abnormalities, ranging from ventricular septal defects and early lethality to cardiac rhythm disturbances. These mice also featured a striking cell-cycle abnormality in myocytes, leading to hyperplasia of the heart with nuclear division persisting postnatally. Remarkably, the persistence in these mice of the other identical copy of miR-1-2 (that is, miR-1-1) did not compensate for the loss of miR-1-2, at least for many aspects of its function. While it is likely that mice lacking both miR-1-1 and miR-1-2 will have increasingly severe abnormalities, the range of defects upon the deletion of miR-1-2 highlighted the ability of miRNAs to regulate multiple diverse targets in vivo . The subtle dysregulation of numerous developmental genes may contribute to the embryonic defects observed in miR-1-2 mutants. These included: (1) Hrt2/Hey2, a member of the Hairy family of transcriptional repressors that mediates Notch signalling, which can itself cause heart disease ; and (2) Hand1, a bHLH transcription factor involved in ventricular development and septation that, in combination with Hand2 (a paralog of Hand1), is known to regulate expansion of the embryonic cardiac ventricles in a gene dosage-dependent manner . Furthermore, in miR-1-2 mutants, the observed abnormality in the propagation of cardiac electrical activity, despite normal anatomy and function, was correlated with the upregulation of the direct target Irx5, a transcription factor, resulting in ventricular repolarization abnormalities and a predisposition to arrhythmias.
Jiang et al. added one more piece to the puzzle represented by the miR-1/miR-133a cluster. They extensively characterized genetically engineered mice deficient for either miR-133a-1, or miR-133a-2, or both as well as mice overexpressing miR-133a . While miR-133a-1 and miR-133a-2 seemed to have redundant functions and did not cause obvious cardiac abnormalities when deleted individually, targeted deletion of both miRNAs resulted in cardiac malformations and embryonic or postnatal lethality. miR-133a double knockout mice displayed two distinct lethal phenotypes: (1) either large ventricular sept defects (VSDs), dilated right ventricles, and atria leading to death shortly after birth; or (2) survival into adulthood, no VSDs but dilated cardiomyopathy (DCM), cardiac fibrosis and heart failure. Surprisingly, miR-133a deficiency did not lead to hypertrophic cardiomyopathy, as one would have been expected from previous studies, in which miR-133a-antagomir treatment induced cardiac hypertrophy in mice . Several genes involved in cardiomyocyte cell cycle control, such as Cyclin D1, Cyclin D2 and Cyclin B1, were found to be significantly upregulated in miR-133a deficient hearts as well as several smooth muscle genes, such as smooth muscle-Actin, Transgelins, Calponin I and the myogenic transcription factor SRF.
In a further attempt to dissect the effects of miR-133a on cardiomyocyte proliferation, Liu et al. overexpressed miR-133a under the control of the cardiac β-myosin heavy chain promoter. Surprisingly, transgenic animals died by embryonic day 15.5 (E15.5) due to VSDs and diminished cardiomyocyte proliferation, which resulted in ventricular walls only consisting of two to three cell layers that were unable to fulfill the hemodynamic needs of the developing mouse .
Morton et al. reported that miR-138 is expressed in specific domains of the zebrafish heart and is required to establish appropriate chamber-specific gene expression patterns. Disruption of miR-138 function led to expansion in the expression of ventricular-specific genes, normally restricted to the atrio-ventricular valve region, and, ultimately, to disrupted ventricular cardiomyocyte morphology and cardiac function. Furthermore, the authors demonstrated that miR-138 helps in establishing discrete domains of gene expression during cardiac morphogenesis by targeting multiple members of the retinoic acid signaling pathway .
van Rooij and colleagues described cardiac hypertrophy and failure in a mouse model overexpressing mir-195, which is generally upregulated in hypertrophic human hearts . Overexpression of miR-195 under the control of the α-myosin heavy chain (Mhc) promoter initially induced cardiac growth with disorganization of cardiomyocytes, which progressed to a dilated heart phenotype by 6 weeks of age. More striking was the dramatic increase in size of individual cardiomyocytes in miR-195 transgenic mice compared to normal mice. Furthermore, ratios of heart weight to body weight were also dramatically increased in miR-195 transgenic (Tg) animals as compared to wild-type littermates, indicating that overexpression of miR-195 was sufficient to stimulate cardiac growth. Thus, the cardiac remodelling induced in the miR-195 Tg animals was specifically caused by the functional effects of this miRNA rather than a general nonspecific effect resulting from miRNA overexpression, suggesting that increased expression of miR-195 induced hypertrophic signalling, leading to cardiac failure.
Based on all the previously described findings it is tempting to speculate a possible role of specific miRNAs in human genetic forms of heart hypertrophy and failure. This hypothesis is also supported by the dysregulation of miRNA expression observed in several cardiovascular diseases in man [71–73].
Multiple lines of evidence indicate the potential role of miRNAs in neuronal cell development and maturation. Both the mouse and human brain express a large spectrum of distinct miRNAs compared with other organs [74, 75]. Therefore, the implications of dysregulation of miRNA networks in human diseases affecting the CNS are potentially enormous.
In recent years, different conditional Dicer null mouse lines in the brain have been generated. They have provided initial insight into the in vivo role of miRNAs in the mammalian CNS and particularly in the neuronal maintenance of the mouse brain [76–79].
Schaefer and colleagues described the phenotypic characterization of Dicer null mice in Purkinje cells of the cerebellum. They performed the inactivation of Dicer exclusively in the post-mitotic Purkinje cells by using the Purkinje cell-specific Pcp2 promoter-driven Cre recombinase. This inactivation led to the relatively rapid disappearance of cerebellar-expressed miRNAs followed by a slow degeneration of Purkinje cells. The loss of Dicer and the decay of miRNAs had no immediate impact on Purkinje cell function, as assessed by electrophysiological studies and analysis of animal locomotion. However, the continuous lack of miRNAs led eventually to Purkinje cell death and ataxia, suggesting that a long-term absence of miRNAs in these cells results in a neurodegenerative process .
In a recent work, the inactivation of Dicer in the cortex and hippocampus beginning at embryonic day 15.5 resulted in dramatic effects on cellular and tissue morphology and led to gross brain malformations including microcephaly, increased brain ventricle size, and reduction in size of white matter tracts, leading to an early postnatal death . Furthermore, mutant mice were ataxic with visible tremors during motility. Ataxic gait was detected by postnatal day 14-15, but often occurred as early as postnatal day 12. Dicer mutant animals also displayed hind limb crossing, typical of animals with motor impairment. Therefore, loss of miRNA function in some mouse brain regions during late development results in a significantly decreased lifespan as a consequence of severe malformations as well as motor impairments due to an increased cortical apoptosis .
To determine the role of miRNAs in dopaminoceptive neurons, Cuellar et al. ablated Dicer in mice by using a dopamine receptor-1 (Dr-1) promoter-driven Cre. The mutant animals displayed a range of phenotypes including ataxia, front and hind limb clasping, reduced brain size and smaller neurons. Surprisingly, dopaminoceptive neurons without Dicer survived during the life of the animal in contrast with other mouse models in which neurodegeneration was observed in the absence of Dicer .
miRNAs have also been studied in early neurogenesis during the development of the mammalian cerebral cortex and the switch of neural stem and progenitor cells from proliferation to differentiation. Dicer ablation in neuroepithelial cells at embryonic day (E) 9.5 resulted in massive hypotrophy of the postnatal cortex and death of the mice shortly after weaning. Remarkably, the primary target cells of Dicer ablation, the neuroepithelial cells and the neurogenic progenitors derived from them, were unaffected by miRNA depletion with regard to cell cycle progression, cell division, differentiation and viability during the early stage of neurogenesis and only underwent apoptosis starting at E14.5, suggesting that progenitors are less dependent on miRNAs than their differentiated progeny .
miRNA function was studied also for another part of the CNS (that is, the retina). Damiani et al. described a partial ablation of Dicer in the developing mouse retina by using a Cre line under the Chx10 promoter, a gene mostly expressed in retinal progenitors and specific adult retinal interneuronal cells. These mice apparently showed no visible impact on early postnatal retinal structure and function. Retinal lamination appeared normal and all expected retinal cell types were represented. However, as observed for the other Dicer null mutants, progressive and widespread structural and functional abnormalities were detected, culminating in loss of photoreceptor-mediated responses to light and extensive retinal degeneration . Therefore, the observation that progressive retinal degeneration occurred after removal of Dicer raises the possibility that miRNAs are involved in retinal neurodegenerative disorders.
In summary, although removing Dicer is conceptually a crude experimental approach, the aforementioned results support the hypothesis that defects in the miRNA regulatory network in the brain are a potential cause of neurodegenerative disease.
A functional role for miRNAs in more specific neurological processes is emerging, and their dysfunction could have direct relevance for our understanding of neurodegenerative disorders . This conclusion is supported by several in vitro examples using both gain- and loss-of-function experiments. For example, the introduction of artificial miRNAs mimicking upregulation or antisense oligonucleotides induces loss of function of primary neurons in culture [82–85].
The next challenge will be to characterize in vivo individual miRNAs and specific families of miRNAs in depth, which are predicted to contribute to the proper CNS function. An initial step towards this goal is the recent study of Walker and Harland. The authors show through loss-of-function experiments that in Xenopus laevis miR-24a is necessary for proper neural retina development by regulating apoptosis through Caspase 9 targeting .
Vertebrates have evolved complex genetic programmes that simultaneously regulate the development and function of hematopoietic cells, resulting in the capacity to activate specific responses against invading foreign pathogens while maintaining self-tolerance. From recent studies, miRNAs are emerging as major players in the molecular circuitry that controls the development and differentiation of haematopoietic lineages .
Genetic disruption of different steps in miRNA biogenesis in mice has highlighted the key role of miRNAs during haematopoiesis. Dicer ablation in the T-lineage, whilst not abolishing the development of T-lymphocytes, affected their functionality [87, 88]. Interestingly, ablation of Dicer in regulatory T cells (Treg cells) resulted in a much more severe phenotype. Mice lacking Dicer expression in Treg cells failed to differentiate functional Treg cells and developed a severe autoimmune disease, leading to death within the first few weeks of life .
Knocking-out Dicer activity in early B-cell progenitors determined a block at the pro-B cell stage during the differentiation process leading to mature activated B-cells. Gene-expression profiling revealed a miR-17-92 signature in the 3'UTRs of genes upregulated in Dicer-deficient pro-B cells; the proapoptotic molecule Bim, a top miR-17-92 target, was also highly upregulated. Surprisingly, B cell development was partially rescued by ablation of Bim or transgenic expression of the prosurvival protein Bcl-2 .
In mice the specific role of single miRNAs in the development and function of the immune system is starting to be elucidated through targeted deletion approaches. The pioneer knockout of miR-155 in mice (the first mouse knockout for a single miRNA) revealed an essential role in the acquired immunity for this miRNA. In fact, despite miR-155 null mice developed normally, immune system analysis revealed that miR-155 depletion led to pleiotropic defects in the function of B cells, T cells and dendritic cells. These mice were unable to gain acquired immunity in response to vaccination, demonstrating that miR-155 is indispensable for normal adaptive immune responses [91, 92].
Another functional example derives from the study of Ventura et al. (2008) who demonstrated that the miR-17-92 cluster is involved in controlling B-lymphocyte proliferation. Deletion of this miRNA cluster was lethal in mice resulting in lung hypoplasia, ventricular sept defects and impairment of the pro-B to pre-B transition. Absence of miR-17-92led to increased levels of the pro-apoptotic protein Bim and inhibited B cell development at the pro-B to pre-B transition. Furthermore, while ablation of miR-106b-25 or miR-106a-363 (the two paralogous clusters) had no obvious phenotypic consequences, compound mutant embryos lacking both miR-106b-25 and miR-17-92 died at mid-gestation . On the contrary, over-expression of miR-17-92 cluster in mice led to lymphoproliferative and autoimmune diseases that were associated with self-reactive antibody production .
Finally, Johnnidis et al. described the generation of a knockout mouse for miR-223, which highlighted its role in granulocyte differentiation. The myeloid-specific miR-223 negatively regulated progenitor proliferation and granulocyte differentiation. Moreover, mutant mice had an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. These data support a model in which miR-223 acts as a fine-tuner of granulocyte production and the inflammatory response .
The fact that miRNAs are involved in the modulation of T cell selection, T cell receptor sensitivity as well as Treg cell development in normal immune responses, suggests that these molecules may also be involved in the development of immune system disorders of genetic origin such as immunodeficiencies or autoimmune diseases.
In mouse, conditional inactivation of Dicer has been achieved in different other tissues in order to study the global function of miRNAs [23, 96–101]. Using transgenes to drive Cre expression in discrete regions of the limb mesoderm, Harfe et al. found that removal of Dicer determined developmental delays, due in part to massive cell death as well as to dysregulation of specific gene expression, and brought to the formation of a much smaller limb. Strikingly, however, the authors did not detect defects in basic patterning or in tissue-specific differentiation of Dicer-deficient limb buds . This class of skeletal defects was previously observed in mice with compound mutations in Prx1 and Prx2 genes .
To better understand the role of miRNAs in skin- and hair follicle biology, Andl and colleagues generated mice carrying an epidermal-specific Dicer deletion. These mice presented stunted and hypoproliferative hair follicles. Normal hair shafts were not produced in the Dicer mutant and the follicles lacked stem cell markers and degenerated. In contrast to decreased follicular proliferation, the epidermis became hyperproliferative. These results reveal the critical role played by Dicer in the skin and the key aspect that miRNAs may have in epidermal and hair-follicle development and function . Moreover, the existence of skin-specific miRNAs involved in normal epidermal and follicular development, such as the miR-200, the miR-19 and miR-20 families, indicate that their therapeutic expression or inhibition might also be relevant to epidermal pathology .
To study Dicer function in the later events of lung formation, Harris and collaborators inactivated Dicer in the mouse lung epithelium using a Shh-Cre allele. As a result, the mutant lung presented a few large epithelial pouches as opposed to the numerous fine branches that are seen in a normal lung. Phenotypic differences between mutant and normal lungs were apparent, significantly, even before detection of an increase in epithelial cell death, leading the authors to propose that Dicer may play a specific role in regulating lung epithelial morphogenesis independent of its requirement in cell survival .
Dicer activity is essential for skeletal muscle development during embryogenesis and postnatal life. O'Rourke and colleagues (2007) showed that Dicer inactivation in skeletal muscle resulted in lower levels of muscle-specific miRNAs. Moreover, Dicer muscle mutants died perinatally and were characterized by skeletal muscle hypoplasia. Reduced skeletal muscle, in turn, was accompanied by abnormal myofibre morphology. The skeletal muscle defects associated with loss of Dicer function were explained by increased apoptosis. Furthermore, decrease in muscle mass in Dicer mutants was strikingly similar to the phenotypes associated with muscular dystrophies and aged skeletal muscle. This finding suggests that, in humans, DICER mutations, or disrupted miRNA-mediated gene regulation, should contribute to skeletal muscle myopathy and age-related sarcopenia .
The study of Pastorelli and co-workers demonstrated that loss of Dicer in the developing mouse reproductive tract, under the control of Amhr2-Cre-mediated deletion, resulted in morphologic and functional defects in the reproductive tracts of female but not of male mice (before 3 months of age).
Recently, Sekine and colleagues have described the conditional Dicer ablation in the mouse liver. This resulted in prominent steatosis and in the depletion of glycogen storage. Dicer-deficient liver exhibited increased growth-promoting gene expression and robust expression of fetal stage-specific genes. The consequence of Dicer elimination included both increased hepatocyte proliferation and overwhelming apoptosis .
Finally, two different Dicer knockout strategies demonstrated that miRNAs are required for the development and differentiation of sensory epithelia and the maintenance of the sensory neurons of the inner ear . Based on studies carried out in animal models, it is clear that miRNA dysfunction may lead to severe alterations in the function of all tissues/organs that have been analysed up to now. In the majority of the aforementioned cases, the aberrant phenotypes observed are the consequence of a global impairment of miRNA processing (that is, Dicer knockout approaches), a condition that is highly unlikely to contribute to the pathogenesis of human genetic diseases. Nevertheless, the fact that in some organs (that is, the heart, the eye and the immune system) the dysfunction of single miRNAs may underlie phenotypes, strongly resembling those observed in human disease, suggests that miRNAs should be considered potential candidates in the pathogenesis of human genetic disorders, even monogenetic forms, likewise protein-coding genes.
microRNAs are emerging as key regulators of the cell transcriptome due to their ability to finely tune gene dosage. In the last few years, they have been shown to be involved in the regulation of many cellular processes and their role in the proper differentiation and function of tissues and organs is only starting to be unravelled. It is also becoming increasingly clear that miRNAs, similarly to protein-coding genes, may harbour mutations leading to human genetic conditions, even 'classical' monogenic forms. The number of cases in which mutations in miRNAs, or in their targets, have been convincingly shown to have a pathogenic role in human genetic diseases is still limited. This may not only be explained by the recent characterization of miRNAs at the genomic level, which will now allow us to carry out the appropriate analyses, but also by the fact that the 3'UTR of mRNAs have, until recently, been generally neglected as potential sources of sequence variations with a potentially pathogenic effect in genetic diseases. However, both the improvement in experimental procedures, aimed at the identification of mutations based on efficient sequencing protocols, and the increasing knowledge in miRNA function are predicted to fill the latter gaps, underscoring the role played by miRNAs in the pathogenesis of human genetic disorders in the coming years.
We apologize to our colleagues whose insightful work was not included due to size constraints. We are grateful to Luciana Borrelli for editing the original manuscript. This work was supported by a grant from the Italian Telethon Foundation.
NM, VAG and SB wrote the review manuscript. The authors read and approved the final manuscript.
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The subjunctive imperfect is very rarely employed in French; generally it only appears in literature and is viewed as archaic. It can in all instances be replaced by the subjunctive present. The subjunctive imperfect is employed in any instance in which the subjunctive is required, provided the trigger verb is in a past tense. In the example "Il fallait que le garçon allât à l'école", the subjunctive trigger verb "falloir" is in the imperfect, thus "aller" has been conjugated in the subjunctive imperfect. French speakers would normally express this as "Il fallait que le garçon aille à l'école", where "aller" has been conjugated in the present subjunctive.
For regular -ir verbs, regular -re verbs and irregular verbs, the imperfect subjunctive stem is the conjugation of the verb in the 3rd person singular form of the simple past with the final "t" removed.
To conjugate the imperfect subjunctive, add the appropriate ending to the imperfect subjunctive stem.
The verb venir is only irregular in the 3rd person singular.
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FRIEND, LLERENA BEAUFORT (1903–1995). Llerena B. Friend, historian, teacher, and librarian, the daughter of Everest MacDonald and Llerena Collinsworth (Perry) Friend, was born on October 19, 1903, in Dublin, Texas. She attended public schools in Vernon, Wichita Falls, and Electra before going to the University of Texas in Austin. She received her B.A. in 1924, M.A. in 1928, and Ph.D. in 1951 from that institution. Friend was a teacher at Vernon High School from 1924 to 1926 and at Wichita Falls High School from 1926 to 1944. In 1945 she became a research associate in Texas history for the Texas State Historical Association at the University of Texas. She worked on the preparation of the Handbook of Texas until 1950, when she became the founding director of the Barker Texas History Center, a position she held until September 1, 1969. In addition to her extensive work as librarian for Texas history sources, she also taught Texas history at the university. During her lifetime Friend wrote numerous articles and book reviews. Her book Sam Houston, The Great Designer was published in 1954 and received the Summerfield Roberts Award. She also edited several books, including Check List of Texas Imprints, 1861–1876 (1963), M. K. Kellogg's Texas Journal, 1872 (1967), and Talks on Texas Books by Walter Prescott Webb (1970).
In 1969 Friend retired from the University of Texas as professor emeritus. She was a member of numerous organizations, including the Ashbel Literary Society, the Philosophical Society of Texas, the Texas Institute of Letters, the Wichita County Historical Commission, and the Rolling Plains Civil War Roundtable. She served as National Chairman of Academic Standards for six years with Alpha Chi Omega and was a fellow and life member of the Texas State Historical Association and a life member of the Western History Association. In 1971 she received the Texas Library Association Award and the Texas State Historical Association's H. Bailey Carroll Award. She won the Alpha Chi Omega award of achievement in 1972. Friend moved to Wichita Falls in 1975 and was active in civic and cultural affairs. In 1976 Governor Dolph Briscoe appointed her to the Texas State Historical Records Advisory Board, and in 1987 she was nominated to the Texas Women's Hall of Fame. She donated most of her papers to the Special Collections Library at Midwestern State University in Wichita Falls. She was a Methodist and never married. Friend died in Wichita Falls on September 8, 1995.
Austin American-Statesman, September 10, 1995. Vertical Files, Dolph Briscoe Center for American History, University of Texas at Austin.
Handbook of Texas Online, Laurie E. Jasinski, "FRIEND, LLERENA BEAUFORT," accessed April 22, 2019, http://www.tshaonline.org/handbook/online/articles/ffrqv.
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What risks are involved in riding a motorcycle? Motorcycles can be a fast, convenient, and affordable way to get around. On the other hand, they are considerably smaller and lighter than cars. Also, they only have two wheels and a rider is always exposed as opposed to a driver who is protected inside a car that has protective features such as a roll cage or airbags. Motorbike riders are 35 times more likely to be involved in a serious accident than drivers in passenger cars.
These factors make riding a motorcycle riskier than driving a car. They also make motorcycle wrecks more likely to cause death or serious injuries. It is estimated that close to 4,000 motorcyclists are killed every year on U.S highways and another 80,000 sustain injuries in motorcycle wrecks.
Other risk factors include motorbikes being smaller and less likely to be seen in comparison to cars. Especially at intersections. Motorbikes are also more vulnerable to objects and hindrances on the road, such as debris, potholes, snow, and ice. Additionally, riding a motorbike requires more skill than driving a car. Unskilled riders make up a disproportionate number of motorcycle wrecks. There's also the fact that there are types of motorbikes such as sport bikes that encourage high speed, fast acceleration, and other types of high-risk behavior.
The law considers a person negligent when they behave in a manner that is thoughtless or careless and in so doing cause another person to be injured. Drivers and riders are expected and required to exercise caution to avoid injuring other road users, be they pedestrians, other riders, or drivers. If someone is injured as a result of a driver not exercising that caution, they are considered liable.
In a large number of motorcycle accidents, it is the driver of a car or truck that has been negligent. The negligence can be caused by running a red light or failing to check their mirrors before taking a left turn. In other cases, it is the motorcycle rider who has been negligent. A rider who swerves in front of a car and causes it to crash can be held liable for the injuries suffered by the occupants of a car.
Perhaps you, a family member, or friend has been involved in an accident that left serious injuries. Typically, the negligent party will not readily admit and accept liability. They will call their insurance company and the company will try to make a quick settlement, offering a minimal appoint in compensation rather than providing compensation that is fair and adequate for the injuries sustained.
This is when you need to bring in 'the Real Brad'. This is the nickname given to Brad Pistotnik, the founder of Brad Pistotnik Law for the firm's success in winning millions of dollars in damages for clients. Brad Pistotnik, the firm's founder and his team has a record of success that goes over 30 years back.
Choose Brad Pistotnik Law to represent you and be part of their success stories. The firm will carry out investigations to prove liability and ensure you get fair compensation.
Contact the law firm on 316-684-4400 or call Brad himself on 316-706-5020. His assistant Tony Atterbury can be reached on 316-617-9237. Trust and leave it to 'The Bull Attorneys'.
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Joara was a large Native American settlement, a regional chiefdom of the Mississippian culture, located in what is now Burke County, North Carolina, about 300 miles in the interior in the foothills of the Blue Ridge Mountains. Joara is notable as a significant archaeological and historic site. It was a place of encounter in 1540 between the Mississippian people and the party of Spanish conquistador Hernando De Soto.
A later expedition under Juan Pardo in 1567 created the first brief European settlement in the interior of the continent, establishing Fort San Juan at this site, together with other forts to the west. It is thought to be the first and the largest of the forts that Pardo established in an attempt to colonize the American South On July 22, 2013, archeologists announced evidence of the long-suspected Fort San Juan at Joara, after previous excavations revealed European as well as Mississippian artifacts.
In the 21st century, archaeological finds from excavations have established evidence of both substantial Mississippian and sustained Spanish 16th-century settlement in the interior of North Carolina. Joara was also the site of Fort San Juan, established by the Juan Pardo expedition as the earliest Spanish outpost (1567–1568) in the interior of what is now North Carolina. This was 40 years before the English settlement at Jamestown and nearly 20 years before their "Lost Colony" at Roanoke Island.
Established about AD 1000, Joara was the largest Mississippian culture settlement within the current boundaries of North Carolina. In 1540 a party of Spanish conquistador Hernando De Soto encountered the people at this chiefdom site. It was still thriving in January 1567 when the Spanish soldiers under Captain Juan Pardo arrived. Pardo established a base there for the winter, called the settlement Cuenca, and built Fort San Juan. After 18 months, the natives killed the soldiers at the fort and burned the structures down. That same year the natives destroyed all six forts in the southeast interior and killed all but one of the 120 men Pardo had stationed in them. As a result, the Spanish ended their colonizing effort in the southeastern interior.
Joara is thought to have been settled some time after AD 1000 by the Mississippian culture, which built an earthwork mound at the site. It was a regional chiefdom, established on the west bank of Upper Creek and within sight of Table Rock, a dominant geographical feature of the area. The Joara natives comprised the eastern extent of Mississippian Mound Builder culture, which was centered in the Mississippi and Ohio river valleys. By the time of the first European contact by the Spanish with Native Americans in the foothills of the southern Appalachians, Joara had already grown to be the largest Mississippian-culture settlement in present-day North Carolina. The town served as the political center of a regional chiefdom that controlled many of the surrounding native settlements.
Most contemporary scholars, following John Swanton, connect the various spellings of Joara with the Cheraw, a Siouan language-speaking people. The later historic Catawba Nation are likely descendants of the natives at Joara.
Cofitachequi and the neighboring Coosa chiefdoms were developed by ancestral Muskogean-speaking groups, who apparently claimed other areas as tributary. The Creek people are their descendants. The scholar T.H. Lewis at first associated the term Xualla with the modern Qualla Boundary and thought it was Cherokee, but most modern scholars no longer believe this. Charles Hudson alone among modern scholars argues that Joara may be a Cherokee name; but the Cherokee were not moundbuilders and were not the first to develop the site.
In 1540, Hernando de Soto led a Spanish army up the eastern edge of the Appalachian mountains through present-day Georgia, South Carolina and North Carolina. This expedition recorded the first European contact with the people of Joara, which de Soto's chroniclers called Xuala. De Soto brought the queen of Cofitachequi province to Joara as an involuntary member of his entourage. The chroniclers also state that the queen claimed political dominion at this time over Joara province as well as the province of "Chalaque", and that the natives in both places respected her office. She managed to escape after reaching Joara.
On December 1, 1566, Captain Juan Pardo and 125 men departed from Santa Elena, a center of Spanish Florida (located on present-day Parris Island, Beaufort County, South Carolina) under orders from Governor Pedro Menéndez de Avilés to claim the interior for Spain. Pardo was to pacify the native inhabitants, convert them to Catholicism, and establish a route to Spanish silver mines near Zacatecas, Mexico. The Spanish thought they were much closer to the mines than they were in fact.
Shortly after May 1568, news reached Santa Elena that the native population had burned the six Spanish forts established by Juan Pardo and killed all but one of the 120 Spanish men stationed in those garrisons. Captain Pardo never returned to the area, and Spain ended all attempts to conquer and colonize the southeastern interior. Captain Juan Pardo's narrative of his travels and settlement at Joara, written by his scribe Bandera, were discovered and translated into English in the 1980s. They have contributed to a significant reassessment of the history of Spanish colonization in the interior of North America.
Although the location of Joara and Fort San Juan were forgotten, local inhabitants found numerous native artifacts in certain areas of the upper Catawba River Valley. Unlike areas in which mounds were protected, during the early 1950s farmers bulldozed Joara's twelve-foot-high earthen platform mound to make way for cultivation. The location of the mound is now recognizable only as a two-foot rise in the field but current owners vow to protect the site.
In 1986, a breakthrough occurred at the Berry excavation site (named for the family who own the property). Archaeologists discovered 16th-century Spanish artifacts. This evidence, supported by Bandera's 16th century narrative, caused a reevaluation of Pardo's route through the Upper Catawba Valley. Further evidence suggests the Berry Site is the location of Joara and Fort San Juan. The archaeological site has demonstrated the extent to which the Spanish attempted to establish a colonial foothold in the interior of the Southeast.
Further excavations at the Berry site throughout the 1990s and 2000s have yielded remains of native Joara settlement and burned Spanish huts, and more 16th-century Spanish artifacts, including olive jar fragments, a spike, and a knife. In 2007, the team excavated Structure 5 and found a Spanish iron scale, as well as evidence of Spanish building techniques. These artifacts were not trade goods but objects used by the Spanish in settlements. Joara is particularly interesting for the interaction between Native Americans and Spanish, who were relatively few in number and depended on the natives for food. Archaeologists expect to find evidence that will reveal more about events there.
Archaeologists familiar with the area have concluded this is the site of Joara and Fort San Juan. It supports documented Spanish settlement of 1567–1568, as well as the natives' burning of the fort. The discovery is requiring a reassessment of the history of European contact with Native Americans.
In July 2013, archeologists reported finding evidence of the remains of the fort itself at the site, including the remnants of burned palisades and what appeared to be the main structure within the fort.
↑ Charles Hudson, The Juan Pardo Expeditions: Explorations of the Carolinas and Tennessee, 1566–1568 (Tuscaloosa, Ala.: University of Alabama Press, 2005), 25.
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McLaren's Lando Norris won the European Formula 3 Championship against drivers on the books of BMW, Mercedes, Ferrari and Force India. Who were the stars of the season?
Lando Norris won the title, but the McLaren protege was just one of four super-talents who fought out the Formula 3 European Championship this season.
One by one the challenges of Callum Ilott, Joel Eriksson and Maximilian Gunther - each of whom would be as worthy of the tag of Euro F3 champion as many past title winners - fell away. It was the relentless pace of Norris, who rarely had a bad day, and the remarkable hard work of the Carlin team that sealed things.
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At home we all own things that have a high price, but would never consider selling. It might be a ring, a watch or a rare Forest third shirt that would sell for big money on eBay. But we don’t sell it, because it means something to us. We value it more than its real price.
If you think about it, we value footballers. For most fans, the ones we value the most are those that ‘one of our own’. We’ve all enjoyed that warm, fuzzy feeling when Oliver Burke, Joe Worrall and Matty Cash have excelled in the Garibaldi – sometimes lifting the club from the depths of despair with their passion.
With Ben Brereton set to leave Forest for Blackburn Rovers, the feeling for most is sadness, perhaps anger. We all loved seeing him score goals in our youth teams – seemingly he was a man amongst boys. And then there was that goal against Aston Villa. For a while we did not talk about him much, in case he was stolen away by the Premier League scouts watching his every move on the pitch.
But the easiest thing in the world would be write an article like I did here about selling Oliver Burke. That episode was the death throes of a failed regime, looking for a quick buck to fund astonishingly bad mistakes. I don’t think this decision comes from remotely the same place. The current Forest ownership may not get everything right all the time, but the calibre of the whole operation is obviously quite different.
It is clear that they are trying to revitalise a fantastic club, to fill the ground every week and give us a team that is fit to wear a shirt adorned by two stars. They have employed a proven manager with top notch contacts. They are trying to restore Forest to football’s elite for a new generation – not just preserve it as a museum to bygone times for more fortunate older fans to enjoy. So I think we need to see decisions in that context. In good faith.
However, we shouldn’t delude ourselves that these decisions are easy and without a considerable risk. It is remarkably difficult to predict the course of a football career. That’s why some players like Stan Collymore played at several clubs before he became football’s hottest property, and others such as Craig Westcarr shone brightly in youth football but ended up playing at lower levels. Only those with hindsight can call it right every time.
In particular, it is difficult to predict the futures of players who operate in the spine of a team. It takes longer for a goalkeeper, a central defender and particularly, a modern lone centre forward to learn their trade. Forest striker Daryl Murphy scored only 20 goals by his mid- to late-20s, before maturing into a successful target man for Ipswich. Many Forest fans on social media scoffed at the abilities of Jamaal Lascelles when we sold him. He is now worth 10 times the amount we received for him because centre halves mature later.
There are also examples of players who haven’t kicked on, where Premier League scouts have backed away. We all are entitled to our opinions, but it’s hubris to suggest we know 100% how Ben Brereton will do in two, five or 10 years.
However, we have to ask: what might be some of the factors that have fed into the decision to sell Brereton? Karanka has made it clear he likes Brereton and huge bids for Joe Worrall were rejected last January. But football is changing quickly. This thread by Swiss Ramble is a stark reminder of the money being pumped into the top level of the game. The result is massive inequalities that trickle down through parachute payments and make life far more difficult for clubs like Forest who always have an eye on FFP.
Forest are quite a unique club given the massive expectation in relation to their size. The reasons behind that are obvious. Any owner of Nottingham Forest has bought the club because of its success and will demand a return to the glory days, and most fans will back them at first.
Owners will look at Sunderland who enjoyed parachute payments and were relegated out of sight. They will look at MK Dons, recently of the Championship, who had a long-serving, promising manager and clear strategy, disappear into League Two as a lack of investment left them uncompetitive, in an empty stadium. In this brutal league, if you stand still, you are toast. Former Forest captains are now playing for Pune and New England Revolution and, aside from Barrie McKay, every player who left Forest in the summer went to a lower level or have not been picked up, and that is frightening.
As the fans filed out early of the two Christmas defeats last season, I realised that Forest were a different club to Mark Warburton’s former club Brentford, with completely different pressures and dynamics. While I was (and still am) happy to give young Academy players time, football crowds are a raw democracy, and the clear evidence from our 21,000 season card sales are that fans wanted to push the club forwards in a different way. And I think they know the risks around FFP that entails. There is no plan in football that doesn’t involve a high element of risk – and that includes Blackburn spending big on a raw teenage striker. Wolves may have taken the shorter route to success, but may argue when they receive their Sky money that their plan is better than Brentford’s – it depends on what the goal is though, of course.
When we look at successful clubs moving from the Championship to the Premier League, spending money is a common thread. From Bournemouth, to Leicester City, ready-made players are seen as the quickest way to success. Sadly, it seems a matter of time before a club ‘sells out”’and makes a statement at the expense of their Academies.
Burnley’s goalkeeper crisis is a case in point – they don’t look to their Academy, but a third England international in signing Joe Hart. Clearly, someone at Benfica has decided that there’s no time to wait for Joao Carvalho to mature into a top Champions’ League player. From Pep to Eddie Howe, top managers are signing players and not developing any more homegrown players than Karanka is doing through Matty Cash and Ben Osborn.
It’s a sad thing, but it’s a real thing. But we shouldn’t sugarcoat the past either. Billy Walker bought experienced players in the late 1950s such as Eddie Baily and Doug Lishman to get Forest back into Division One. Brian Clough bought Peter Shilton and Hans van Breukelen when he had Chris Woods and Steve Sutton coming through. He spent a million pounds well on Trevor Francis, but wasted it on Justin Fashanu.
Frank Clark rebuilt the spine of Forest team to achieve his goals – with investment rather than youth development. There were signings that didn’t work out, and more signings were needed later to get over the line. Only Steve Stone broke through that season. It’s even harder now. On BBC Radio Nottingham, Steve Hodge spoke honestly about the barriers which face young players in the English game.
Money, footballing trends and expectation trickles down to what’s happening at Forest. With recent managers lasting no more than a year at the club, and FFP lurking in the shadows, we start to see the external conditions that drive these types of decisions. I am sure they are very tough decisions which are made with a heavy heart. But every strategy is a risk. Every ambitious club are making big, divisive, risky calls on buying and selling the Carvalhos and Breretons.
We don’t yet know how the transfer business will be concluded at the City Ground. But we need to recognise that the things we value as fans may not be the same as a manager. Mark Warburton gave youth a chance, but did not last to see the benefits down the line. Decisions football managers are making will have an element of self-preservation. We’ve probably all had to make hard decisions in our lives where we recognise the risk, consider the downsides, but choose to be pragmatic.
Despite all of this, I personally wouldn’t sell Ben Brereton. For me the value of our young players is something bigger than their market price. One of the best things about the summer was the unity of the fanbase behind the club, and this decision eats away at that too much. But it’s different if your job is on the line. Whatever happens the Academy must remain a part of our strategy and not just a cash cow. Perhaps it might be that the standards change, and only the performance levels of Matty Cash are good enough going forward. But it must still play a vital role.
A lot of good things have happened at Forest over the last year. These changes will hopefully be lasting changes which give us a club to be proud of once again. Along the way there will be lots of decisions – some good, some not so good. Some we’ll agree with, some we won’t. Some will pay off, some will backfire. That is football. We should share our opinions and views but we don’t have the gift of hindsight before the event. The positivity at the start of the season was something to behold. Let’s not panic, learn from the past, stick together and see how it pans out.
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0.995343 |
Python Program to Make a Simple Calculator. In this example you will learn to create a simple calculator that can add, subtract, multiply or divide depending upon the input from the user. To understand this example, you should have the knowledge of following Python programming topics: Python Functions; Python Function Arguments; Python User-defined Functions; Source Code: … how to find device name from mac address Next time please include your motivation in the question. In its current form it apparently confuses people and some of them tend to assume that you will be calling verbatim get_function_name_as_string(my_function) and expecting "my_function" as the result.
Next time please include your motivation in the question. In its current form it apparently confuses people and some of them tend to assume that you will be calling verbatim get_function_name_as_string(my_function) and expecting "my_function" as the result.
Sorted() function in Python Striver If you like GeeksforGeeks and would like to contribute, you can also write an article using contribute.geeksforgeeks.org or mail your article to [email protected].
With the python module inspect, one can inspect (not kidding) the run-time python stack. Among other things, this makes it possible to get the name of the current function or callers.
You can change a list to a tuple in Python by using the tuple() function. Pass your list to this function and you will get a tuple back! Pass your list to this function and you will get a tuple back! Remember : tuples are immutable.
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0.996813 |
Be willing to lead a team of Operators and lead by example.
ROLE INFORMATION: my client is currently looking to recruit for an experienced Production Technician. Ideally the successful candidate will have come from a Process or heavy manufacturing background. You will be responsible for leading a team of 10 operatives, producing a high volume of good quality products while adhering to health and safety procedures. You will also be responsible for monitoring production levels against KPI’s and identifying any areas the production line can be improved.
The successful candidate will have to carry out product quality checks to ensure high quality standards are kept. This position would suit someone wanting to progress their career in production management.
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0.939659 |
Ontology is the most fundamental branch of Metaphysics, the study of Being and Existence, as well as the basic Categories of things in general. A Being is anything that can be said to 'be' in various senses of the word 'be'. The verb "to be" has many different meanings and can therefore be rather ambiguous, and because "to be" has so many different meanings, there are, accordingly, many different ways of Being.
Aristotle described Ontology as "the Science of Being qua Being." The word "qua", by the way, means "with regard to the aspect of". Accordingly, Ontology is the Science of Being with regard to the aspect of Being, the study of beings in-so-far as they exist. Even more precisely, Ontology concerns how we determine what Categories of Being are, which are fundamental, and whether or not, and in what sense, items in those categories can be said to "be."
Different philosophers have made various lists of the fundamental Categories of Being throughout the History of Philosophy. Before the rise of the Sciences in the Western Renaissance, Ontology, taken with Metaphysics more generally, was the central focus of philosophical concern. One strong reason was because this directly related to Theology (or the Philosophy of Religion) and the existence of God. Science directly challenged these connections, and slowly, Ontology was reduced to an historical curiosity. Representative ontological thought is readily cited, but ground-breaking work is found in Plato, Aristotle, Neoplatonism, Anselm of Canterbury, Thomas Aquinas, Rene Descartes, Baruch Spinoza, Gottfried Leibniz, Immanuel Kant and Friedrich Wilhelm Joseph von Schelling, to name a few. In Modern Philosophy and Contemporary Philosophy, Ontology was taken up by physicists who were already asking very similar questions using the Scientific Method.
To be sure, Ontology is being done today, though not under its ancient name. It is found in many branches of Physics and the other Sciences. Quantum Mechanics, String Theory, and Quantum Philosophy in general, are direct descendants of the ontological traditions, which naturally grew beyond the historical distinctions between Universals and Particulars, into questions of Particle States, Dimensions and Probabilities. The basic ontological questions of the nature of Existence are even more relevant to Quantum Mechanics today, as notions of solid Matter and any distinct, separate existence of Objects are challenged by the new discoveries.
Even in areas seemingly unrelated to Philosophy, such as Computer Science, Ontology is about asking what a Programming "object" is (not an easy question to answer, given various programming languages, schemas, and practices), and what types of computer Architectures are to be used. In areas like Marketing or Sales, ontological issues lie right at the heart of what a "Brand" is, and how to deal with "Brand Names" and even "Product Lines", not to mention the Legal connections with Intellectual Property and Management connections with "Business Processes". In Business as well as Government, ontological questions abound about the use and Management of Information, and how to gain a competitive advantage over an opponent or adversary though the manipulation of Information, either in a Public Relations sense, or in a Warfare one.
The Objecthood or "Problem of Substance"
Is it possible to give an account of the existence of physical Objects?
Is Existence a Property, Substance, or State?
When does an object go out of Existence, as opposed to Change?
Some content adapted from the Wikinfo article "Ontology" under the GNU Free Documentation License.
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0.942976 |
(CNN) - Sen. John Kerry will voluntarily pay $500,000 in taxes to the state of Massachusetts - a move that forestalls a potential investigation into whether the Bay State's senior senator attempted to evade the hefty levy by docking his $7 million yacht in Rhode Island.
"We've reached out to the Massachusetts Department of Revenue and made clear that, whether owed or not, we intend to pay the equivalent taxes as if the boat's home port were currently in Massachusetts," Kerry said in statement. "That payment is being made promptly."
The decision came after Kerry faced a series of questions over why the Massachusetts Democrat decided to dock his new multi-million dollar sloop in neighboring Rhode Island even though it had been reportedly spotted in Massachusetts waters and Kerry maintains residences in Boston and Nantucket.
Rhode Island has been known as a tax-haven for boaters after the state repealed its sales and use tax on boats in the early 1990's. Kerry, who recently purchased the 76-foot yacht in Rhode Island, therefore avoided close to a half-million in taxes.
But the Massachusetts Department of Revenue has long been on the lookout for Bay Staters who dock their boats in Rhode Island and use them in Massachusetts. The Department mandates such boaters file a form with the state so use and excise taxes can be levied. If no form is filed, Massachusetts can take possession of boats it determines use its waters a sufficient number of times, the Boston Globe reports.
The Department of Revenue said Tuesday it had not launched an investigation into the matter.
The senator's office has said Kerry was not seeking to avoid taxes but instead docked the yacht in a Newport, Rhode Island boatyard for "maintenance, upkeep, and charter purposes."
So THIS is how the DemocRATS have "drained the swamp"??!!!
Just ANOTHER stinking DemocRAT tax cheat and evader! They just LOVE to TAX everybody else and spend like drunken fools. Rangel, now Kerry. I think every member of Congress needs to be thoroughly audited and the cheats driven from office. Where's the "zero tolerance" for this type of BS.
THROW THE TAX CHEATIN' BUMS OUT!!!
PAY YOUR FREAKING TAXES, WASHINGTON!!!!
So who could blame him? IMHO, this is not like avoiding your income tax (Geithner), hiding money offshore (all those rich people in the Bahamas or Switzerland) or paying illegal help off the books, rather it's like making a choice between stores in some ways. Shop at Target versus shopping at Macy's. If he docks in Rhode Island it will more of an inconvenience and that is a choice he's making to save money, right?
Funny. He 'reached out' after he was caught, and ONLY because he was caught. Join the Rangel club of tax cheats.
And still the Nutwork Nations who read this article found a way to blame the Republicans, Bush and Cheney for this. That dope inspired crazy streak is why they are going down so bad in the November elections.
Just like Geithner, Daschle, Rangle and now Kerry, Democrats want YOU to pay more taxes while they try to get around paying taxes themselves.
Thank you Senator Kerry for giving us another reason throw all of the Democrats out of Congress in November.
Who is in touch with the people?
Caught with his hand in the cookie jar......he had little choice, now did he?
Yes–guilty until proven innocent! That seems to be the way of things lately. As if everyone responding here has been 100% truthful on their tax return??
If this were a Republican, the media would be going to town on them. There would be calls for their resignation and probably a bill before congress condemning them. The double standard is old. I am sick and tired of BOTH sides of the isle.
Is Charels Rangals being given the same options .
Seems as though some political hack in Massachusetts sought to try to embarass a MA Senator that might have found a less expensive place to dock his boat.
Instead, Kerry capitulates to the extortion because he doesn't need a tabloid exploitation of something he has EVERY RIGHT TO Do.
MASSACHUSETTS EXTORTS A HALF A MILLION DOLLARS.
Where is the other senator ... Tea Party darling ... Scott Brown ... come down on this tax issue?
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0.999997 |
What's the source of anti-cyclist/anti-mass transit/pro-automobile bias?
1. The news media started reporting "trouble" before the ride even began.
4. 250 cylists were reported arrested on charges of running red lights and assault. The actual publicly available police record - available the day after the ride - shows that only 101 were booked at the Hall of Justice, most of them from a random sweep on Sacramento Street. Only six people were charged with serious crimes and at least two of them were pedestrians in business attire with no involvement with Critical Mass! The news media has yet to report these facts (still is as of this writing: 8/9/97, 9:55 AM).
5. The ride was inaccurately called "mayhem" and "chaotic" when in fact - except for the very predictable conflicts that occasionally occured when cyclists instead of police officers manned the intersections - it was an entirely normal ride.
6. At approximately 7:30 PM, police set up a roadblock at Market Street bu Fifth Street.
7. Cyclists and pedestrians (who were obeying all traffic laws) who caught in this roadblock were assaulted (shoved, knocked to the ground, struck with clubs, kicked, pepper sprayed, etc.) by a small group of out of control police officers.
8. Video evidence indicates at least one member of the "official" press was there taking photos - and this story has yet to make it to the "mainstream" press even though it has been on this widely visited web site since August 1, 1997. Note: the riot occured one block from the headquarters of the San Francisco Chronicle.
A theory on why the San Francisco media was so quick to lead the attack on the riders and then cover the facts.
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0.999999 |
Question: Which is the most fluid revision of the following paragraph? There was a monkey on a rocket ship. The rocket ship flew over the irrigation ditch. The monkey was eating papayas.
There was a monkey eating papayas on a rocket ship. The rocket ship flew over the irrigation ditch.
There was a monkey on a rocket ship, which flew over the irrigation ditch. The monkey was eating papayas.
There was a monkey on a rocket ship, which flew over the irrigation ditch and the monkey was eating papayas.
While eating papayas, the monkey flew over the irrigation ditch on a rocket.
The correct answer is: While eating papayas, the monkey flew over the irrigation ditch on a rocket.
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0.991337 |
Hi! this is a essay for my english class. The question is to write about a valuable life lesson that you have learned.
I know that i had many grammar problems so can someone kindly correct my essay and gives suggestions to improve my essay. Thank You So Much!!
I had not once learned valuable lessons in life. One of the life lessons that I learned is to be thankful and appreciate for those that around me. Maybe it is true that we do not appreciate what we had until we lost them and there are moments in life that when you miss someone so much that you just want to pick them out from your dream and hug them for real. I did not experience these until my grandmother passed away.
My grandmother was the one that watches me grow up and takes care of me when I was a little girl because my parents had to work and were away from home. She loved me so much that she would do anything for me but I did not realize this until she passed away. Since she was the only adult at home she had to do all the household chores and takes care of me at the same time. Everyday after school, she would wait for me at the doorway and asks me what I wanted to eat for lunch and she would cook the food for me immediately. Every times when I go out to play with my friends she would asks me where I was going and when I'm going to be home, so that she knows when to prepare the dinner for me. As I grow older, I started to hate the way that she waits for me everyday at the doorway and asks me where I was going. I told her that I am older now and that she doesn't have to treat me like a little girl anymore. However, she continued to act the same way as usual. One day when I came home from school and saw her standing there waiting for me, which I did not expected, I was very angry and had a big argument with her. I yelled at her and told her that I am older now and that I do not need her anymore. She did not say anything to me and I ran out the house. I came home very late that night and walk up to my room quietly. I was surprised to find a bow of rice and two plates of dishes on the table in my room. I did not eat the food and dump the whole thing into the trash can. The next morning I woke up early and went to school without saying anything to her.
Two months later my parents decided to immigrate to America. My mother told me that my grandmother said that she did not wanted to go with us to America because she felt that she is too old and would just be an encumbrance for the family. I was depressed that I had to leave the place where I grew up but at the same time I was glad that my grandmother is not leaving with us. In the airport on the day that I was leaving, she told me to take care of myself when I get there and it is the first time that I saw her cried. I wanted to cry too when I saw the tears rolling down from her face, but I turn my head away and did not even say good bye to her. After arrived in America, I was occupied with learning English and did not call home to her even though I heard from my parents that she became really sick after we left. I remember that it was on a cold December day when I heard the news from my parents that my grandmother had passed away. After hearing the news, I can not help it and the tears continue to roll down from my face. In my heart, I felt that something that is always there is suddenly gone and I can not stop crying.
Four years had passed since my grandmother passed away. Every time when I look at her pictures, the tears just begin to roll down from my face. I felt very regret for never apologize to her for the argument that we had and all the strong words that I had said to her. I felt very regret for never thank her for all the things that she had done for me. If, I had another chance, I would tell her that "I love you grandma."
People will treat you the way you allow them to treat you. Respect and love yourself and others will do the same.
4. What you resist, persists.
What you focus on expands and what you resist, not only does it persist, but it also grows in size. And if you want to shrink something and make it disappear from your life, you need to stop feeding it by fighting against it.
A lot of times we get so focused on our big dreams and goals, that we forget to enjoy this journey called life. Always remember that life is all about this moment. Life is all about the journey and less about the destination.
7. If you don’t believe in yourself, nobody will.
Don’t expect others to see gold where you can only see dust. If you don’t believe in yourself, if you don’t believe that you are capable, a worthy human being, chances are that nobody will. You will act on that belief and people will treat you based on what you think about yourself, based on how you treat yourself and based on how you act and behave in the world.
If you think life is unfair, and that bad thing always happen to you, chances are that life will treat you unfairly, and you will always have many reasons to complain about. Because just how there is a law of gravity, there is also a law of attraction, and based on this law, you attract in your life that which you think about all day long, you attract that which you are, because you see, like attracts like.
9. If you love yourself, chances are that others will love you also.
It’s all about self-love, it all starts with self-love. If you don’t have the love for yourself, how can you expect to get it from somebody else? Love yourself and others will love you also.
There is a difference between being lonely and being in solitude. When you are in solitude, you take advantage of it to get in touch with your inner self, to meditate and to quiet your mind, and that constant need to be around others in order for you to no longer feel lonely, will disappear. Wayne Dyer talks about this in such a wonderful way, saying that we can never be lonely if we like the person we’re alone with. If you like yourself, if you have no problem with your own person, if you have accepted yourself completely, you will be content with having some quiet time, away from all the noise. You will feel happy when alone and also when surrounded by other people.
Fear, that crazy fear who won’t allow us to move forward, who won’t allow us to grow and transform our lives and of those around us will always be present in our lives. Even though many of us know that fear does not exist and that fear is only in our mind, we choose to be paralyzed by it and we choose to allow it to control our lives, our dreams, our goals and the level of our happiness. Fear will be present whenever you want to stretch, whenever you want to get out of your comfort zone and whenever you want to do more, be more, have more. What we need to do is look beyond it, and always be aware of the fact that most of the things we fear never happen, because FEAR is nothing more than False Expectation Appearing Real.
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0.999921 |
One of my favorite things to do as a child was go to the library, and there are so many benefits of going to your local library that I'd like to share with you. If you feel like it's a waste of time having to sift through books, or look through catalogs for books, please don't let that keep you away. There are so many beneficial and enjoyable things to do at your library that most people don't take advantage of. The library isn't outdated like some people believe, and the benefits of going to your local library almost increase every year. Be inspired by some of my top reasons, and then visit the library in your town or city as soon as you get a chance!
One of my favorite things to do with my mom as a child was go to the library and if you're a mom, one of the top benefits of going to your local library is connecting with your children. It's important to teach children the benefit of reading, and research has shown it can even help make them smarter and perform better in school. That aside, however, bonding is a top benefit of taking your children to the library. Not only can you read together, but look for books that your children enjoy, and you can even teach them the alphabet, or teach them to read through tools at your local library. I promise, they'll always remember these fond memories that the shared with you at the library, and it's most definitely not a waste of your time when your children are considered.
The library is a fantastic place for adults to learn new things, or enhance skills they already have. For instance, many classes are offered at the local library, along with seminars and book clubs. This can be a great time for socializing, learning new things, and you never know- you might just find your next dream career this way. Some of my favorite classes for adults include cooking, finance, home decor, entrepreneur classes and computer classes. This can be a great resource for someone in college, or an adult looking for a new skill or job. Book clubs are also one of the most popular social activities for adults to exchange ideas and thoughts, and it's a great way to meet new people if you've never tried it.
Let's get down to the nitty gritty about what's really fabulous about the library. It's free! Sure, there might be some fees you'll come across in the library like new DVD rentals, or possibly a class or two. And, don't forget late fees! If you're late returning books, you might incur fees that way too. Yet, most of the time, every book you choose and other resources you use at the library will be free of charge. I'm much more likely to go to the library to check out a new book, or get put on a waiting list to check it out if it's a new release than I am paying $20 for that book at the store and never reading it again. Plus, you can always check it out again later if you want, and it's free of charge all over again!
Did you know you can rent audio equipment at your local library too? Depending on your budget, there are different brands that each branch has available. You can usually find cassette players, CD players and even some Blu-Ray players at your local library. This is great if you're a student on a budget that doesn't want to invest in a permanent piece of equipment, or if you only need it a few times. Most of the time, you might not be able to take it home for an extended period of time without paying a fee, but you can always use it at the library for free. And, most all libraries stay open late for students and working adults. This means you can use it at almost any time of the day or evening if you need to.
For all you eReader fanatics out there, you're missing out if you're not going to your local library! One of the biggest benefits of going to your local library are the check-out selections of Kindle books or eReader books. Amazon.com has partnered with many libraries across the country to provide these books to the public. I think this is one of the most innovative free tools we've seen yet. Kindle books fo free? Yes please! Just be sure you check them back in when it's time so you don't pay a late fee.
Let's say you're going through a legal process, or just need to get something notarized and don't know a notary, nor want to pay for one. Simply go to your local library! I won a contest last year for a cash prize and had to have a form notorized, but didn't want to pay for the service. So, I just went down to my local libary. There is always a notary on staff during most business hours of the day. The best way to check is to call ahead of time to make sure. It's a free service the libary uses for the public's convenience and can really come in handy in a bind. Be sure you bring all your paperwork, and your driver's license or ID, since you'll need it for identification verification.
I hope you see now that there are many benefits of going to your local library, more than for simple leisure. Do you visit your local library?
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0.917416 |
Ask any New Zealand business owner if social media is important when connecting with their audience and there will be lots of agreement. In fact, most people will say that social media has been a key transformative force behind the marketing of brands. While forming those connections with consumers through the right channels is imperative to success, the right social media monitoring strategy is crucial to ensuring that a business's resources are being funnelled and used in the most efficient way.
Social media is where consumers connect with each other as well as with businesses, and businesses do the same. Personalising the content that a business puts on its social media pages is only one aspect of a successful social media marketing strategy though. Without the ability to extract the right data that tells the true story of a brand's popularity, it can be nearly impossible for a business to determine the success of their efforts and what needs to be changed.
In addition to a social media strategy, NZ businesses also need to develop a strategy that monitors the effects of their efforts. While having consumers like and/or share a post, picture or video is one way of garnering feedback about social media outreach, it doesn't provide a complete picture of what's going on behind the scenes.
Listening to what NZ has to say about a business online requires gathering the information provided by a large volume of messages in order to reflect on the data provided. This data is then used to analyse the success of the business's efforts.
Social media monitoring can also provide a framework that keeps a busy company's social media presence organised and cohesive. By building a brand with relevant keywords that help identify the key elements of a business, for example, it can be easier to track the reactions of the intended audience.
In order to develop a strong and successful marketing strategy, a robust system of social media monitoring is necessary. Only through the use of an objective tool such as this can the strategy be tweaked in meaningful ways that lead to success.
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0.90148 |
What is the Human Resources Cycle?
Also known as the Human Resources Life Cycle or the Employee Life Cycle and refers to the stages of an employees time in a particular organisation and the shifting roles the Human Resources function play in each of those stages.
As you can see they are all describing the roles HR play within the working life-span of the employee from pulling together job descriptions through recruitment, deployment, management, development and exit. The only real difference is the level of detail or focus in the various models.
In effect the HR Cycle is simply attaching the roles of HR to the stages employees journey through whilst they are in the company.
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0.999956 |
To make the syrup, combine sugar, water, lemon, cinnamon, and cloves in a large saucepan and bring mixture to a boil. Simmer over medium heat, uncovered, for 25 to 30 minutes. Turn off heat and stir in honey until dissolved. Let syrup cool at room temperature and chill.
Preheat oven to 300˚F. Remove thawed phyllo from boxes and arrange on a work surface and cover with a damp kitchen towel. Melt butter in a medium saucepan and skim away and discard the foam from the top. Pour off the melted butter into another saucepan, leaving behind and discarding the water from the butter.
Butter a baking sheet 18 X 13-inches. Arrange one layer of phyllo in pan and butter phyllo. Make 11 more layers in the same manner, being sure to butter the phyllo well.
In a bowl combine walnuts, sugar, and cinnamon. Sprinkle a cup of the nut mixture over the phyllo and top with three layers of phyllo, buttering in between each layer of phyllo. Continue to make more layers in the same manner until all the nuts are used. Arrange 14 sheets of phyllo over the last of the nuts, being sure to butter between each layer of phyllo well. With a sharp knife cut baklava into diamonds or triangles about 2 inches in diameter.
Bake baklava in the center of the oven for 2 hours, or until golden brown. If the baklava browns too quickly reduce oven to 275˚ F. Remove from oven and immediately pour chilled syrup over hot baklava. Makes about 32 pieces of baklava.
is to pour cold syrup onto hot baklava.
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0.804404 |
Liaquat Ali Khan (1896-1951) was the first prime minister of Pakistan. He played an important role in the negotiations leading to the creation of Pakistan and then in the consolidation of the new state.
On Oct. 1, 1896, Liaquat Ali Khan was born at Karnal in Punjab, India. His family were wealthy landowners who later moved to the United Provinces. He was educated at Aligarh and Oxford University. After qualifying as a barrister in England in 1922, he returned to India.
Liaquat was elected to the Legislative Council of the United Provinces in 1926, where he served for the next 14 years. During this period he was active in the affairs of the Muslim League, and in 1937 he became its secretary. Genial and able to mingle easily with all classes, he was a useful counterpoise to the austere Mohammad Ali Jinnah, with whom he worked closely in building up the Muslim League as an effective political organization after 1937. Liaquat was elected to the Central Legislative Assembly in 1940, where, as deputy leader of the Muslim League party, he strengthened the Muslim demand for a separate home-land.
In 1946, when independence for India was being negotiated with the British, Liaquat was appointed finance minister in the interim government. His "poor man's budget," which put heavy taxes on the rich and threatened to investigate the activities of the great industrialists, was regarded as an attack on the Indian National Congress, which the industrialists helped to finance.
After partition on Aug. 15, 1947, Liaquat became prime minister of Pakistan. Although at first he was subordinate to Jinnah, the governor general, after Jinnah's death in 1948 he emerged as the most powerful figure in the nation. Two major issues were used by his opponents, however, to undermine the stability of his regime. One was relations with India, which had been embittered by the struggle over Kashmir. Open war seemed a possibility in 1950, but Liaquat's journey to Delhi, where he signed an agreement with Jawaharlal Nehru pledging cooperation between the two countries, lessened some of the tension. This action was fiercely criticized by militant groups in Pakistan as a concession to India.
The other issue was the demand by orthodox Moslems to declare Pakistan an Islamic state, with all laws conforming to the Koran. Liaquat, who was a liberal democrat, with strong commitments to modernization, opposed this demand as reactionary. His compromise, as accepted by the legislators, was that Pakistan was a state where "Moslems would be enabled to lead their lives … in accord with the teachings of Islam." He was not able to halt the growing factionalism, however, and a fanatic assassinated him on Oct. 16, 1951.
A brief account of Liaquat's career is given in S. M. Ikram, Modern Muslim India and the Birth of Pakistan (1950; 2d ed. 1965). His speeches are collected in M. Rafique Afzal, ed., Speeches and Statements of Quaid-i-Millat Liaquat Ali Khan, 1941-51 (1967).
"Liaquat Ali Khan." YourDictionary, n.d. Web. 09 April 2019. <https://biography.yourdictionary.com/liaquat-ali-khan>.
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0.999942 |
"Insurgent" continues shortly after the events of the first movie, having Jeanine finding a box that can only be opened by a Divergent and searching for all the Divergents (Which was previously shown in the trailers.) and also discovering that not all Divergents are equal as some Divergents are better than the others and obviously, the latter was Tris.
VERDICT: I'm not saying that I didn't like the movie, but it really could've been better. I didn't like it that MUCH because everything was too surreal. Everything was too coincidental.
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0.975841 |
Chelsea Football Club were formed in 1905 and play their home games at Stamford Bridge which is in London,England.
The club has won 4 league titles,7 FA Cups,4 League Cups,1 Europa League and 1 Champions League in their long history.
Their first league title came in 1955 but they then had to wait another 50 years before they won their next one,Russian business tycoon Roman Abramovich took over full control of the club in 2003 and invested his money into buying new squads of players and managers which would see Chelsea win plenty of silverware over the coming years.
In 2004 Chelsea brought in Jose Mourinho from FC Porto to be their new manager as former manager Claudio Ranieri was unable to deliver any trophies,in Jose Mourinho's first season Chelsea won the league title and the League Cup,the following year they retained the League title,Chelsea then won the FA and League Cup double in 2007 before Chelsea replaced Jose Mourinho with Avram Grant who led Chelsea to their first Champions League Final but they lost to English rivals Manchester United on penalties.
After failing to win any trophies Avram Grant was replaced by Guus Hiddink who guided Chelsea to another FA Cup,Guus Hiddink only stayed one season and Chelsea brought in successful Italian manager Carlo Ancelotti who won another League title and FA Cup.
After 2 years at the club Carlo Ancelotti was replaced by his assistant Roberto Di Matteo who went on to win an incredible FA Cup and Champions League double in his first season beating formidable teams such as Barcelona and Bayern Munich along the way,with expectation being incredibly high the following season Chelsea started badly and Di matteo was replaced by Spaniard Rafa Benitez and in his one and only season he won the Europa League.
Chelsea have now turned back the clock and have re-appointed their former manager Jose Mourinho and will be hoping he can emulate his recent success at the club.
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0.999003 |
You will read an article about telecommuting. Answer the questions based on what you have read.
If you had your choice, would you rather sit in an office all day to make a living or work from the comfort of your own home? Nowadays, more and more businesses are allowing employees to work at least part of the week from home. The idea of “telecommuting” isn’t that new and for many it’s been technically possible since the Internet became widely accessible. Some employers, however, have been less willing to allow the practice for fear that employees who were not being watched would become lazy and undisciplined. Actually, recent evidence has shown that these fears are mostly unwarranted and that businesses can actually save a lot of money on rent by converting more of their staff over to telecommuters.
In a normal telecommuting situation, a worker will be given assignments and asked to complete them or report on them, as in any other office job. The major difference is that most communication is done using the telephone, email and instant messaging. Some employers allow workers to choose which hours they will work, others require them to be online during a normal work day. Either way, most telecommuters have the freedom to work from home or wherever else they would like.
Yet telecommuters often find that their freedom comes with a cost. Those who work outside the office may discover that their employers are more willing to ask them to work long or strange hours. In situations where there are other family members at home, it can be difficult to keep work life and home life separate. Other chores around the house can also serve as distractions, and there’s the matter of getting office supplies like printers and desks. Working at a coffee shop or a library may be a solution, but some locations put time limits on Internet use. Sometimes employees actually take a room in their house and convert it over to a home office — this can be quite helpful in creating an ideal working environment and provides the added benefit of a few dollars back in the bank when tax time comes around.
The benefits to employer and employee seem clear — surveys show that the ability to work from home is interesting to possible employees. The one thing that has not been perfected yet is the work meeting. Holding a meeting on the phone or over the computer is not as effective as meeting in person because it can be difficult to converse with a group without seeing the people you are talking to. Still, who wouldn’t want to be able to work in their pajamas?
Some industry analysts have pointed out Yahoo’s confused strategy and less than stellar stock performance over the past five years. Maybe Mayer is suggesting a path out of the woods for Yahoo.
1. Which ONE of the following is the passage mainly about?
2. Which TWO of the following accurately restate information in the passage?
Employees cannot handle the distractions that come with working from home.
The possibility of telecommuting may be useful in recruiting employees.
Telecommuters may have assignments and hours that closely resemble those of on-site employees.
Telecommuting provides more cost and time benefits to employers than employees.
Employers sometimes prefer telecommuting because it affects work quality.
Those who telecommute have more freedom but less flexibility than office co-workers.
3. Which TWO of the following are mentioned as negative aspects of telecommuting?
Employees are required to obtain their own supplies for home offices.
Employers often force employees to work strange hours from home.
Employees and employers find it difficult to hold productive meetings.
Telecommuters often find it difficult for their employers to trust them.
Telecommuters can find it challenging to manage the tax implications of a home office.
Telecommuters struggle to find a balance between work and home life.
4. Which TWO options accurately describe elements of telecommuting as it is described in the passage?
Employees are requested to make regular trips to the office.
Employers often send documents by email and post to telecommuters.
Employers often tell employees where they can and cannot work.
Employees are often asked to do work as if they were in the office.
Employees are expected to use telephones and computers to communicate.
Employers typically require employees to keep regular office hours.
5. Based on the passage, which TWO of the following might be economic effects of the growth of telecommuting?
Furniture manufacturers increase sales of home office suites.
Coffeehouses compete on the basis of free Internet use offers.
Commercial property developers rent smaller and smaller office spaces to companies.
The concept of a “work week” is disappearing from many people’s lives.
Businesses are hiring more and more part-time workers and job sharers.
Employees accept lower pay for more flexible hours when they take new jobs.
6. Which TWO of the following describe changes a company is likely to make in response to telecommuting trends?
7. Which TWO of the following assertions would Marissa Mayer be likely to support, based on information in the passage?
Online collaboration is not as productive as face-to-face collaboration.
Good business decisions depend on effective team work.
Employee satisfaction can influence company policies.
People waste time socializing when they work in a single location.
Stock performance is connected to the work culture of a company.
Communication among work colleagues is harder when they are physically separated.
8. Based on her explanation to Yahoo staff, which TWO of the following assumptions does Marissa Mayer make about Yahoo?
Yahoo employees do not communicate well.
The company is currently not as quick to market as its competition.
Having all employees work side-by-side creates a more effective business strategy.
Changing employment rules is an essential part of taking charge.
The company needs better ideas from its employees to ensure its success.
Telecommuting has caused the company’s current lackluster performance.
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0.962179 |
What is the art process?
We live in a society that is product and goal oriented. We are constantly focused on the outcome. Aside from the stress that this mode of being induces, it totally stifles the creative process. Art stimulates and develops the imagination and critical thinking, and refines cognitive, physical, emotional and creative skills. We are creative when we experiment, question, use our imagination and shift perceptions. The idea behind “The Art Process” is to unleash creativity by focusing on the process of art using a variety of materials.
1. To remove blocks or obstacles to the creative process.
2. Find a new way to problem solve in art,life and the workplace.
Children below a certain age are process oriented, so they are already in “The Art Process” mode.
1. Engage them more fully in “the art process” by encouraging exploration, experimentation and individuality in a nurturing, non judgmental environment.
2. Encourage a relationship to art and art history by exposing them to various styles, artists and cultures.
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0.999946 |
This Saturday, November 23, 2013, will mark the one-year anniversary of the death of father and teacher Tom Samson. On July 22, 2013, the Toronto Star published a story outlining how the Samson family hired prominent criminal lawyer Edward Sapiano to set the record straight as to how Tom was killed by a careless motorist. They knew that Tom was a safe cyclist and they were shocked when the police told them they would not be charging the driver with any traffic infractions. Sapiano was successful insofar that the police have changed their report: But Sapiano went further to say he believed that the initial conclusions – which are still a matter of public record -- were the result of a shoddy investigation, something he suggested is indicative of a systemic failure by police to conduct thorough investigations when cyclists or pedestrians are killed after being struck by cars on city streets. From the Star article: “A drug-dealing criminal who is shot and killed during a deal gone bad gets a higher degree of investigative services from the TPS,” Sapiano wrote in a letter to the Toronto Police Service. On behalf of the Samson family, Sapiano is calling on police and the Crown to reopen the case, now that they’re acknowledging Samson was stationary, waiting to turn left, as he was lawfully obliged to be, when he was hit from behind.
Sapiano also obtained a copy of Miguel Oliveira’s [the driver who killed Tom] driving record. Between July 2010 and last December, Oliveira had eight driving infractions, including failing to come to a stop, disobeying a police signal, violating novice driving conditions and speeding. Safe cycling advocate, Eleanor McMahon, whose husband Greg was killed while riding his bicycle, worked for years to bring something now known as “Greg’s law” into legislation, which gives the police the power to immediately impound the vehicle of someone found driving while under suspension. Yet, when the driver that killed Tom finally turned himself in, his blood was not tested and he was not charged with anything other than failing to remain at the scene.
The death of cyclist Darcy Allan Sheppard in Yorkville in Toronto was also fraught with investigative discrepancies – due, in large part, to the high-profile of the driver of the car: he was a former attorney general. Darcy Allan’s father, Al senior, is relieved (especially for the sake of his grandchildren) that the record has finally been set straight with a book about the horrific incident and Darcy Allan Sheppard’s life, called Lost Boy. Read our review of the book here.
In 2012, Toronto, Canada’s largest city, with a population of around 3 million people, had triple the amount of traffic-related injuries compared to Montreal, despite a population difference of only 700,000 people. This year alone has seen 51 traffic-related deaths in Toronto. This number is up from the 32 fatalities in 2012 and accounts for the 16 motorists and passengers, 3 cyclists and 32 pedestrians killed in traffic collisions in the GTA. These numbers are the highest they have been in the last five years. It’s clear that the traffic infrastructure and legislation we currently have in Toronto is not enough to keep people safe.
Besides better infrastructure for cyclists, which we call for regularly here at dandyhorsemagazine.com, we also need to look at the way the police investigate traffic collisions where cyclists have been injured or killed. Many articles in popular international publications like the New York Times, The Times (UK), The Economist and the L.A. Times have recently called for stronger and clearer laws around traffic collisions for vulnerable road users. Car crashes are the leading cause of death of people aged 5-34 in the USA.
Between 2006 and 2010, there were 129 cycling fatalities in Ontario. These deaths, along with the deaths of 95 pedestrians in Ontario in 2010 prompted Ontario’s Chief Coroner to investigate traffic safety. In the summer of 2012, the coroner summarized the findings of his office regarding cycling fatalities as being preventable through infrastructure, education, legislation and enforcement. The locations of the deaths of cyclists in Toronto’s streets have been documented and made available to the public on a memorial map, developed by photographer and cyclist, Martin Reis (seen below) -- many of the collisions involve large trucks.
Large motorized vehicles are particularly dangerous for pedestrians and cyclists: and the coroner also found that too many pedestrian and cycling fatalities were the result of collisions with heavy trucks. The City of Toronto’s Toronto Bicycle/Motor-Vehicle Collision Study (2003) found that large trucks were overrepresented in both cycling and pedestrian fatalities. Toronto recently mourned the death of Carla Warrilow who was struck by a truck trailer on Spadina near Dundas. Jenna Morrison was killed by a right-turning truck on Sterling at Dundas in Toronto where the city – two years later – has just now finally installed a set of traffic lights. In both coroners’ reports to date investigating cyclist and pedestrian fatalities, it is recommended that side guards for trucks be made mandatory. These side guards, already mandatory in other jurisdictions, including China and the UK, would prevent more vulnerable road users from being pulled underneath if they were to be hit by a truck. There have been public petitions in Ontario and Quebec to make side guards mandatory. MP Olivia Chow originally brought forth a private members bill to mandate truck side guards and has been instrumental in pushing for side guard legislation. A group called SafeTrucks is now supporting the most recent bill called the cyclists-pedestrian protection act: Sign the petition and find out more about how you can help here.
Clearly, biking and walking are not dangerous activities in themselves – cars and trucks are what bring danger to our streets. Distracted driving needs stiffer penalties. As a society we must focus on solutions that will reduce the number of cycling and pedestrian fatalities. In the EU, many jurisdictions already legislate that drivers should have presumed liability in cycling accidents, and some jurisdictions in the USA are now moving towards laws to help protect more vulnerable road users.
We reiterate the need for better legislation and more effective infrastructure for cyclists. In Canada, the evidence demonstrating how dedicated bike-friendly infrastructure increases the safety of the cyclist has already been established. In Montreal, some of these recommendations are already in place, and the results are reflected in that they have fewer documented injuries and deaths.
A couple years ago the Globe and Mail printed an infographic showing how Toronto leads Canada in cycling deaths.
And the ensuing coroner’s report on cyclist deaths in Ontario then said that 100% of these deaths were preventable.
What has been done since these reports to improve safety?
Not much it would seem.
Today is World Day of Remembrance for Road Traffic Victims, endorsed by the United Nations.
The group, Advocacy for the Respect of Cyclists (ARC) in Toronto has organized memorial rides for nearly every cyclist killed in traffic since 1996. Here is the memorial map of the locations of cyclist’s deaths in Toronto that photographer and cyclist Martin Reis maintains. We remember fallen cyclists in Toronto.
Struck by a truck on Spadina and Dundas. Succumbed to injuries several days later.
Killed by a truck while riding along Lakeshore.
Killed in multi-vehicle collision caused by an impaired driver.
Samson, a schoolteacher, was killed in a hit-and-run collision during the early morning.
Rankin was a bike courier riding down University when he was struck and killed by a cab driver. The police initially threw his belongings – evidence for the investigation – in the garbage.
Struck and killed by a truck on Sterling Road near Dundas.
Struck by a car at the intersection of Greenwood and Plains Road.
Struck and killed by streetcar at Spadina and Lakeshore.
Struck and killed by two cars while travelling south on Colborne Lodge Drive and attempting to cross Lakeshore.
Bike courier killed at Bloor and Bay. Criminal charges laid against the driver were dropped in May 2010.
Struck by a streetcar on Spadina and Nassau. Succumbed to his injuries two days later.
Struck and killed by an SUV at the intersection of Thretheway and Tepper.
Shot and killed while riding bike on Sultan Pool Drive.
Struck and killed on Eglinton and Braemar. Aged 57.
Killed by a truck thief.
Aged 7. Killed while riding her bike along a crosswalk on Bay Mills and Birchmount.
Struck and killed by dump truck at Bayview and Fifeshire.
Struck and killed by cement truck.
Struck and killed by a truck on Keele and Finch.
University of Toronto professor struck and killed by a truck on Avenue and Cortleigh.
Social worker struck by truck at Leslie and Eastern.
Comic book artist struck and killed by truck at Gladstone and Queen.
Struck and killed by garbage truck at Horner and Kipling. Aged 11.
Photographer. Killed in a collision with a heavy truck.
Bike courier killed on his way home from work by a drunk driver.
Struck by car at Martin Grove and Finch. Succumbed to injuries the next day.
Old Kingston Road and Orchard Park.
Struck by an SUV at Bloor and Islington.
Struck at Kipling and New Toronto. Died the next day.
Struck by a vehicle while riding his bike with his wife. Succumbed later to his injuries.
Struck and killed by a tanker truck at Spadina and Clarence Square.
Aged 7. Struck by car at Martin Grove and Westway. Succumbed to injuries the next day.
Struck by minivan at Oak Park and Lumsden.
Killed at Queen and Beech. Aged 25.
Andrews was struck and killed while riding through intersection at Dufferin and Bloor.
Struck by car at Allen and Eglinton. Aged 14.
Struck and killed by school bus after being doored by a car.
Succumbed to injuries four days after her collision with a van on Queensway and Roncesville.
Struck by car on Keele and Wilson. Succumbed to injuries the next day.
Killed at Mt. Pleasant and Roxborough intersection.
Killed by truck on Bathurst and Queen.
Killed by car a King and George.
Singer/Songwriter struck and killed by a truck at Bloor and Church intersection.
Struck and killed by garbage truck at Sackville and Gerrard East. Driver of truck was initially charged with dangerous driving, but was later acquitted.
Aged 16 years, died at Ellesmere and Birkdale.
We gratefully acknowledge the work of Martin Reis on keeping this important public record and for photographing ghost bike memorials, collision sites and other important bike events in Toronto. These are important documents in keeping the public record straight.
Lost Boy: Book review by Derek Chadbourne with comment from Al Sheppard Sr.
There needs to be more pressure on the shytstem… or have more tourists pegged on Bixis!!
Hi there, thank you for this and for continuing to educate and inform us about the social and political realities behind cycling accidents and fatalities. I’m a year-round cyclist and sometimes the risks really scare me. More than anything, I think I worry for my family and friends who also ride. Why aren’t we being more protected through simple measures like the truck side rail guard?
I’d also like to request that you remove this offensive phrase: ““A drug-dealing criminal who is shot and killed during a deal gone bad gets a higher degree of investigative services from the TPS.” This phrase speaks to a really repugnant callousness toward human life. Yes, drug dealers get murdered. And when they do, it is just as heart-breaking and just as much a loss as when any other human life is lost–and deserves the same level of concern, justice, healing and accountability. This phrase alludes to classist and racially-loaded stereotypes about who is a drug dealer and suggests that their lives are of lesser value and that their deaths deserve less attention. Please remove it and address the white middle class biases in your organization that would have led to your publishing this. thank you.
I’d love to know the source of car crashes being the leading cause of death for people 5-34 in the US so I can use it in my advocacy. Thanks!
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0.966038 |
What to do and how to keep mosquitoes away in a more efficient and less costly manner?
To ensure effectiveness conduct experiments to check methods which have been tested and proven elsewhere or have been described in literature. If necessary, efforts must be made to develop new methods.
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0.999244 |
How does the acceleration of a model rocket compare to the Space Shuttle? By using the resultant force and mass, acceleration can be calculated.
The two forces acting on rockets at the moment of launch are the thrust upwards and the weight downwards. Weight is the force due to gravity and is calculated (at the Earth’s surface) by multiplying the mass (kilograms) by 9.8.
The resultant force on each rocket is calculated using the equation resultant force = thrust – weight.
acceleration = resultant force (newtons, N) divided by mass (kilograms, kg).
One model rocket has a mass of 50 grams and a rocket engine that produces a thrust of 5 N for 1 second.
To find the weight, 50 g needs to be changed into kilograms by dividing by 1000. This gives a mass of 0.050 kg. Weight is mass (in kg) x 9.8, which gives 0.050 x 9.8 = 0.49 N.
The resultant force is the thrust – weight = 5 – 0.49 = 4.51 N (unrounded).
Acceleration = resultant force divided by mass = 4.51 ÷ 0.050 = 90 metres per second squared (90 m/s2). This means that, every second, the speed of the rocket increases by 90 m/s.
This is nine times the normal acceleration due to gravity.
The same method can be used for a full-sized rocket such as the Space Shuttle.
The Space Shuttle mission that launched on 24 February 2011 was called STS-133. It had a lift-off mass of 2 million kilograms (2000 tonnes). This means the total weight at lift-off is 2 million x 9.8, which is approximately 20 million newtons (20 mega newtons).
The thrust of each of the big white solid rocket boosters on the side was 12.5 million newtons, and the three main engines at the tail end of the bit that looks like a plane (the Space Shuttle orbiter) had a combined thrust of 5.5 million newtons. This gives a massive total thrust of 30.5 million newtons!
Resultant force = thrust – weight = 30.5 million – 20 million = 10.5 million newtons.
Acceleration = resultant force ÷ mass = 10.5 million ÷ 2 million = 5.25 m/s2.
The acceleration of the model rocket at 90 m/s2 is far greater than the Space Shuttle at 5.25 m/s2, but there is a significant difference in the motion after launch.
Firstly, the model rocket only had enough propellant for 1 second of thrust. After 1 second, it reaches a maximum speed of 90 m/s (ignoring drag and mass change), but after that 1 second of thrust, the model rocket starts to lose speed due to the weight and drag forces both acting in the opposite direction to its motion.
After 124 seconds, the shuttle has already reached an altitude of 45 km and is travelling at 1380 m/s (4973 km/h). At this time (once all of the fuel is consumed), the SRBs separate away from the external tank (the big orange part). Fuel continues to be pumped to the three main engines for another 6 minutes. Acceleration continues until the Space Shuttle orbiter eventually reaches a speed of 28,000 km/h and an altitude over 300 km. This allows it to orbit around the Earth.
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0.999535 |
Summer is here, and boy has it been a hot one! I’ve been trying to stick to the AC as much as possible, but it’s undeniable that the sunlight is good for the soul and for our vitamin D supplies. However, as life-giving as the sun may be, it can also be very destructive, especially if we neglect to protect ourselves. I’m here to help you protect yourself during this summer!
Sun exposure is risky because of the damage Ultra Violet lights A and B cause. In the short term UV rays can cause painful sunburn, whereas in the long term they are responsible for premature skin aging as well as skin cancer. According to the US Department of Health, UV radiation is likely responsible for most cases of skin cancer in the United States, and it follows that it is also responsible for the bulk of skin cancer cases worldwide. My family has a history of skin cancer (unsurprising – my pale great grandparents immigrated from dark Slavic countries to the sunny Middle East in the 1930’s) so my mother has always instilled in me proper respect for sunscreen, and taught me how to wear it properly.
Before I start talking sunscreen, some obvious ways to avoid sun damage include: staying out of the sun, and wearing hats, sunglasses, hats, and long sleeves on sunny days. However, being a cosmetician, I want to talk about the products we can put on our skin to protect ourselves.
First, it is important to choose a broad-spectrum sunscreen, one that will protect from both UVA and UVB rays. Scientists only recently learned that UVA rays can also cause skin cancer, so for a very long time sunscreens were only effective at blocking UVB rays. Thankfully, UVA-blocking sunscreens are now becoming more available. To find out if a sunscreen will protect you from UVA, search the ingredients list for the following ingredients: stabilized avobenzone, ecamsule (a.k.a. MexorylTM), oxybenzone, titanium dioxide, and zinc oxide.
Personally, my skin finds chemical sunscreens like avobenzone and oxybenzone irritating, and I prefer to stick to physical ones like titanium dioxide and zinc oxide. One of the big benefits of physical sunscreen is that there is no wait time, they are effective the second they are applied. Chemical sunscreens only start protecting your skin 15 minutes after they have been applied. Additionally, some chemical sunscreen ingredients are considered harmful to marine life, so they should absolutely be avoided if you intend to go swimming in the ocean. Those include oxybenzone and octinoxate, which have been recently banned in Hawaii.
2) How much sunscreen to apply?
For the face, the commonly recommended amount of sunscreen is a ¼ teaspoon. Have you ever measured out a ¼ teaspoon? It’s the equivalent of 1.2 mL – probably a lot more than what you would normally imagine (and probably more than what you normally apply). It’s also important not to neglect the hands, neck, and any other visible body parts.
Sunscreen should be reapplied after every two hours of exposure. This means that if you work outside, you should reapply every two hours, but if you work in an office chances are that one application in the morning is enough.
Every waterproof sunscreen will lose some of its efficacy after time spent in water (doesn’t matter if you had a dip in the pool, or just worked up a sweat), so on days spent on the beach it should be reapplied every 40 minutes to an hour.
In the evenings you want to load your skin up with antioxidant ingredients, like those found in the natural oils in Nairian’s moisturizers. Antioxidants help stop the free radical damage that the sun causes, so it is very possible they can keep the skin looking youthful in the long term and to support the action of a great sunscreen.
So by all means, go out and enjoy the lovely weather. Just make sure to protect yourself!
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0.997385 |
जो तुमसे बात पर निर्भर करता है, you’re going to hear a number of answers to this question. संक्षिप्त जवाब हाँ है, टैटू चोट, कुछ हद तक. टैटू दर्द का अनुभव व्यापक रूप से भिन्न होता है, टैटू की नियुक्ति पर निर्भर करता है, आकार, tattooer का कौशल, और ग्राहक की व्यक्तिगत सहिष्णुता. Many tattoos are more irritating than painful, especially during the healing stage, when they tend to get very itchy. You certainly shouldn’t let fear of pain dissuade you from getting a tattoo, although you may want to think about placement if pain is a big concern for you.
Some companies sell numbing cream for tattoos, a practice which has met with mixed response from the tattoo community. Some artists think that since tattoos hurt, it is not unreasonable to numb the skin beforehand. Others are concerned that these compounds may compromise the integrity of the inks used, or they may increase the risk of infection. More importantly, numbing creams take a while to work and they wear off quickly, so they may not be as effective as the body’s natural tools for fighting pain.
It is important to remember that everyone’s response to pain is slightly different. You can decrease the potential of a painful tattoo by talking to your tattoo artist about your concerns and eating a healthy meal beforehand to settle your stomach. Stay hydrated as well, as this will promote rapid healing of the site. You should never be ashamed to ask for a break in the tattooing, and you should alert your artist if you feel faint or uncomfortable. Tattoo artists are well aware that tattoos hurt and that different people handle the pain differently, and they will not criticize you for asking for a break.
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0.95038 |
John and Jane Rankin, 1872.
John Rankin was a Presbyterian minister and a prominent member of the Underground Railroad network that assisted fugitives from slavery in the years before the American Civil War.
Rankin was born on February 4, 1793, in Tennessee. He attended Washington College in Virginia, and became a minister in the Presbyterian Church. Rankin dedicated his life to abolishing slavery in America. In 1818, Rankin formed an anti-slavery society in Carlisle, Kentucky. Slavery was legal in Kentucky and Rankin was criticized for his views. He eventually moved to Ripley, Ohio. Slavery was illegal in Ohio. While many Ohioans opposed the ending of slavery, the people of the state were generally more receptive to abolitionists than their neighbors in Kentucky.
In Ripley, Rankin served as a "conductor" on the Underground Railroad and opened his home to African Americans seeking freedom. His home stood on a three hundred-foot high hill that overlooked the Ohio River. Rankin would signal fugitive slaves in Kentucky with a lantern, letting them know when it was safe for them to cross the river. He kept the runaways hidden until it was safe for them to travel further north. The United States Constitution and the Fugitive Slave Law of 1850 permitted slave owners to reclaim fugitive slaves, even if the African Americans resided in a free state like Ohio. To truly gain their freedom, runaways had to leave the United States. Underground Railroad stops provided runaway slaves with safe houses all of the way to Canada. Rankin gave shelter and food to as many as two thousand runaway slaves during his career with the Underground Railroad. Harriet Beecher Stowe immortalized Rankin's efforts to help African Americans in her book, Uncle Tom's Cabin. Rankin's home was the first stop in Ohio for Eliza, one of the book's main characters, as she sought freedom in the North.
Rankin spent most of his life in Ohio as a Presbyterian minister. He helped establish the Free Presbyterian Church of America, which prohibited slave owners from becoming members. Rankin also helped form an anti-slavery society in New York and established the Ohio Anti-Slavery Society in 1835.
In 1829, he established Ripley College. At its peak, the college had 250 students. In 1831, Rankin enrolled the first African-American student in the school. Many of the college's students came from Kentucky and did not share Rankin's abolitionist views. Some students left Ripley College and did not return. Rankin also lectured across the North for the American Anti-Slavery Society. He was often the victim of mob violence. Rankin died on March 18, 1886, in Ironton, Ohio.
Hagedorn, Ann. Beyond the River: The Untold Story of the Heroes of the Underground Railroad. New York, NY: Simon & Schuster, 2002.
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0.998218 |
What is a blocked tear duct, and how do I know if my baby has one?
Blocked tear ducts are quite common in newborns. In fact, 6% of all babies develop a blocked tear duct in one or both eyes. Each of your baby's eyes has tiny tear ducts that allow tears to drain into the eyes. At birth, there is no guarantee that one or more of these tear ducts will be completely open, and even if they are open at birth they can become clogged during the first few months of life. When this happens, it can result in some redness near the corners of the eyes (towards the nose), and a build-up of goop/gunk in that same area. Sometimes you won't know that your baby has a clogged tear duct other than the fact that he or she is not producing any tears when crying! If a tear duct is clogged it is not allowing tears to release into the eye. The tears will then build up in the ducts and can cause an infection if not treated properly.
How can I help my baby's blocked tear duct?
First, use clean water on a soft cloth to wipe the goop/gunk out of your baby's eye. As an easy rule, do this every time you change your baby's diaper (or about 10 times a day).
Second, you can massage your baby's tear ducts. The tear ducts can sometimes become unblocked if you gently massage from the corner of the eye towards the nose. Use gentle pressure with a clean fingertip.
Third, you can place a couple drops of breast milk into the corner of the eye near the nose; do this 4-6 times a day, and you will be able to benefit from the antibiotic properties of your breast milk. Also, Ocusoft makes baby eyelid and eyelash cleaner, which can be very helpful.
Fourth, see your doctor! Advice on any website is no substitute for visiting your doctor and getting the advice of a trained expert! Your doctor can also advice you on additional treatment options, such as prescription ointments and manual draining procedures.
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0.999889 |
Portland voters overwhelmingly renewed a small property tax to pay for child abuse prevention and early childhood education.
In partial returns Tuesday, 80 percent of voters supported a third renewal of the Portland children's levy, which voters instituted in 2002.
It will raise about $24 million a year through 2023 to fund early childhood programs, help for foster children, anti-child abuse efforts and similar services. The yearly bill for property owners will be about 42 cents per $1,000 of assessed value.
Passage is a victory for departing Portland Commissioner Dan Saltzman, its chief champion.
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0.984671 |
The pathogenic yeast Cryptococcus neoformans causes life-threatening meningoencephalitis in individuals suffering from HIV/AIDS. The cyclic-AMP/protein kinase A (PKA) signal transduction pathway regulates the production of extracellular virulence factors in C. neoformans, but the influence of the pathway on the secretome has not been investigated. In this study, we performed quantitative proteomics using galactose-inducible and glucose-repressible expression of the PKA1 gene encoding the catalytic subunit of PKA to identify regulated proteins in the secretome.
The proteins in the supernatants of cultures of C. neoformans were precipitated and identified using liquid chromatography-coupled tandem mass spectrometry. We also employed multiple reaction monitoring in a targeted approach to identify fungal proteins in samples from macrophages after phagocytosis of C. neoformans cells, as well as from the blood and bronchoalveolar fluid of infected mice.
We identified 61 secreted proteins and found that changes in PKA1 expression influenced the extracellular abundance of five proteins, including the Cig1 and Aph1 proteins with known roles in virulence. We also observed a change in the secretome profile upon induction of Pka1 from proteins primarily involved in catabolic and metabolic processes to an expanded set that included proteins for translational regulation and the response to stress. We further characterized the secretome data using enrichment analysis and by predicting conventional versus non-conventional secretion. Targeted proteomics of the Pka1-regulated proteins allowed us to identify the secreted proteins in lysates of phagocytic cells containing C. neoformans, and in samples from infected mice. This analysis also revealed that modulation of PKA1 expression influences the intracellular survival of cryptococcal cells upon phagocytosis.
Overall, we found that the cAMP/PKA pathway regulates specific components of the secretome including proteins that affect the virulence of C. neoformans. The detection of secreted cryptococcal proteins from infected phagocytic cells and tissue samples suggests their potential utility as biomarkers of infection. The proteomics data are available via ProteomeXchange with identifiers PXD002731 and PASS00736.
Cryptococcus neoformans is an opportunistic, yeast-like fungus that is a significant threat to immunocompromised individuals such as patients with HIV/AIDS [1, 2]. The ability of C. neoformans to cause disease depends on the production of virulence factors including a polysaccharide capsule, melanin deposition in the cell wall, the ability to grow at 37 °C, and the secretion of extracellular enzymes [3–8]. Extracellular enzymes with roles in virulence include phospholipases, which hydrolyze ester bonds and aid in the degradation and destabilization of host cell membranes and cell lysis, and urease, which hydrolyzes urea to ammonia and carbamate, inducing a localized increase in pH [9–12]. Proteinases may also cause tissue damage, provide nutrients to the pathogen and facilitate migration to the central nervous system [13–15]. In general, the secretion of extracellular enzymes is important for fungal survival within the host but a comprehensive investigation of the secretome and its regulation by the cyclic-AMP/Protein Kinase A (PKA) signal transduction pathway has not been performed for C. neoformans.
The cAMP/PKA pathway regulates capsule production, melanin formation, mating, and virulence in C. neoformans [16–20]. Components of the pathway include a Gα protein (Gpa1), adenylyl cyclase (Cac1), adenylyl cyclase-associated protein (Aca1), a candidate receptor (Gpr4), phosphodiesterases (Pde1 and Pde2), and the PKA catalytic (Pka1, Pka2) and regulatory (Pkr1) subunits. In response to environmental signals, including exogenous methionine and nutrient starvation, the G-protein coupled receptor (GPCR), Gpr4 undergoes a conformational change to activate Cacl and subsequently stimulate the production of cAMP. Mutations in genes encoding the Gpa1, Cac1, Aca1, and Pka1 proteins result in reduced formation of capsule and melanin, as well as sterility and attenuated virulence in a mouse model of cryptococcosis [16, 21]. In particular, Pka1 is a key regulator of virulence in C. neoformans. In contrast, disruption of the gene encoding Pkr1 results in enlargement of the capsule and hypervirulence .
Previous transcriptional profiling experiments compared a wild-type strain with pka1Δ and pkr1Δ mutants of C. neoformans, and identified differences in transcript levels for genes related to cell wall synthesis, transport (e.g., iron uptake), the tricarboxylic acid cycle, and glycolysis . Differential expression patterns were also observed for genes encoding ribosomal proteins, stress and chaperone functions, secretory pathway components and phospholipid biosynthetic enzymes. Specifically, loss of PKA1 influenced the expression of genes involved in secretion, and Pka1 was hypothesized to influence capsule formation by regulating expression of secretory pathway components that control the export of capsular polysaccharide to the cell surface. Additionally, the secretion inhibitors brefeldin A, nocodazole, monensin, and NEM reduced capsule size, a phenotype similar to that observed in a pka1 mutant . In general, the mechanisms and components required for the export of capsule polysaccharide and other virulence factors in C. neoformans are poorly understood. Beyond the role of PKA, other studies have examined exocytosis functions (Sec6, Sec14), the secretion of phospholipases, and the involvement of extracellular vesicles [23–28]. Additionally, O’Meara et al. (2010) recently demonstrated that PKA influences capsule attachment via phosphorylation of the pH-responsive transcription factor Rim101, a key regulator of cell wall functions.
The role of PKA in secretion in C. neoformans has also been examined with strains carrying galactose-inducible and glucose-repressible versions of PKA1 and PKR1 constructed by inserting the GAL7 promoter upstream of the genes . Elevated Pka1 activity, stimulated by growth of the P GAL7 ::PKA1 strain in galactose-containing media, was found to influence capsule thickness, cell size, ploidy, and vacuole enlargement . The authors also showed that Pka1 activity was required for wild-type levels of melanization and laccase activity, and influenced the correct localization of laccase. The ability to regulate expression of PKA1 and, subsequently, the activity of Pka1, is a powerful tool for investigating the mechanisms of its influence on the secretion of virulence factors and secretory pathway components.
In this study, we used the strain with galactose-inducible and glucose-repressible expression of PKA1 to investigate the influence of Pka1 on the secretome using quantitative proteomics. We identified 61 different secreted proteins and found that Pka1 regulated the extracellular abundance of five. These proteins included three enzymes (α-amylase, acid phosphatase, and glyoxal oxidase), the Cig1 protein (cytokine-inducing glycoprotein) associated with virulence and heme uptake, and a novel protein containing a carbohydrate-binding domain (CNAG_05312). We also observed a change in the secretome profile under Pka1-inducing conditions from proteins involved primarily in catabolic and metabolic processes to an expanded set that included proteins for translational regulation and the response to stress. Enrichment analysis of our Pka1-influenced secretome data compared to the whole genome showed over-representation of genes associated with a broad spectrum of processes including metabolic and catabolic processing. Although no enrichment was observed between our secretome data and the Fungal Secretome KnowledgeBase (FunSecKB), a comparison of GO terms between the data sets showed the majority of our identified proteins to be represented in the FunSecKB. Next, we exploited our secretome data using a targeted proteomics approach to identify potential biomarkers of cryptococcal infection. Multiple Reaction Monitoring (MRM) in the presence of stable isotope dilutions (SID) allows for identification and quantification of specific peptides in a sample. Specifically, we were able to identify Pka1-regulated proteins of C. neoformans in host samples including blood, bronchoalveolar lavage fluid, and infected macrophage lysates. Overall, our study reveals that the cAMP/PKA pathway regulates specific components of the secretome including the Cig1 and Aph1 proteins that contribute to virulence in C. neoformans.
Given the virulence defect of a pka1 mutant, we hypothesized that Pka1 influences the secretion of proteins associated with the virulence and survival of C. neoformans in the host. To test this idea, we quantitatively identified proteins secreted by C. neoformans in the context of regulated expression of PKA1. For our initial analysis, we collected supernatant cultures of WT and P GAL7 ::PKA1 strains grown under Pka1-repressed (glucose) and Pka1-induced (galactose) conditions at 16, 48, 72, and 120 h post-inoculation (hpi), and analyzed the samples using quantitative mass spectrometry. The analysis of these supernatant samples resulted in the identification of 164 (54 quantifiable) and 207 (83 quantifiable) proteins under Pka1-repressed and Pka1-induced conditions, respectively (see Additional file 1: Table S1; Additional file 2: Table S2). As shown in Table 1, 23 proteins were identified and quantified under Pka1-repressed and Pka1-induced conditions at the specified time-points. We found that none of the changes in protein abundance between the two conditions were statistically significant (p > 0.05) and therefore, concluded that Pka1 did not influence the abundance of any of the observed proteins under the conditions tested. However, upon comparison of the unique proteins identified under either Pka1-repressed or Pka1-induced conditions, using Gene Ontology (GO) term biological classifications at all time points, we were able to observe overall changes in the secretome profiles under the influence of Pka1 (Fig. 1). Additional differentially expressed proteins may be present in the samples, but we were unable to measure their abundance and they were therefore not included for further analysis. Under Pka1-repressed conditions, the majority of secreted proteins were associated with catabolic and metabolic (33 %), unknown (20 %), and hypothetical (20 %) processes (totaling 73 %), with additional proteins associated with transport (8 %), oxidation-reduction processes (4 %), dephosphorylation (4 %), proteolysis (4 %), glycolysis (4 %), and regulation of transcription (3 %). Conversely, a change in the secretome profile was observed under the Pka1-induction condition. Here, we again observed the majority of proteins to be associated with catabolic and metabolic (26 %), unknown (19 %), and hypothetical (17 %) processes (totaling 62 %). A slight decline was found for proteins associated with transport (from 8 to 6 %), oxidation-reduction processes (from 4 to 3 %), dephosphorylation (from 4 to 2 %), proteolysis (from 4 to 3 %), and regulation of transcription (from 3 to 0 %). However, a greater emphasis was found for proteins associated with glycolysis (from 4 to 6 %), response to stress (from 0 to 8 %), translation (from 0 to 7 %), and nucleosome assembly (from 0 to 3 %). Although, our secretome analysis at specific times did not identify Pka1-regulated proteins, a change toward the secretion of proteins for glycolysis, translational regulation, nucleosome assembly, and the response to stress was observed upon induction of PKA1 expression.
Given that we identified secreted proteins from strains with modulated Pka1 activity, but did not observe any proteins whose abundance was directly regulated by Pka1, we extended our analysis to examine protein secretion at an intermediate time point of 96 hpi, and we used an alternative, less stringent method for protein precipitation (EtOH/acetate). We chose an end-point collection time of 96 hpi based on our coverage of a range of other time points in the previous analysis and because this time was sufficient for the culture to reach stationary phase and to accumulate proteins in the extracellular environment. Additionally, because we did not observe changes in protein abundance under regulation of Pka1 following the time-point analysis, we used the alternative protein precipitation method in an attempt to obtain a more comprehensive view of the secretome. We collected supernatant cultures of WT and P GAL7 ::PKA1 strains grown under Pka1-repressed (glucose) and Pka1-induced (galactose) conditions at 96 hpi and analyzed the samples using quantitative mass spectrometry. Similar trends in protein abundance were observed for the majority of proteins in both experimental approaches (EtOH and TCA/acetone precipitation) (see Additional file 3: Table S3) . Although the variability of the time-point analysis was relatively high, the reproducibility observed from the end-point analysis suggested that collecting the samples at different time-points impacted the protein abundance and contributed to the observed variability. This impact may be associated with culture sampling, as well as changes in capsule production during the early- to mid-log growth phases of the fungal cultures . We identified 61 proteins under Pka1-repressed conditions of which 34 were successfully dimethyl-labeled and quantified (Table 2; see Additional file 4: Table S4). These 34 proteins covered a broad spectrum of biological classifications (17 categories) for GO terms, including proteins associated with catabolic and metabolic processes, ubiquitination, transport, dephosphorylation, glycolysis, oxidation-reduction, translation, proteolysis, and the response to stress. Under Pka1-induced conditions, we identified 38 proteins, of which 21 were successfully dimethyl-labeled and quantified (Table 3; see Additional file 5: Table S5). These 21 proteins covered 11 biological classifications for GO terms and included proteins associated with catabolic and metabolic processes, along with ubiquitination, transport, dephosphorylation, oxidation-reduction, proteolysis, and the response to stress. In total, 17 proteins were present under both Pka1-repressed and Pka1-induced conditions. A comparison of changes in abundance under Pka1-repressed and Pka1-induced conditions of these 17 proteins revealed that five showed statistically significant differences (p-value < 0.05, Student’s t-test) in abundance in response to regulation of Pka1 (Fig. 2). We concluded that the extracellular abundance of these five proteins was influenced by PKA and we focused our subsequent analysis on these proteins. Under Pka1-induced conditions, a cytokine-inducing glycoprotein (Cig1), an α-amylase, a glyoxal oxidase, and a novel protein (CNAG_05312) each showed an increase in abundance, whereas an acid phosphatase (Aph1) showed a decrease in abundance. Taken together, these findings suggest that Pka1 regulates the extracellular abundance of specific proteins secreted by C. neoformans.
Based on our identification and quantification of 192 proteins in the secretome of C. neoformans, we next sought to classify the corresponding genes according to their GO terms of biological process, cellular component, and molecular function. Our goal was to assess whether subsets of genes showed significant over-representation relative to all genes in C. neoformans. To perform the enrichment analysis, all unique proteins identified under Pka1-repressed conditions were combined into a single data set as were proteins identified under Pka1-induced conditions. As shown in Fig. 3, the identified secreted proteins under Pka1-repressed conditions were enriched in 15 biological categories, with the most significant enrichment associated with carbohydrate metabolic process, catabolic process, generation of precursor metabolites and energy, organic substance metabolic process, and primary metabolic process. Under Pka1-induced conditions, enrichment was only associated with the five most significantly enriched categories under Pka1-repressed conditions. Classification by cellular components showed the most significant enrichment associated with the cytoplasm under both conditions, which may be an artifact of the classification process or indicative of the location of protein synthesis (see Additional file 6: Figure S1), whereas classification by molecular function showed no enrichment.
Our gene sets were also compared to all reported secreted proteins in the Fungal Secretome Knowledge Base (FunSecKB) for C. neoformans strain JEC21 [31, 32]. The analysis showed no significant enrichment; however, similarities among the identified GO terms were observed (Fig. 4). Forty-seven GO term categories were shared between the FunSecKB and our identified proteins under Pka1-repressed and Pka1-induced conditions; the greatest number of proteins being associated with metabolic processes. Twenty-five categories were represented only in our secretome data, and one category (GO:0009607; response to biotic stimulus) was represented only in the FunSecKB. Upon comparison of GO term categories for cellular components, 16 categories were shared between the FunSecKB and our identified proteins under Pka1-repressed and Pka1-induced conditions; the greatest number of proteins being associated with the cell, cytoplasm, and intracellular categories (see Additional file 7: Figure S2). Upon comparison of GO term categories for molecular function, 17 categories were shared between the FunSecKB and our identified proteins under Pka1-repressed and Pka1-induced conditions; the greatest number of proteins associated with binding as well as enzyme activity (see Additional file 8: Figure S3). Taken together, the enrichment analysis of our secretome data under modulation of Pka1 activity compared to the whole genome showed over-representation of genes associated with a broad spectrum of processes including metabolic and catabolic processing. Although no enrichment was observed between our secretome data and the FunSecKB, a comparison of GO terms between the data sets showed all but one of our identified proteins to be represented in the FunSecKB.
We next examined the secreted proteins, under modulation of Pka1 activity, for the presence of predicted signal peptides and GPI anchors. Specifically, we used SignalP 4.1, Signal-3 L, and Phobius for the prediction of protein extracellular location based on the presence or absence of N-terminal signal peptides. The presence of a signal peptide suggests conventional secretion versus potential non-conventional export if a signal peptide is absent. Additionally, we used GPI-SOM to predict the presence or absence of a GPI-anchor on proteins, indicative of plasma membrane association, which may or may not be capable of dissociation and subsequent protein secretion. Of the 61 proteins used for this analysis, 14 had both an N-terminal signal peptide and a GPI-anchor protein, 17 had only an N-terminal signal peptide, one had a GPI-anchor but no N-terminal signal peptide, and 29 proteins did not have an N-terminal signal peptide or a GPI-anchor (Table 4). Taken together, these results suggest that C. neoformans may employ a non-conventional secretory pathway for regulation of part of its secretome, including potential protein secretion via vesicle export .
Based on our identification and quantification of five secreted proteins regulated by Pka1 in C. neoformans, we evaluated whether transcript levels were also influenced by Pka1 regulation and whether there was a correlation with the observed regulation of protein abundance. Specifically, we performed qRT-PCR on RNA collected at 16 and 96 hpi from cells grown in Pka1-repressed and Pka1-induced conditions for the WT and P GAL7 ::PKA1 strains, and compared the observed values to our quantitative proteomic results at 96 hpi. Figure 5 summarizes the RNA expression levels at 16 hpi and 96 hpi and protein abundance at 96 hpi for Cig1, the acid phosphatase Aph1, an α-amylase, a glyoxal oxidase, and a novel protein (CNAG_05312). Cig1 and the novel protein both showed down-regulation of their transcripts under Pka1-repressed conditions at 16 and 96 hpi, followed by minimal or slight up-regulation with induced Pka1 activity. α-Amylase and glyoxal oxidase showed an initial peak in transcript levels at 16 hpi, followed by minimal change or a decrease in RNA levels at 96 hpi under Pka1-repressed conditions, and the transcript levels decreased in response to Pka1 induction. Acid phosphatase showed elevated transcript levels upon PKA1 repression at both time points, compared to a drop in RNA levels at 16 hpi or no change at 96 hpi upon induction of PKA1. In general, Pka1 appears to positively regulate the transcript levels of Cig1 and the novel protein (CNAG_05312), and to negatively regulate the transcript levels of the other three proteins. Taken together, our results suggest that although Pka1 activity influences the transcript levels and extracellular abundance of the five proteins, a correlation between transcript and protein levels was not always observed, and this was particularly notable for glyoxal oxidase. The differences may indicate additional levels of potential influence of Pka1 beyond transcriptional regulation, including differences in mRNA versus protein stability, the timing of expression and the regulation of protein export. For example, more detailed studies will be needed to examine the timing of intracellular and extracellular accumulation of the glyoxal oxidase protein relative to transcription of the gene.
Based on our identification of five Pka1-regulated proteins, including two with roles in virulence, we hypothesized that these proteins would be secreted during infection and that they might be potentially useful biomarkers of cryptococcosis. To test this idea, we used Multiple Reaction Monitoring (MRM), a powerful and targeted proteomics approach for the relative quantitative measurement of target proteins. In the presence of an internal standard, a stable isotope-labeled peptide, the amount of natural protein can be measured by comparing the signals to the labeled species. The isotopically labeled, proteotypic peptides terminate with C-terminal heavy arginine or lysine (C-term Arg U-13C6;U-15N4 or Lys U-13C6;U-15N2). In principle, the stable isotopes have the same physiochemical properties as the natural peptides and only differ by mass resulting in co-elution of the peptides. However, studies have suggested that in the presence of complex biological samples, such as blood or serum, the retention times between the peptides can shift, impacting the co-elution patterns . We specifically applied MRM to detect Cig1, Aph1, glyoxal oxidase, α-amylase, and the novel protein (CNAG_05312) in samples from a macrophage-like cell line and from infected mice.
The samples from the J774A.1 macrophage-like cell line came from cells inoculated with WT and P GAL7 ::PKA1 strains under Pka1-repressed (DMEM medium supplemented with glucose) and Pka1-induced (DMEM medium supplemented with galactose) conditions. Intracellular uptake at 2 hpi showed a significant difference in the number of colony forming units (CFUs) per macrophage between the WT and P GAL7 ::PKA1 strains under Pka1-repressed conditions, but not under induced conditions (Fig. 6a). This difference is most likely due to the absence of the capsule for the Pka1-repressed cells, a phenotype that enhances phagocytosis. By 24 hpi, rates of intracellular fungal cells per macrophage were significantly different for WT and P GAL7 ::PKA1 strains under both conditions (Fig. 6c). Specifically, intracellular rates of infection at 24 hpi in repressed conditions were 11.49 ± 2.11 % for the WT and 55.67 ± 12.76 % for P GAL7 ::PKA1 strains. However, intracellular rates under induced conditions were 9.06 ± 2.91 % for WT and 1.97 ± 0.82 % for P GAL7 ::PKA1 strains. Importantly, intracellular uptake rates showed no differences between WT, P GAL7 ::PKA1, and the pka1Δ strains under controlled growth conditions (DMEM – high glucose (0.45 %)) at 2 and 24 hpi (Fig. 6b, d). These results indicate that modulation of PKA1 expression influences the intracellular survival of cryptococcal cells.
MRM on macrophage lysates infected with fungal cells at 24 hpi identified the Pka1-regulated and secreted proteins α-amylase and glyoxal oxidase in both induced and repressed conditions. Figure 7 shows representative chromatographic co-elution patterns of the isotopically-labeled and natural peptides, which allowed for relative quantification of peptides in the replicates of the experiment. For both enzymes, the highest amount of protein was detected in the WT strain in DMEM medium under Pka1-repressed conditions, whereas the P GAL7 ::PKA1 strain under Pka1-induction showed the lowest amount of secreted protein. This observation may be associated with reduced intracellular rates of the P GAL7 ::PKA1 strain due to the presence of an enlarged capsule. Overall, we were able to detect 29.8 ± 37.0 fmol of α-amylase and 149.1 ± 130.0 fmol of glyoxal oxidase in 5 μg of total protein from the macrophage lysate following the uptake of P Gal7 ::PKA1 under Pka1-induced conditions at 24 hpi.
The samples from infected mice included BAL and blood from animals inoculated with the WT strain. Three mice were selected for each type of in vivo analysis based on previous studies of cryptococcosis [34–37]. Representative chromatograms of isotopically-labeled and natural peptides detected in mouse BAL are presented in Fig. 8. The MRM analysis identified Cig1, α-amylase, glyoxal oxidase, and the novel protein (CNAG_05312) in BAL following infection with WT cells. In 5 μg of total protein, glyoxal oxidase was the most abundant protein with detection at 779.5 ± 436.1 fmol, followed by the novel protein (CNAG_05312) at 451.0 ± 90.5 fmol, Cig1 at 291.3 ± 54.5 fmol, and α-amylase with the lowest abundance at 40.1 ± 9.4 fmol. Lastly, we were able to detect Cig1, glyoxal oxidase, and the novel protein (CNAG_05312) in blood. Representative chromatograms of the isotopically-labeled and natural peptides detected in mouse blood are presented in Fig. 9. Again, glyoxal oxidase was the most abundant protein detected at 319.4 ± 272.7 fmol, followed by Cig1 at 62.0 ± 17.4 fmol, and the novel protein (CNAG_05312) at 3.1 ± 3.8 fmol in 5 μg of total protein. Aph1 levels were below the limit of detection in all samples. Taken together, our targeted proteomics approach identified and quantified the Pka1-regulated secreted proteins as potential biomarkers following host challenge with cryptococcal cells.
The secretion of extracellular enzymes and virulence-associated factors is important for the proliferation and survival of pathogens in the host environment. For the pathogenic yeast C. neoformans, virulence depends to a large extent on the export of polysaccharide to form a capsule, as well as targeted delivery of laccase to the cell wall for deposition of melanin, and secretion of extracellular enzymes [23, 24, 28, 38]. The cyclic-AMP/Protein Kinase A signal transduction pathway plays a key role in regulating these processes but the underlying mechanisms remain to be understood in detail [16, 17]. We therefore used a P GAL7 ::PKA1 strain under Pka1-repressed and Pka1-induced conditions in this study to investigate the influence of Pka1 on the secretome of C. neoformans. Quantitative proteomics allowed us to identify 61 different proteins in the secretome including a subset of five whose abundance was regulated by Pka1. These five proteins include a cytokine-inducing glycoprotein (Cig1), an α-amylase, a glyoxal oxidase, an acid phosphatase (Aph1), and a novel protein (CNAG_05312). We also observed a change in the secretome profile upon induction of PKA1 expression thus establishing a view of the impact of PKA activity on the extracellular protein composition. In general, this analysis highlighted the enrichment of Pka1-regulated biological processes in the secretome, revealed potential targets for conventional and non-conventional modes of secretion, and provided candidate biomarkers for investigating cryptococcosis.
Our analysis revealed a change in the abundance of secreted C. neoformans proteins associated with glycolysis, translational regulation, nucleosome assembly, and stress response over a time course from 16 to 120 h. We speculate that some of these proteins may result from packaging in vesicles known to transit through the cell wall and accumulate in the extracellular environment [24, 39]. In this case, modulation of PKA activity may indirectly influence the proteome of vesicles as a reflection of an impact on the intracellular proteome. This idea is supported by our observed influence of PKA1 modulation on the abundance of the translation machinery because ribosomal proteins, in particular, are abundant in extracellular vesicles . It is also well known that PKA influences the transcription of ribosomal protein genes in other organisms and this influence is conserved in C. neoformans [22, 40]. Our analysis of the intracellular proteome also revealed suppression of ribosomal cellular protein abundance upon induction of Pka1 (Geddes et al., unpublished data). We also observed a connection between Pka1 activation and the abundance of glycolytic proteins. This is interesting in light of previous reports demonstrating the importance of glycolysis for virulence and the persistence of C. neoformans in the cerebral spinal fluid . These findings are consistent with a previous analysis of the transcriptome, which showed that Pka1 influences the levels of transcript for genes involved in glycolysis . Furthermore, the observed influence of Pka1 induction on the secretion of proteins associated with stress response is consistent with observed Pka1 regulation at the transcriptional level. In this context, we identified a heat shock protein 70 (Hsc70-4), which is associated with the response to stress and which was previously localized to the cell surface of C. neoformans . The observed connection between the stress response and Pka1 induction may indicate coordination for facilitation of fungal survival and proliferation during colonization of vertebrate hosts.
The influence of PKA on the abundance of the mannoprotein Cig1 is of particular interest because we previously showed that its transcript is one of the most abundant in cells grown in low iron medium . In addition, the protein is important for iron acquisition from heme and virulence in C. neoformans . We found that the extracellular abundance of Cig1 increased upon induction of Pka1 and that transcript levels and protein abundance were well correlated. CIG1 is positively regulated by the pH-responsive transcription factor Rim101, which in turn is activated by the cAMP/PKA pathway . Therefore, the regulation of CIG1 mRNA and Cig1 protein levels observed upon induction of Pka1 likely reflect regulation by Rim101. This finding is consistent with recent discoveries that Rim101 controls cell wall composition and capsule attachment via an influence on the expression of cell wall biosynthetic genes [46, 47].
In general, a number of proteins associated with cell wall synthesis and integrity, pathogenesis and the immune response were prominent in the secretome of C. neoformans upon modulation of PKA1 expression. These proteins included an endo-1,3(4)-β glucanase and a 1,3-β-glucanosyltransferase, both of which have been previously identified in studies of the extracellular proteomes of C. neoformans and other fungal pathogens such as Histoplasma capsulatum [28, 48–51]. Endo-1,3(4)-β glucanase is located in the surface layers of the cell wall or in the capsule and has roles in metabolism, autolysis, and cell separation [50, 52]. The 1,3-β-glucanosyltransferase is described as a glycolipid protein anchored to the cell membrane in yeasts and may have a role in virulence . Our proteomic analysis also identified chitin deacetylases associated with the formation of chitin and cell wall integrity, and the enzyme laccase, which is responsible for melanin deposition in the cell wall and influences cryptococcal virulence [28, 51, 54–57]. These findings are consistent with our previous transcriptomic analysis, which revealed an influence of PKA on the expression of cell wall associated genes .
We also identified a novel protein (CNAG_05312) with a pattern of mRNA and protein regulation by Pka1 activity that was quite similar to that of Cig1. This novel protein contains a predicted carbohydrate-binding domain and was annotated as a macrophage-activating glycoprotein (reminiscent of the cytokine-inducing glycoprotein designation of Cig1). These observations suggest that further investigation is warranted for this protein in the context of iron acquisition and virulence. This idea is reinforced by the finding that Rim101 also positively regulates expression of the CNAG_05312 gene . Interestingly, the CNAG_05312 gene is also regulated at the transcript level by the transcription factor Gat201 that, like Pka1, influences capsule size, virulence, and uptake by macrophages [58, 59]. Considering these similar phenotypes, it is possible that Gat201 and Pka1/Rim101 both regulate the expression of the CNAG_05312 protein and subsequently influence the activation of macrophages during infection. Overall, our investigation of the secretome reinforced connections between modulation of Pka1 activity, Rim101 and cell wall integrity, and it revealed an impact of PKA on the extracellular abundance of proteins with known (Cig1) and potential (the novel CNAG_05312 protein) influences on virulence.
Pka1 also positively regulated the abundance in the secretome of an α-amylase and a glyoxal oxidase which were previously identified in the extracellular proteome of C. neoformans [28, 51]. Amylases are associated with carbohydrate metabolism, particularly starch degradation for energy production . In C. neoformans, the secretion of amylases in the PKA-regulated strains was reported previously and we were able to measure and confirm α-amylase activity in the extracellular medium . Glyoxal oxidases are extracellular H2O2-producing enzymes associated with cellulose metabolism . There is evidence that glyoxal oxidase activity is involved in filamentous growth and pathogenicity of Ustilago maydis, as well as fertility in Cryptococcus gattii [61, 62]. A similar pattern in response to PKA1 expression was observed upon comparison of the transcript and protein levels for both the α-amylase and the glyoxal oxidase. A direct correlation between transcript levels and protein abundance was not as evident as for Cig1. This could potentially be due to post-transcriptional regulation, differences in mRNA and protein half-lives and issues with timing . It is also possible that PKA may regulate additional processes to influence extracellular protein abundance, such as the activity of the secretory pathway. Overall, the secretome data revealed a new connection between PKA regulation and the α-amylase and glyoxal oxidase enzymes, and this discovery indicates that further analysis of their potential roles in virulence is warranted.
The extracellular abundance of the acid phosphatase Aph1 and its transcript levels were negatively regulated by induction of PKA1 expression thus revealing an opposite pattern of regulation compared with the other four genes. Phosphatases have been predicted to have roles in cell wall biosynthesis, cell signaling, phosphate scavenging, and in adhesion of C. neoformans to epithelial cells [24, 28, 64–67]. The APH1 gene was recently characterized and its expression was found to be induced by phosphate limitation; the Aph1 protein was also the major conventionally secreted acid phosphatase in C. neoformans . Aph1 was also shown to hydrolyze a variety of substrates to potentially scavenge phosphate from the environment, and an aph1 deletion mutant had a slight virulence defect in both Galleria mellonella and mouse models of cryptococcosis. The latter phenotype is consistent with our recent study showing that a high affinity phosphate uptake system is required for growth on low-phosphate medium, for formation of the virulence factors melanin and capsule, for survival in macrophages, and for virulence in mice . This study also revealed that defects in PKA influence the growth of C. neoformans on phosphate-limited medium. Our discovery of PKA regulation of Aph1 abundance in the secretome therefore further reinforces a connection between phosphate acquisition and PKA regulation associated with virulence.
Our profiling of the secretome upon modulation of Pka1 activity confirmed the presence of previously identified extracellular and vesicular proteins, including those associated with virulence and fungal survival within the host, as well as novel secreted proteins. We identified the classically secreted C. neoformans protein, laccase, associated with fungal virulence, but other proteins such as urease and phospholipase B were not identified in our study. Their absence could be attributed to growth conditions, precipitation methods, supernatant collection times, and relative abundance in the secretome. A recent proteome study that removed free capsular polysaccharide from the extracellular environment identified 105 secreted proteins and a direct comparison with our study showed an overlap of 52 % . Previous investigation of the proteins in extracellular vesicles of C. neoformans also showed an overlap of nearly 56 % with proteins identified in our study [24, 39]. This overlap is primarily associated with proteins not typically expected in the secretome. For example, ATP subunits/carriers, translation elongation factor, actin, and multiple ribosomal proteins were identified and their presence was attributed to packaging in extracellular vesicles, and not necessarily due to direct secretion. In the absence of an N-terminal signal peptide, proteins may be exported via non-conventional secretion. This may include the use of membrane-bound, extracellular vesicles capable of traversing the cell wall, the possible fusion of multi-vesicular bodies with the plasma membrane, or the capture of cytosolic material to form vesicles (blebbing), as discussed above [23, 24, 69–72]. Taken together, our profile of secreted proteins in C. neoformans is in agreement with previous secretome studies. However, our ability to modulate Pka1 activity provides an opportunity to identify novel proteins in the extracellular environment as well as identify proteins specifically regulated by Pka1. This approach led to the unique identification of the novel secreted protein (CNAG_05312) that was specifically associated with modulation of Pka1 activity and not found in other proteomic studies.
Biomarkers are indicators of normal or pathogenic processes as well as the efficacy of therapy . In this regard, targeted detection of secreted cryptococcal proteins provides an opportunity to identify potential biomarkers for early diagnosis of infection and to monitor antifungal therapy. Early and rapid diagnosis remains limited for systemic fungal infections, such as those caused by Candida and Aspergillus species, as well as C. neoformans and C. gattii . Biomarkers of infection by specific fungal species would therefore be valuable for identification and for precise measurements of fungal burden. A recent study using the presence of the cell wall component galactomannan in BAL as a diagnostic tool for invasive fungal disease highlights an opportunity for biomarker discovery in fungal pathogens . Additionally, the use of targeted proteomics (and MRM in particular) is a novel approach to study the secretion of virulence factors in C. neoformans, particularly in the context of signaling functions like PKA that sense conditions relevant to the host environment.
The secreted proteins that we identified to be regulated in abundance by Pka1 provide an opportunity to develop diagnostic biomarkers that are also informative about signaling via the cAMP/PKA pathway in vitro and during infection. For example, Cig1 is an important candidate biomarker given its abundance in iron-starved cells and its role in virulence through iron acquisition and uptake. Our ability to detect Cig1 in the blood and BAL fluid of infected animals confirms its expression and establishes the protein as a potential biomarker. These findings may also indicate a role for Cig1 in iron uptake in these environments although, interestingly, we did not detect Cig1 in macrophage lysates. Based on our observed differences in intracellular replication, Pka1 seems to impact the intracellular environment of macrophages. In this regard, we did detect the glyoxal oxidase and α-amylase proteins by MRM in macrophages containing cryptococcal cells. Expression of these proteins has not previously been reported during interactions with macrophages, although the production of H2O2 and induction of oxidative stress via glyoxal oxidase could potentially influence intracellular survival. It is known that oxidative stress induces autophagy in macrophages and can impair phagocytic activity [76, 77]. Additionally, loss of an α-amylase in H. capsulatum attenuated the ability of the fungus to kill macrophages and to colonize murine lungs . This influence appeared to be related to the ability to produce α-(1,3)-glucan. The regulation of glyoxal oxidase and α-amylase by Pka1 activity and their detection in macrophage lysates suggests that it would be interesting to examine the roles of these enzymes in intracellular survival and virulence. Our approach with MRM is also informative about tissue specific expression of fungal proteins during disease. In addition to the examples described above, we found that colonization of murine lungs resulted in secretion of α-amylase, glyoxal oxidase and the novel protein from gene CNAG_05312. The novel protein was also found in blood and, given its similar regulation with Cig1 these results suggest future studies on the role of this protein in iron acquisition and virulence.
In this study we characterized the overall impact of PKA1 modulation on the secretome and discovered five proteins regulated by Pka1. The identified proteins had known roles associated with cell wall functions, fungal survival within the host, and virulence. Our identification of a novel protein with potential roles in iron uptake and virulence also suggested a previously unknown connection between Pka1 and Gat201. We were also able to detect Pka1-regulated secreted proteins in biological samples as potential biomarkers, providing a new opportunity for diagnosing fungal infection and monitoring disease progression.
The C. neoformans var. grubii wild-type strain H99 (WT) and the P GAL7 ::PKA1 strain with galactose-inducible/glucose repressible expression of PKA1 were used for this study [16, 29]. The strains were maintained on yeast extract peptone dextrose (YPD) medium (1 % yeast extract, 2 % peptone, 2 % dextrose, and 2 % agar). For studies involving regulation of PKA1, cells of the WT and regulated strains were pre-grown overnight with agitation at 30 °C in YPD broth, transferred to yeast nitrogen base medium with amino acids (YNB, Sigma-Aldrich) and incubated overnight with agitation at 30 °C. Cell counts were performed and 5 x 107 cells/ml were transferred to Minimal Medium (MM) (29.4 mM KH2PO4, 10 mM MgSO4 • 7H2O, 13 mM glycine, 3 μM thiamine, 0.27 % carbon source) containing either glucose (MM + D) or galactose (MM + G). For end-point studies, cells were incubated with agitation at 30 °C in MM + D or MM + G for 96 h; for time-course studies, cells were incubated with agitation at 30 °C in MM + D or MM + G for 16, 48, 72, and 120 h. Time points were selected based on previous studies on the timing of protein secretion as well as the analysis of proteins in extracellular vesicles of C. neoformans, which used samples collected at 48 and 72 h of growth [23, 24, 64]. Samples were collected in triplicate for analysis.
To collect supernatant samples, cells were removed by centrifugation at 3,500 rpm for 15 min at 4 °C and the culture medium was transferred to new tubes; this step was repeated four times until all cell debris had been removed. Supernatant samples were kept on ice and total protein concentration was measured by a BCA-Protein-assay (Pierce). Ultrapure bovine serum albumin was used as a calibration standard. In addition to using two approaches for protein precipitation as described below, we also used a combination of sample collection time points (time-point and end-point analyses) to maximize protein detection and obtain a comprehensive view of the secretome. The first approach involved a time-course study in which a stringent trichloroacetic acid (TCA)/acetone precipitation was performed . In brief, an aliquot of culture supernatant (50 μg total protein) was mixed with five volumes of ice-cold TCA/acetone (20 %/80 % w/v) and incubated overnight at −20 °C. Precipitated proteins were collected by centrifugation at 10,000 rpm for 20 min at 4 °C. The pellet was washed four times with ice-cold acetone, air-dried and stored at −20 °C. The second approach, which was less stringent than the TCA/acetone method, was used for the end-point studies and involved ethanol (EtOH)/acetate precipitation . In brief, an aliquot of culture supernatant (50 μg total protein) was diluted with 4 volumes of absolute EtOH, 2.5 M NaCH3COO was used to bring the solution to 50 mM NaCH3COO, pH 5.0 and 20 μg of glycogen was added to the sample. Samples were vortexed and incubated at room temperature for 2 h with periodic agitation. Precipitated proteins were collected by centrifugation at 15,000 rpm for 10 min at 4 °C. The pellet was washed twice with EtOH, then air-dried and stored at −20 °C. All supernatant samples were subjected to in-solution digestion using ACS grade chemicals or HPLC grade solvents (Thermo Scientific and Sigma-Aldrich) . In brief, the precipitated protein pellet was solubilized in digestion buffer (1 % sodium deoxycholate, 50 mM NH4HCO3), incubated at 99 °C for 5 min with agitation, followed by reduction (2 mM of dithiothreitol (DTT) for 25 min at 56 °C), alkylation (4 mM of iodoacetamide (IAA) for 30 min at room temperature in the dark), and trypsinization (0.5 μg/μl of sequencing grade modified trypsin (Promega)) overnight at 37 °C. Based on our results, the TCA/acetone precipitation method appeared to be more stringent, perhaps due to more extensive washing in the protocol.
Digested peptides from supernatants were desalted, concentrated, and filtered on C18 STop And Go Extraction (STAGE) tips . Reductive dimethylation using formaldehyde isotopologues was performed to differentially label peptides from the different experimental conditions. Light formaldehyde (CH2O) and medium formaldehyde (CD2O) (Cambridge Isotope Laboratories, Andover, MA) were combined with cyanoborohydride (NaBH3CN, Sigma-Aldrich) to give a 4 Da difference for labeled peptides . Samples from the WT strain were routinely labeled with light formaldehyde, and P GAL7 ::PKA1 samples were labeled with medium formaldehyde. Briefly, eluted and dried STAGE-tip peptides were resuspended in 100 mM triethylammonium bicarbonate, and incubated in 200 mM formaldehyde and 20 mM sodium cyanoborohydride for 90 min in the dark. After labeling, 125 mM NH4Cl was added and incubated for 10 min to react with excess formaldehyde, followed by the addition of acetic acid to a pH < 2.5 to degrade sodium cyanoborohydride. For each comparison, equal amounts of labeled peptides were mixed and desalted on C18 STAGE tips.
Purified peptides were analyzed using a linear-trapping quadrupole - Orbitrap mass spectrometer (LTQ-Orbitrap Velos; Thermo Fisher Scientific) on-line coupled to an Agilent 1290 Series HPLC using a nanospray ionization source (Thermo Fisher Scientific). This includes a 2-cm-long, 100-μm-inner diameter fused silica trap column, 50-μm-inner diameter fused silica fritted analytical column and a 20-μm-inner diameter fused silica gold coated spray tip (6-μm-diameter opening, pulled on a P-2000 laser puller from Sutter Instruments, coated on Leica EM SCD005 Super Cool Sputtering Device). The trap column was packed with 5 μm-diameter Aqua C-18 beads (Phenomenex, www.phenomenex.com) while the analytical column was packed with 3.0 μm-diameter Reprosil-Pur C-18-AQ beads (Dr. Maisch, www.Dr-Maisch.com). Buffer A consisted of 0.5 % aqueous acetic acid, and buffer B consisted of 0.5 % acetic acid and 80 % acetonitrile in water. Samples were resuspended in buffer A and loaded with the same buffer. Standard 90 min gradients were run from 10 % B to 32 % B over 51 min, then from 32 % B to 40 % B in the next 5 min, then increased to 100 % B over a 2 min period, held at 100 % B for 2.5 min, and then dropped to 0 % B for another 20 min to recondition the column. The HPLC system included Agilent 1290 series Pump and Autosampler with Thermostat; temperature was set at 6 °C. The sample was loaded on the trap column at 5 μl/min and the analysis was performed at 0.1 μl/min. The LTQ-Orbitrap was set to acquire a full-range scan at 60,000 resolution from 350 to 1600 Th in the Orbitrap to simultaneously fragment the top ten peptide ions by CID and top 5 by HCD (resolution 7500) in each cycle in the LTQ (minimum intensity 1000 counts). Parent ions were then excluded from MS/MS for the next 30 s. Singly charged ions were excluded since in ESI mode peptides usually carry multiple charges. The Orbitrap was continuously recalibrated using lock-mass function . Mass accuracy included an error of mass measurement within 5 ppm and did not exceed 10 ppm.
For analysis of mass spectrometry data, centroid fragment peak lists were processed with Proteome Discoverer v. 1.2 (Thermo Fisher Scientific). The search was performed with the Mascot algorithm (v. 2.4) against a database comprised of 6,692 predicted protein sequences from the source organism C. neoformans H99 database (C. neoformans var. grubii H99 Sequencing Project, Broad Institute of Harvard and MIT, http://www.broadinstitute.org/) using the following parameters: peptide mass accuracy 10 parts per million; fragment mass accuracy 0.6 Da; trypsin enzyme specificity with 1 max missed cleavages; fixed modifications - carbamidomethyl, variable modifications - methionine oxidation, deamidated N, Q and N-acetyl peptides, dimethyl (K), dimethyl (N-term), dimethyl 2H(4) (K), and dimethyl 2H(4) (N-term), ESI-TRAP fragment characteristics. Only those peptides with Ion Scores exceeding the individually calculated 99 % confidence limit (as opposed to the average limit for the whole experiment) were considered as accurately identified. The acceptance criteria for protein identification were as follows: only proteins containing at least one unique peptide with a Mascot score > 25 were considered in the dataset. Quantitative ratios were extracted from the raw data using Proteome Discoverer. Proteome Discoverer parameters – Event Detector: mass precision 4 ppm (corresponds to extracted ion chromatograms at ±12 ppm max error), S/N threshold 1; Precursor Ion Quantifier method set for ‘2 labels’ for the formaldehyde labeled samples; Quantitation Method – Ratio Calculation – Replace Missing Quantitation Values with Minimum Intensity – yes, Use Single Peak Quantitation Channels – yes, − Protein Quantification – Use All Peptides – yes.
Experimentally determined fold changes for WT and P GAL7 ::PKA1 strains grown under Pka1-repressed (glucose-containing medium) and Pka1-induced (galactose-containing medium) conditions were converted to a log2 scale and the average fold change and standard deviation were used for analysis. A fold change of >10 was used as a cut-off limit for the time-point and end-point analyses. For the comparative analysis of the time-point samples, the statistical significance of the fold changes of the identified secreted proteins present under both Pka1-repressed and Pka1-induced conditions and at equivalent time points (i.e. 16, 48, 72, and 120 hpi) was assessed for an influence of PKA regulation using a Student’s t-test (p-value < 0.05). For the comparative analysis of the end-point samples, the statistical significance of the fold changes of the identified secreted proteins present under both Pka1-repressed and Pka1-induced conditions was evaluated using a Student’s t-test (p-value < 0.05). To confirm the statistically significant Pka1-regulated proteins identified from the end-point analysis, a multiple-hypothesis testing correction was performed on the secretome data using the Benjamini and Hochberg method with a false discovery rate of 0.05.
Proteins were characterized with Gene Ontology (GO) terms using a local installation of Blast2GO . Gene annotation data of the C. neoformans H99 reference genome were retrieved from the Broad Institute (May 2014) and a copy of the non-redundant (nr) protein database was downloaded from NCBI (May 2014) . The most current associations between the nr protein database and GO terms were retrieved in May 2014 from Blast2GO. GO terms were assigned to WT proteins and filtered using default settings of the Blast2GO pipeline . We performed GO term enrichment analyses for sets of proteins using hypergeometric tests and the Benjamini and Hochberg false discovery rate multiple testing correction (p-value < 0.05) implemented in the R packages GSEABase and GOstats. GO term categories containing singleton entries were excluded. GO categories and enrichment datasets were visualized using the R package ggplot2 . For time-point analyses, GO term classification was performed on unique proteins identified under either Pka1-repressed or Pka1-induced conditions to highlight the overall influence of Pka1 regulation on the secretome profile.
SignalP 4.1 (http://www.cbs.dtu.dk/services/SignalP/) was used to predict whether identified proteins were secreted based on the presence of a signal peptide. Identified protein sequences were also analyzed using Signal-3 L (http://www.csbio.sjtu.edu.cn/bioinf/Signal-3L/) and Phobius (http://phobius.sbc.su.se) to confirm results. Additionally, secreted proteins were analyzed for the presence of a glycophosphatidylinositol (GPI) anchor using GPI-SOM (http://gpi.unibe.ch).
Cells from WT and P GAL7 ::PKA1 strains were prepared for the examination of gene expression by overnight growth in YNB medium followed by dilution to 5.0 x 107 cells/ml in 5 ml of MM + D or MM + G and incubation at 30 °C with agitation for 16 and 96 h. Samples were collected in triplicate for analysis. Cells were collected at the designated time points, flash frozen in liquid N2, and stored at −80 °C. Total RNA was extracted using an EZ-10 DNAaway RNA Miniprep kit (Bio Basic) according to the manufacturer’s protocol. Complementary DNA was synthesized using a Verso cDNA kit (Thermo Scientific) and used for quantitative real-time PCR (qRT-PCR). Primers were designed using Primer3 v.4.0 (http://bioinfo.ut.ee/primer3-0.4.0/) and targeted to the 3’ regions of transcripts. qRT-PCR primer sequences (see Additional file 9: Table S6). Relative gene expression was quantified using the Applied Biosystems 7500 Fast Real-time PCR system. Control genes CNAG_00483 (Actin) and CNAG_06699 (GAPDH) were used for normalization, and tested for statistical significance using the Student’s t-test. As a control, PKA1 RNA expression levels under Pka1-repressed and Pka1-induced conditions in the WT and P GAL7 ::PKA1 strains were also analyzed at various time points to confirm the regulated PKA expression (see Additional file 10: Figure S4).
To confirm qRT-PCR results, total RNA was isolated for the P GAL7 ::PKA1 strain grown in 50 ml of MM + D or MM + G for 16 h. Briefly, cell pellets were collected and flash frozen in liquid N2, followed by overnight lyophilization. One milliliter of buffer 1 (2 % SDS, 68 mM Na3C6H5O7, 132 mM C6H8O7, 10 mM EDTA) was added to the samples, along with 600 μl of glass beads; samples were subjected to bead beating for two, 3 min intervals at power 3 (BioSpec, Mini-Beadbeater) and subsequently stored on ice. Next, 340 μl of buffer 2 (4 M NaCl, 17 mM Na3C6H5O7, 33 mM C6H8O7) was added and samples were inverted several times and incubated on ice for 5 min. Samples were then centrifuged at 15,000 rpm for 10 min, the supernatant fraction was collected and transferred to a new tube, one volume of isopropanol was added, and samples were mixed and incubated at room temperature for 15 min. The pellet was collected following centrifugation at 15,000 rpm for 5 min, and washing of the pellet with 70 % DEPC (Diethylpyrocarbonate)-EtOH was performed. The pellet was collected, air dried, and dissolved in 20 μl of DEPC-H2O. The hybridization probes were prepared with a PCR-amplified DNA fragment of CNAG_00483 (Actin) or CNAG_00396 (PKA1) using specific primers (see Additional file 9: Table S6) and labeled with 32P using an Oligolabeling kit (Amersham Biosciences). Scanned images were analyzed using a Bio-Rad ChemiDoc MP Imaging System (see Additional file 11: Figure S5).
The survival rates of the WT, pka1Δ mutant, and P GAL7 ::PKA1 strains during incubation with macrophages were determined and lysates were prepared for protein analysis . Briefly, cells of the J774A.1 macrophage-like cell line were grown to 80 % confluence in Dulbecco’s Modified Eagle’s Medium (DMEM; Sigma) supplemented with 10 % fetal bovine serum and 2 mM L-glutamine at 37 °C and 5 % CO2. The macrophages were stimulated 1 h prior to infection with 150 ng/ml phorbol myristate acetate (PMA). Fungal cells were grown in YNB overnight at 30 °C, followed by inoculation in MM + D or MM + G at 5.0 x 107 cells/ml. Following overnight growth, the fungal cells were washed with phosphate-buffered saline (PBS, Invitrogen) and opsonized with 0.5 μg/ml of the anti-capsule monoclonal antibody 18B7 in DMEM or DMEM supplemented with 0.20 % glucose or galactose (30 min at 37 °C). Stimulated macrophages were infected with 2.0 x 105 opsonized fungal cells at a multiplicity of infection (MOI) of 1:1 for 2 h and 24 h at 37 °C and 5 % CO2. To measure fungal survival, macrophages containing internalized cryptococcal cells were washed thoroughly four times with PBS and then lysed in 1 ml of sterile dH2O for 30 min at room temperature. Lysate dilutions were plated on YPD agar and incubated at 30 °C for 48 h, at which time the resulting colony forming units (CFUs) were counted and intracellular rates of infection (%) were calculated as the ratio of the CFUs at 2 h and 24 h over the initial number of macrophages. The statistical significance of differences between WT, pka1Δ mutant, and P GAL7 ::PKA1 strains were determined by unpaired t-tests. For proteomic analysis, lysates from infected macrophage at 24 h of incubation were collected, flash frozen in liquid N2 and stored at −80 °C.
Female BALB/c mice (10–12 weeks old) obtained from Charles River Laboratories (Senneville, Ontario, Canada) were used to collect bronchoalveolar lavage (BAL) and blood samples following cryptococcal infection. Three different cultures of C. neoformans WT cells were grown overnight in YPD at 30 °C with agitation, washed in PBS and re-suspended at 1.0 x 108 cells/ml in PBS. For collection of BAL, intranasal inoculation of three mice with 100 μl of the different WT cell suspensions (1.0 x 107 cells) was performed. For collection of blood samples, intravenous inoculation of three mice with 100 μl of the WT cell suspensions (1.0 x 107 cells) was performed. Three mice were selected for the analysis based on established methods for studying fungal burden in mouse models of cryptococcosis [34–37]. At 48 hpi, the infected mice were euthanized by CO2 inhalation and 1 ml of BAL fluid and 500 μl of blood samples were collected from each mouse . Mouse lavage and blood samples were flash frozen with liquid N2 and stored at −80 °C. Mouse assays were conducted in accordance with University of British Columbia’s Committee on Animal Care (protocol A13-0093).
Macrophage lysate samples were prepared as described above, followed by trypsin in-solution digestion. Samples were collected for WT and P GAL7 ::PKA1 strains at 24 hpi in triplicate. Mouse BAL samples were prepared as described above, followed by trypsin in-solution digestion. Samples were collected at 48 hpi following WT inoculation of each of the three mice. For mouse blood samples, highly abundant proteins were removed as previously described . Briefly, proteins were precipitated by the addition of two volumes of acetonitrile and 1.0 % acetic acid, followed by centrifugation at 10,000 rpm for 5 min at 4 °C. The supernatant was collected and evaporated and the residual proteins were then subjected to trypsin in-solution digestion as described above. Samples were collected at 48 hpi following WT inoculation of each of the three mice. Following trypsin digestion, all samples were desalted, concentrated, and filtered on high-capacity C18 STAGE tips.
Skyline (v2.1) was used to build and optimize the MRM method for the relative quantification of peptides . Synthesized peptides for MRM analysis were designed in-house using the following parameters: tryptic peptides, 0 max missed cleavages, minimum of seven and maximum of 25 amino acids, excluding peptides containing Met or Cys residues (if possible) and N-terminal glutamine, hydrophobicity between 10–40 (Sequence Specific Retention Calculator, http://hs2.proteome.ca/SSRCalc/SSRCalcX.html), desirable spectral intensities (GenePattern ESPPredictor, http://www.broadinstitute.org/cancer/software/genepattern/modules), and transition settings selecting for precursor charges of 2 and 3, ion charge of 1, monitoring both b and y ions. SpikeTides labeled with stable isotopes (C-term Arg U-13C6;U-15N4 or Lys U-13C6;U-15N2) were purchased from JPT Peptide Technologies GmbH (Berlin, Germany). N-terminal Arginine (R) and Lysine (K) were labeled with a stable isotope mass of 10.008269 and 8.014199, respectively. Collision energy (CE) and fragmentor voltage (FV) for each peptide was predicted utilizing Skyline software and then confirmed experimentally . Doubly and triply charged precursor ions were optimized and three to five transitions were measured per peptide. The final MRM method included the monitoring of a total of 23 peptides, representing five proteins (see Additional file 12: Table S7). Stable isotope-labeled peptides were resuspended in 100 μl of 0.5 % acetic acid with agitation at room temperature. The peptides were further diluted and combined to result in final concentrations of 100 fmol/μl to 1 pmol/μl of each peptide. Five μl of the peptide mixture was injected into an Agilent 6460 Triple Quadrupole (Agilent) for data acquisition and peptide optimization.
MRM assays were performed on an Agilent 6460 Triple Quadrupole coupled with Agilent 1200 Series HPLC. The instrument was operated in positive electrospray ionization mode using MassHunter Workstation Data Acquisition (v.B.04.04, Agilent). Chromatography was performed on a Large Capacity Chip with 160 nl Trap, analytical column was 150 mm x 75 μm, stationary phase for both trapping and analytical columns were Zorbax-SB C-18, 300 A and 5 μm particles (Agilent). Peptides were separated using gradient elution with a stable flow of 0.30 μl/min, beginning with 97 % buffer A (97 % dH2O, 3 % acetonitrile, 0.1 % formic acid (FA)) and 3 % buffer B (10 % dH2O, 90 % ACN, 0.1 % FA) followed by a step gradient of buffer B from 3 to 80 %, which was achieved at 10.5 min. Subsequent equilibration was performed for 4.5 min at 3 % buffer B. The column was maintained at room temperature during analysis, and the samples were kept at 4-7 °C. The MS was operating in selective reaction mode using electrospray ionization in positive ion mode, with a capillary voltage of 1850 V and a source temperature of 325 °C. Cone voltage was static, collision energies and fragmentor voltages were optimized for each compound individually (see Additional file 13: Table S8). Peak identification was performed using MassHunter Qualitative Analysis (Agilent).
Quantification of natural proteins was performed using peak areas relative to the known amounts of added isotopically-labeled synthetic peptides during a multiplexed MRM run. Natural protein levels were identified in triplicate from the following matrices: WT and P GAL7 ::PKA1 macrophage lysate MM + D and MM + G collected at 24 hpi; BAL collected at 48 hpi from three different mice inoculated independently with the WT strain; and blood collected at 48 hpi from three different mice inoculated independently with the WT strain. Each biological sample was assayed independently in triplicate. Experimentally determined peak areas and the subsequent quantification values were converted to a log2 scale, and the average amount of identified peptide +/− S.D. was reported. Positive association of natural peptides to their respective isotopically-labeled peptides was determined based on co-elution patterns. For positive identification of a natural protein in a collected sample, at least one peptide with a minimum of two transitions must be identified or a minimum of two peptides with at least one transition each must be present.
Enzymatic activity was assayed for α-amylase and acid phosphatase. The assays were performed with kits for both enzymes according to the manufacturer’s protocol (BioVision Incorporated) (see Additional file 14: Figure S6). To confirm that proteins identified in the secretome were a result of secretion and not a product of cell lysis, a PCR was performed on secretome samples from Pka1-repressed conditions for WT strain at 96 hpi. Actin (CNAG_00483) and PKA1 (CNAG_00396) were used as control genes for amplification (see Additional file 15: Figure S7) .
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD002731 and the PASSEL partner repository with the dataset identifier PASS00736.
Mouse assays were conducted in accordance with University of British Columbia’s Committee on Animal Care (protocol A13-0093).
The authors thank J. Choi for strain construction, and M. Kretschmer, J. Gouw, J. Rogalski, and N. Scott for discussions and technical assistance. We also thank D. Oliveira for the collection of mouse samples. This work was supported by an NSERC fellowship to JG, CIHR open operating grants to JWK and LJF, and a Burroughs Wellcome Fund Scholar Award in Molecular Pathogenic Mycology (JWK).
JMHG, LJF, and JWK conceived of the study and participated in its design. JMHG carried out the quantitative proteomic sample preparation, data analysis, and interpretation, the targeted proteomic sample preparation, data analysis, and interpretation, validation studies, and drafted the manuscript. DC performed the GO enrichment analyses. MC performed the macrophage assays. NS provided technical assistance for the quantitative proteomic analysis and data processing. JWK assisted in drafting of the manuscript. All authors read and approved the final manuscript.
Lum G, Min XJ. FunSecKB: the Fungal Secretome KnowledgeBase. Database - the Journal of Biological Databases and Curation. 2011;2011: doi:10.1093/database/bar001.
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Could four handguns have saved thousands of lives?
The short answer is yes. Airplanes are controlled by pilots. Without pilots, airplanes are 150 ton 500mph guided petroleum missiles. We have just seen the potential of aircrafts used as assault weapons.
Let me introduce myself. I am an airline Captain for the worlds second largest airline. I have been flying airplanes professionally for twenty one years. I have dealt with engine failures, aircraft system failures, aircraft navigation equipment failures, Air Traffic Control failures and airline management failures. Through it all, nothing has scared me more in aviation than the people I carry in the back of the plane. Why? Because I have had to deal with drug crazed and drunk passengers, air ragers, and people who are just scared. I have learned that all these people are unpredictable and dangerous. (just the opposite of law abiding gun owners). And now we have a new type of passenger. A diabolical warrior filled with more hate than ten Tim McVeighs.
What about Air Marshals? Not the best idea. An Air Marshal in the back of the aircraft can be identified, distracted and overwhelmed, even if armed. The pilots however have a cockpit door to get through. And a kevlar cockpit door would be a formidable obstacle for anyone to breech. Also, there are over eight thousand flight segments per day in the U.S. The cost of putting an Air Marshall on each flight would be prohibitive. Especially when you have two highly qualified professionals in the nerve center (cockpit) of the airplane who can do the job.
Is it dangerous for pilots to carry guns? No. Pilots are some of the most mentally, physically and psychologically tested people on earth. Additionally we are drug and alcohol tested all the time. We are highly educated, have a unique understanding of how mechanical things work, and have eye/hand coordination second to none. We are also required to undergo rigorous recurrent training and checkrides every nine months. (A great place for firearms requal.) There is no safer group of individuals to issue defensive firearms to.
What about shooting in a pressurized cabin? Will the airplane blow up? No. Do not be fooled by movies showing an explosive decompression in the cabin after a gun is fired. The pressurized fuselage of an aircraft already has many holes in it for regulating pressurization and air flow. The aluminum alloy skin of the aircraft is a quarter inch thick and capable of taking direct hits from most handguns without fracture. Even the cabin windows are incredibly thick and strong and capable of taking hits without failure, especially if using a frangible bullet. Even if they did penetrate the fuselage, several additional small holes would not make any difference in the ability to maintain pressure.
But let's not lose the forest for the trees here. Just remember the scenario that would require gunfire in an aircraft. It would be the last line of defense before turning the aircraft over to a terrorist for him to complete his mission - to kill hundreds or thousands of you.
Fights between pilots in the cockpit? Does not happen. In twenty one years of professional flying with five different airlines, I have never been involved in an altercation with another pilot. I have never even heard of this happening. How many police get into arguments, draw their weapons and kill each other while on duty?
Still do not want guns on airplanes eh? In any given week of flying I will carry one to five armed individuals on my aircraft. They are IRS agents, Postal Inspectors, DEA agents, FBI agents, Secret Service agents, state and local law enforcement, and virtually anyone else authorized by the government to carry a weapon. There is no restriction on the size or type of gun they carry.
All I am asking is to not be defenseless. Give me a fighting chance to save my passengers, crew, aircraft and people on the ground from a psycho or terrorist. Lets close this cockpit loophole.
I am hearing over and over on TV and the radio from elected officials how we are going to have to give up freedom and liberties for additional security provided by our government. This is not acceptable. I have a right to defend my family from harm at home. Why can't I have the same right in my aircraft at work? If we adopt a bunker mentality and start voluntarily giving up freedom, then we have already lost. Let me defend my aircraft and cockpit with the best tools available.
So, would four handguns have saved thousands of people from knife wielding terrorists? Please respond to this letter, and if you agree, please start making demands on your elected officials.
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Why is my cat throwing up food after eating?
Regurgitation, or expelling swallowed food through the mouth, can occur if your cat really loves a new food or competes with other pets in your home at mealtime. Here’s what happens: a cat eats so fast that he or she swallows food without chewing and ingests a lot of air, too. Large pieces of food and air in the stomach will likely come back up. If your cat throws up a whole kibble shortly after eating, regurgitation is likely to blame.
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There is no sound or very low volume from one of the speakers.
Follow the steps below to troubleshoot if there is no sound or very low volume from one of the speakers.
Ensure the speaker balance on the stereo system is set to the center position.
Ensure the speaker wire is connected properly to the back of the stereo system.
If the issue is not resolved, replace the speaker wire.
If the issue is still not resolved, remove the speaker connections from the stereo system.
Connect the right speaker to the left speaker input on the stereo system.
Connect the left speaker to the right speaker input on the stereo system.
If the speaker is now working, but the other speaker now has the problem, then the stereo system requires service.
If the same speaker continues to have the problem, then the speaker is faulty and should be repaired or replaced.
The sound level from the boombox speakers is very low.
The sound from the front left and right speakers is very low.
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How is the Bechdel test supposed to be used (individual or general)?
About four years ago, I first heard about the Bechdel test and didn't really understand what it was because I couldn't find a straight answer. I contacted a good friend of mine about it as she helped me become a feminist in the first place and she is usually very happy answering my questions.
The way she described it to me was that it's basically a test to show whether or not women in movies talk about anything else other then a man. The point being to show the general indicator of how much women are treated in film as tools or rewards for the men and plot rather character as their own right, similar to the women in refrigerators trope.
This is how I saw it for years.
However I keep noticing sites, both feminists and sexists using the test for individual films rather then a general examination. The biggest case of this I've seen was last year with Pacific Rim where were arguing about that film failing despite having one of the most strongest female characters in that years blockbusters. At the time I thought It was non issue as the test doesn't say the film is sexist(bit could be used as a warning sign), just that it doesn't pass the test.
But more and more I see the test being used and argued about for individual films such as the marvel films and gravity or asking which Oscar films pass the test. I see feminist blogs and sites I go to and trust calling it the sexist test and all films should pass despite from my understanding is that many sexist films pass it and that ignores all the times when that can be impossible, feminist or otherwise. The Bechdel test website shows all the films individually and I can see no general indicator (if I'm wrong about that please tell me).
Was I misinformed about the test? Is it suppose to be used individually and not used as a general indicator? If it is supposed to be individually, can't that be potentially be dangerous. After all couldn't a writer just have two women talk about not important and go, "well that me done and off the hook" and use them as tool and rewards for the rest of film? Couldn't only restricting yourself to films that pass a single test also be a bad thing as you will be missing out on great feminist works that because other any reason? I'm so confused.
Also, please call me out if I've been sexist. I've been thinking for a long time now on whether or not I should post this because I didn't know if it was a stupid question.
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Yes, dogs can get allergies just like humans do. Dog allergies are often caused by the allergens found in pollen, animal dander, plants, and insects, but dogs can also be allergic to food and medication as well. These allergies can cause symptoms such as excessive itching, scratching, and grooming; rashes; sneezing; watery eyes; paw chewing; and skin inflammation. In some cases, dogs have conditions, such as atopic dermatitis, that is associated with and may be caused by allergies.
Serologic allergy testing may be performed, but it does not always have reliable results. The quality of this kind of testing often depends on the laboratory which analyzes the results. Intradermal testing, whereby small amounts of test allergens are injected in the skin and wheal (a red bump) response is measured, may also used to identify the cause of your pet's allergic reaction.
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The origin of Kannada language, also known as kannarese, can be traced to the early Christian era. Kannada is one of the most well known Dravidian languages of India. It is as old as Tamil, the truest language of the Dravidian family. It is spoken predominantly in the state of Karnataka in India (one of the four southern states in India), though a significant number of Kannada speaking people can also be found in the other states. A good number of people speaking this language who have migrated from India live in other parts of the world such as USA, UAE, Singapore, Australia, UK, etc.
It stands in the 27th place of the most spoken language in the world and there are about 35 million Kannadigas (Kanadda speaking people) in the world. It is one of the official languages of the Republic of India and the official and administrative language of the Indian state, Karnataka. The earliest inscriptional records in Kannada are from the 6th century. Kannada script which is closely similar to Telugu script in origin. Kannada has a number of regional and social dialects and has marked distinctions between formal and informal usage.
Kannada script originated from southern Bramhi lipi of Ashoka period. With time, it underwent so many changes in the reign of Sathavahanas, Kadambas, Gangas, Rastrakutas, and Hoysalas. A mixture of Telugu-Kannada scripts has been used in Kadambas of Banavasi and the early Chalukya of Badami inscriptions in the west even before the Seventh Century. In the middle of the seventh century a new variety of the Telugu-Kannada scripts was developed. Only in the 13th century, the modern Kannada and Telugu scripts were developed. Other languages like Konkani, Kodava and Tulu use only Kannada script.
The early development of the Kannada language was independent of the Sanskrit influence. However during later centuries, Kannada, like the other Dravidian languages was greatly influenced by Sanskrit in terms of vocabulary, grammar and literary style. As such, Kannada shares a large number of structural features with other Indian language scripts. The writing system of Kannada script includes the principles that governs the phonetics and is a system of syllabic and phonemic writing.
The earliest inscriptional records in Kannada are from the 6th century. We can not determine the origin of Kannada literature from early (pre 800 AD) pieces of work available now. The oldest extant book is king Nripatunga's literary critique Kavi Raja Marga (around 840AD). Jainism was a popular religion at that time and there were some Jaina poets like Srivijaya and Guna Varman. During the 10th century, a new tradition by mixing prose and verse with the campu (an Indian verse form) style was introduced. The poets Pampa, Ponna and Ranna, known as the Three Gems of Kannada literature , extensively wrote on episodes from the Ramayana and Mahabharata and Jain legends and biographies. Then Chavunda Raya wrote the history of all the 24 Jaina tirthankaras (saintly teachers).
Around the 11th century, Kannada literature experienced a setback due to invasion from Tamil kings and only a few literary works could be seen done in this period. The inscriptions of this period illustrate many variations of meters and structural variety. These inscriptions are a wealth of information for historical data, cultural life and study of Kannada language and literature of early times.
In the second half of the 12th century, Jainism was on decline and puranic Veerashaivism was gaining grounds. In the wake of veerashaiva theosophy, a very distinct phase of writing began to gain importance. A spate of literary works in praise of Lord Shiva from famous writers like Harihara, Raghavanka and Kereya Padmarasa, emerged during the 12th and 13th centuries. The Poetess Akkamahadevi is known for her bhakti poetries. However she has advocated strongly against the religious rituals. In the meantime the Jains, too came out with legendary histories of various tirthankaras (propagators). A comparative study of contemporary religions has been done by Samayaparikshe of Brahmasiva ( c. 1150 A.D.) with his emphasis on the superiority of Jainism, the religion he followed. He is a bitter critic of all the other sects and their beliefs. The development of poems, literary criticism, grammar, natural science and translations from Sanskrit literary works is the highlight of the 13th century.
Eminent poets like Bhima Kavi, Padmanaka, Mallanarya, Singiraja and Chamarasa lived in the realm of Vijayanagara kings and have made invaluable contribution to the Kannada literature with their bhakti poetries. The Bhakti movement lasted till the 16th century. The Ramayana, Mahabharata and Puranas were translated afresh using the folk meters, satpadi and regale. Dasa Sahithya, devotional songs of dasas (slaves of the Lord) sung in praise of God, were compiled, which formed an important part of popular literature.
Dramatization of Puranic tales named Yakshagana in musical form, was a novel tradition of late 18th century and this tradition paved way for a number of celebrated creations of folk poetry.
Till late 19th century there was a lull in Kannada literature. Works based on Sanskrit models, like Shakuntala of Basavappa Shastri continued till the late 19th century. The Christian missionaries put in some efforts with which the Academy of Kannada Literature was set up in Bangalore in 1914. Gradually, so many translations were made from English, Bengali and Marathi literature. Apart from the pioneers of novel writing, Kerur and Galaganatha, Shivarama Karanta, K. V. Puttapa, G P Rajaratnam, Basavaraja Kattimani and Nanjanagudu Tirumalamba (the first major woman writer in modern Kannada) are some more eminent novelists worth mentioning.
Nanjanagudu Tirumalamba is the first major woman writer in modern Kannada. Short story writers such as Panje Mangesha Rao and Masti Venkatesha Ayyangar made entry in this period. Kannada poetry soared to a new height with innovative poets like B. M. Shrikanthayya. Institutions like University of Mysore, Kannada Sahitya Parishad, etc. are doing a commendable job in pushing the Kannada literature further.
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What is the difference between disloyal or unloyal?
The adjectives disloyal and unloyal both describe a lack of loyalty. Disloyal is widely regarded as the correct version, but unloyal is also acceptable.
Although unloyal is acceptable, disloyal is universally preferred.
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towards your future in nursing. I asked him the first question. Nursing is limitless, with the only boundaries being set by the beholder. The number one item I have learned from my hospital experience is that I belong in the community promoting health and wellness so patients do not end up in the hospital. It provides personal individualized treatments and working with patients and their families as well as other health professionals to provide the highest quality of healthcare. I began hamlet tragic flaw essay to shadow _ to see first hand the day to day activities of a family nurse practitioner. Nurses in the present would be in way over their heads without them, and nursing assistants should not be taken for granted. My years in the health industry and as a personal trainer have given me skills listen closely to individuals and effectively communicate with others.
Be aware that not every school calls your essay a personal statement.
Allen College, for example, calls it a biographical sketch, and Johns Hopkins University calls it a written expression of goals.
Becoming a Nurse Practitioner through the school will prove challenging and intense, but has the lifelong reward of a career that has meaning and value.
He was volunteering in a hospital working with paralyzed patients. He really had an interest in writing on health and disease. Nursing care required for the prevention of disease and promotion of health, and. Jim was a local resident, and an experienced pilot in the past. Unfortunately they are, and it is Class 11 (High School) My Nursing Home Journey Essay Words: 301 Pages: 1 Paragraphs: 4 Sentences: 20 Read Time: 01:05 The monotonous droning of the machines spilled from the tiny rooms. He worked in Larned, Kansas in a state mental institution for the criminally insane. In medical research there are many deadlines and activities to perform. Nurses are always behind the scenes, making sure everybody is cared for without taking credit for everything they contribute to patient care. He answered, You have to be a good communicator to talk to other doctors and communicate on paper. Thus, I went back to school to obtain my Bachelors of Science Degree in Nursing. Nurses care for people through illness, injury, pain, loss, dying, grieving, birth, growth, aging and health Class 9 (High School) Accountability In Nursing Essay Words: 1204 Pages: 4 Paragraphs: 14 Sentences: 109 Read Time: 04:22 In health care, accountability has become. I believe that the bridge program will provide me with the essential knowledge to not only be a nurse but a primary care professional.
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How do the Titans work in Titanfall 2?
Titanfall 2 is a fast-paced, futuristic shooter where you're backed up by giant robotic mechs. These mechs, known as Titans, come in six varieties, each with its own set of weapons and perks. Here's a quick overview of each Titan to help you decide which one you want to use.
Updated November 30, 2016 to include minor tweaks and the new kits released with the November 30th patch.
All Titans have six different Titan kits to unlock and use. These perks, when combined with your Titan's unique abilities, can make for a powerful machine.
Assault chip: If you like to call down a Titan and let it roam around without you inside, use the assault chip to improve accuracy and to enable your Titan's secondary abilities. Assault chip is immediately available.
Stealth auto-eject: When your Titan is about to explode, you'll eject, invisible, high into the air. Stealth auto-eject is immediately available.
Turbo engine: This gives your Titan one extra dash. If you like to move quickly or you're using a slow Titan, the turbo engine isn't a bad idea. Turbo engine is available immediately.
Overcore: Your Titan starts with a core that's already 30% built. When your core is complete, you get to use a special attack that does a ton of damage. Overcore is available at Titan-level 2 or can be purchased for 5 credits.
Nuclear ejection: When your Titan receives critical damage, you can choose to eject and set off a nuclear explosion that damages all enemy Titans and pilots in the vicinity. Nuclear ejection is available at Titan-level 3 or can be purchased for 5 credits.
Counter ready: When an enemy pilot jumps onto your Titan, you can set off electric smoke to cause them damage. This kit gives you one extra charge of the smoke. Counter ready is available at Titan-level 4 or can be purchased for 5 credits.
When you call in a Titan, a dropship hovers over the map and lets it fall. There are two Titanfall kits you can unlock and use with all Titans.
Dome shield: When your Titan falls, it is enveloped in a shield that protects it from enemy projectiles. Any enemy Titans or pilots who enter the dome receive constant damage. Dome shield is immediately available.
Warpfall: There is a usually a five second delay between you calling in your Titan and it falling to the ground. Warpfall cancels the delay, but you also don't get the protective dome. Warpfall is available at Titan-level 5.
Ion is a Titan that deals low damage, has medium health, and has medium mobility. This is a good Titan for beginners to start with thanks to its rounded stats. Ion is immediately available to all pilots.
Defensive: A vortex shield can be deployed to block and send projectiles back at the enemy.
Scorch is a Titan that does high damage, has high health, and has low mobility. Use this Titan to block off certain areas of the map with damaging thermite. Scorch is immediately available to all pilots.
Primary weapon: The T-203 thermite launcher is a single-shot weapon that launches a thermite grenade. It creates an area of splash damage when it hits something.
Offensive: A firewall is deployed in a straight line toward a target. Any enemies touching the firewall take damage.
Defensive: The thermal shield will melt any incoming projectiles and, if touching an enemy, will cause damage.
Utility: A canister can be launched and will begin emitting gas as soon as it lands. Hit it with some thermite to create a large, fiery area that will kill anything that touches it.
Flame core: Launch a wide thermite wave toward enemies.
Wildfire launcher: The amount of thermite emitted by your primary rifle is upped. Wildfire launcher is available immediately.
Tempered plating: Your Titan is covered in armor that prevents damage from your own thermite. Unlocked at Titan-level 6 or can be purchased with 24 credits.
Inferno shield: Your thermal shield lasts longer and will do more damage when hitting an enemy. Unlocked at Titan-level 7 or can be purchased for 24 credits.
Fuel for the Fire: Use this to make your firewall burn longer. Unlocked at Titan-level 8 or can be purchased for 24 credits.
Scorched earth: Your flame core wave now leaves a wide swath of thermite in its wake.
Northstar is a Titan that deals high damage, has low health, and has medium mobility. Use Northstar on the edges of a map, picking off enemies from afar. It is immediately available to all pilots.
Primary weapon: The plasma railgun is best used at long-range. Charge it up and let loose a powerful shot.
Offensive: Launch a cluster of missiles at your enemy that explode multiple times for high damage.
Defensive: Put down a tether trap that locks Titans in place if they pass over it.
Utility: Use your engines to hover in place — use this to get a better view of your enemy.
Flight core: Take off, hover, and shoot missiles at any enemies within reach.
Piercing shot: Your plasma gun shoots projectiles that pierce through Titans, dealing damage to anyone in its path. Piercing shot is immediately available.
Enhanced payload: When your cluster missiles explode again after the first explosion, they do more damage to a larger radius. Unlocked at Titan-level 6 or can be purchased for 24 credits.
Twin traps: You can throw down two tether traps instead of just one. Unlocked at Titan-level 7 or can be purchased for 24 credits.
Viper thrusters: Your movement speed is increased when you have your flight core enabled. Unlocked at Titan-level 8 or can be purchased for 24 credits.
Threat optics: When you're zoomed in with your rifle, enemies are highlighted for easier target acquisition.
Ronin is a Titan that deals medium damage, has low health, and has high mobility. Use it to get around the map quickly, dealing melee damage to enemy Titans. Ronin is unlocked at pilot-level 7.
Primary weapon: Leadwall is a shotgun that shoots three projectiles in a horizontal line.
Offensive: Launch a wave of energy that slows down enemy Titans while also dealing damage.
Defensive: Use your sword to block incoming enemy projectiles.
Utility: Use phase shifters to quickly move in one direction.
Sword core: Your sword is electrified, dealing more damage and blocking more incoming projectiles.
Ricochet rounds: Your shotgun's rounds will bounce after hitting something, dealing damage to multiple targets in the area. Ricochet rounds are immediately available.
Thunderstorm: You can launch your arc wave twice. Unlocked at Titan-level 6 or can be purchased for 24 credits.
Temporal anomaly: Your phase dash has a shorter recharge time, meaning you can use it more often. Unlocked at Titan-level 7 or can be purchased for 24 credits.
Highlander: Any time you kill an enemy Titan, you'll get more time with your sword core. Unlocked at Titan-level 8 or can be purchased for 24 credits.
Phase reflex: Ronin will phase away from danger when it receives critical damage.
Tone is a Titan that deals medium damage, has medium health, and has medium mobility. This is a great Titan for teamwork thanks to tracking and sonar utilities that reveal enemies. Tone is unlocked at pilot-level 11.
Offensive: Once you have a lock-on, fire your rockets for heavy explosive damage.
Legion is a Titan that deals high damage, has high health, and has low mobility. Thanks to close- and long-range weapon modes, use Legion up close or from afar. This Titan is unlocked at pilot-level 11.
Primary weapon: Legion's minigun, known as the predator cannon, shoots a large number of powerful rounds but has a long spin-up time.
Offensive: Launch a wide power shot that knocks back all enemies at close range, and damage any enemies that are far away but are still hit.
Defensive: Throw up a shield around the barrels of your minigun.
Utility: Choose between either close-range mode or long-range mode depending on your target.
Smart core: You will automatically target enemies while your minigun is up and spinning.
Enhanced ammo capacity: Your minigun holds more ammo. Enhanced ammo capacity is immediately available.
Sensor array: Your Smart core will stay on longer. Unlocked at Titan-level 6 or can be purchased for 24 credits.
Bulwark: Your shield can take twice as much damage before disappearing. Unlocked at Titan-level 7 or can be purchased for 24 credits.
Light-weight alloys: While your minigun is firing, you can move faster. Unlocked at Titan-level 8 or can be purchased for 24 credits.
Hidden compartment: Your power shot can now be used twice before recharging.
Let us know which Titan is your favorite to use in the comment section below!
Don't have Titanfall 2 yet? It's never too late.
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0.985286 |
How do you decide which of two equally qualified writers to hire?
You’ve done your research, and you’ve found two writers who are equally qualified to help you write a proposal to a prospective client. It could result in a million dollars in new business. Which writer do you hire?
Expectations: Do they show that they understand what’s expected of them if they are hired?
Inquisitiveness: Do they ask questions that show they are trying to get a better understanding of your company, your client and your proposal?
Problem solving: You explain to them that your would-be client wants the proposal to address a particular business problem. Do they have a clear understanding of the problem? Can they help you in developing solutions?
There’s a risk in hiring writers for a project such as this proposal. But you can manage that risk by doing research on the writers’ professional qualifications, asking them questions, contacting their clients, reviewing their portfolios and asking others in your organization for their recommendations about hiring a writer.
You’re making an investment in hiring a writer, so put the time and effort in to making the right hiring decision.
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Many people always tell me (as their coach) that they will start doing the right things when they are more ready tomorrow.
Some people say that because currently their career is doing fine, they don't need any coaching or upgrading. Others claimed that their bosses did not intend to promote them (as there are no such promotion opportunities) and as such they have not started to think about learning on their own. "I'll learn when I get there", is what they say.
I'm sure you can recognize this: many people live day by day. They will upgrade their skills when they're feeling confident and good. Since currently there is too much workload to handle, they will wait until tomorrow when things are more stable to pick up learning.
Meet Joe - the person that lives as though there is no tomorrow. Joe makes use of each day to the fullest: he will grab opportunities as they come along. He does not improve himself or embark on self-learning according to his whims and fancies but on a continuous basis.
Joe knows that there is no such thing as a lazy learner, only such thing as an unmotivated learner. How did Joe motivate himself to learn? Joe knows that whatever he does (say read a book), the book does not give rise to anything, but it is what Joe reads in himself when he reads the book that matters.
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Hypnosis is the most effective method known today for giving up cigarettes. If you want to give up then this is the way to do it.
Hypnotists help many smokers on a regular basis to achieve their goal of quitting. It is a well-known area of a Hypnotist's work and usually takes just one long session.
Deciding to become a smoker is not usually a logical decision... its generally an emotional decision taken at a subconscious level. It makes sense that any decision to stop needs to be taken by the subconscious too. In a nutshell that is why hypnosis is the most successful way to give up smoking cigarettes.
Many people thinking about quitting can feel that their true choice is being taken away from them. The secret of Hypnosis and NLP is that they get people to use their imagination to create a non-smoking future that is logical. That actually gives them more choice and makes more sense to them. This feels very positive and empowering. Stopping smoking becomes something to look forward to.
To find the most effective method to stop smoking Frank Schmidt and Chockalingham Viswesvaran from the university of Iowa used a meta-analysis, incorporating the results of more than 600 studies totalling nearly 72,000 people.
By using a combination of Hypnosis and NLP the efficacy is increased even further.
- You will reduce your risk of developing illness, disability or death caused by cancer, heart or lung disease.
- You will reduce your risk of gangrene or amputation caused by circulatory problems.
- You will protect the health of those around you by not exposing them to secondhand smoke.
- You will reduce the chances of your children suffering from asthma or glue ear.
- You will improve your fertility levels and your chance of a healthy pregnancy and baby.
- You will improve your breathing and general fitness.
- You will enjoy the taste of food more.
- You will save money - as much as several hundred pounds a month, if you're a heavy smoker (see below).
- You will no longer smell of stale tobacco.
- The appearance of your skin and teeth will improve.
- You will feel more confident in social situations ... you won't be worrying about the secondhand smoke you create anymore.
- As a non-smoker, you may even find you get approached more often by potential new friends and partners when out socialising.
- Your home will smell fresh and you will no longer be staining your walls with nicotine.
- You will reduce the risk of fire in your home.
A 20 a day smoker would save £3285 a year!
A 30 a day smoker would save £4927 a year!!
A 40 a day smoker would save £6570 a year!!!
As a non-smoker what could you do with all that extra money?
Through a combination of Hypnosis, Neuro Linguistic Programming (NLP) and Behavioural Therapy, we’ll help you to become a non-smoker thats happy, healthy, confident and relaxed. We help you break the connections with smoking, whether they are emotional (such as stress or boredom) or physical (such as after a meal or with a drink) and help you feel great about saying “no” to cigarettes and tobacco.
The reason why this is such a successful method is that we can retrain both the conscious and unconscious parts of your mind at the same time.
The conscious part of your mind helps you to rationalise your old unwanted smoking habit, whereas the unconscious part of your mind holds all your current self-limiting and false beliefs about smoking; like how addicted you are to nicotine; how smoking helps you to relax; and, how hard it's going to be quit.
Through Behavioural Therapy we help you to consciously rethink your habits and how you justify them. Through Hypnosis and NLP we help retrain your unconscious mind to exchange your old unwanted beliefs about smoking for your new set of beliefs and behaviours that are more in keeping with your new smoke-free life.
As part of the process, the main reasons why people tend to return to smoking (the withdrawal mood swings, irritability and cravings) can be replaced with feelings of calmness, relaxation, improved self-confidence, increased energy, vitality and overall happiness.
Usually one long double session with a free follow-up session if needed (within 2 months). This can vary from client to client.
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Learn about typical coursework and prerequisites for a master's degree program in child psychology. See what your career options are and explore online study. Schools offering Child Psychology degrees can also be found in these popular choices.
What Types of Courses Will I Take in a Master's in Child Psychology Program?
Prerequisites for a master's program in child psychology vary depending on the school you choose to attend. Some programs require a bachelor's degree in psychology or child development for admission. Others might admit you with a bachelor's degree in another field of study, as long you've taken enough related undergraduate courses to prepare you for graduate study. Additionally, some schools may require you to earn a minimum score on the Graduate Record Exam (GRE).
What Can I Do With My Master's Degree?
After earning your master's degree, you might go on to participate in a counseling or therapy internship and then gain licensure. Requirements vary from state to state, so be sure to check out licensing requirements for the state where you plan to work. Specific jobs available to you as a master's graduate might include child psychologist, educator, school counselor, clinical researcher or school administrator. You might also consider continuing your education to become a child psychiatrist.
You can find online master's degree programs in psychology; however, it's more difficult to find online psychology programs that specialize in child psychology or development. Additionally, you may not be able to complete a psychology program completely online since most require a psychology internship or clinical observation experience.
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Environmental enrichment is important for dogs as it helps stimulate the brain. Its first application took place in zoos for welfare purposes so to help captive animals cope better in their non-natural environments. Bored animals can’t play a game of Sudoku or engage in thumb-twiddling to keep themselves busy, so they end up engaging in vacuum activities such as restless pacing, stereotyped movements or excessive licking or even destructive behaviors such as chewing and digging. While today there are many resources to help dog owners enrich their dog’s environment, it’s important to involve all of the dog’s senses.
Until the 1970’s, it was common belief among neuroscientists that the brain underwent changes only during the critical period and afterward remained in a relatively “static” state throughout adulthood.
New research (Reference 4) has shown that many aspects of the brain can change even into adulthood, leading to the term “neuroplasticity” (plasticity of the brain).
Research on rats (Reference 1,2) has found that when rats were placed in a richer, more stimulating environment where they were cognitively challenged, the were prone to developing a thicker cerebral cortex with a 25 percent increase in synapses.
Additionally, the increase in synapses seemed to be not short lived. Indeed, another study (Reference 3) revealed that when the number of synapses increased in adult rats, their numbers remained high for 30 days despite the rats being returned to an impoverished environment.
What do the results of this research mean to our dogs? It means that young dogs, adult dogs and most of all, old dogs benefit from environmental enrichment.
For dogs, the focus is adding an element of novelty to an otherwise dull day such as teaching the dog a new trick or providing dogs with safe opportunities to engage in natural, instinctive behaviors without getting in trouble.
It’s great news that today there is a lot of interest in providing dogs with environmental enrichment, but often they fail to fulfill all of a dog’s senses.
Sure, it’s good that many dog owners now invest in food-dispensing toys to keep their dogs mentally stimulated as this is first step towards placing mental stimulation away from the back burner, but a dog’s world entails much more than extracting food from a Kong.
Did you know:? Dogs can quickly habituate to toys if the same toys are seen on a daily basis. This doesn’t mean though that you will have to break the bank and purchase a new toy every day just to make your dog happy! Instead, make it a habit to rotate toys. Keep some toys out of sight for some time and then present them again. After not seeing them for a while, the dog should show a renewed interest in them.
Dogs interact with their world through their main five senses: sight, smell, touch, hearing and taste. To enrich a dog’s life, it’s therefore a good idea to incorporate as many senses as possible. Dog walks are often a stimulating way to offer enrichment as dogs are given the opportunity to hear, see and smell many stimuli. Car rides with the window slightly open to allow a fresh flow or air along with its stimulus package of scents, may also be stimulating for dogs. And of course, play dates with friendly dogs, games of fetch, training sessions and dog sports are all great ways to keep dogs exercised and mentally stimulated. Following are several enrichment ideas to address all senses in dogs.
Trivia: Can you guess How many senses dogs have? Hint: it’s not easy as thought!
Warning: While walks can be optimal for many dogs, dogs who are fearful or reactive dogs may perceive the outdoors as overstimulating. Until their behavior issues can be tackled with the help of a professional, for the time being it might be preferable to manage the environment by frequenting quiet places or the tranquility of the yard.
Play hide and seek games with your dog where you go out of vision and your dog must find you. Teach your dog to discriminate toys based on different shapes and colors (keep in mind though how dogs see colors). Some dogs enjoy watching TV and now there are also TV shows made purposely for dogs.
Sight hounds may enjoy chasing flirt poles, while retrievers may love chasing and retrieving balls. Instead of feeding food from a bowl, why not toss kibble for your dog to catch instead? For dogs who aren’t reactive, access to a window can provide a form of sensorial enrichment. While highly visually stimulating, it’s best to avoid using laser pointers for dogs.
Teach your dog how to play the piano. Play round-robin games using different people (with different tones of voice) and take turns calling your dog and rewarding him for coming. Also, you can have fun and train your dog to come at the sound of a whistle.
For further stimulation when whistle training your dog, teach your dog that different whistle pips and blasts mean different things. For example, use a special pip for meal time and one for going on a walk. When your dog is alone during the day, play CD’S purposely made for dogs such as Through a Dog’s Ear. Also, provide toys that make different noises. Many small terriers may enjoy squeaky toys, but be careful as some dogs ingest the squeakers.
A dog’s sense of touch involves receiving information about his internal and external environment. Dogs can be mentally stimulated by offering them toys of different textures such as soft toys, hard toys, crinkly toys etc. Training the dog to walk on different surfaces (on grass, in a puddle, or on steps) may also be fun if you make it rewarding. Small terriers may enjoy walking through agility tunnels.
Petting our dogs is also a way to provide enrichment. Play games with your family where you take turns calling your dog, giving him a treat while briefly petting him.We are used to petting our dogs, but there are other forms of tactile stimulation such as grooming, massage and T- Touch. Find ways your dog likes to be touched the most. Notice how your dog reacts to your touch.
Canine nose work has been gaining popularity. You can train your dog to discriminate between different scents by using essential oils, but check for toxicity before using certain products. There are specific nose work kits available nowadays.
For dogs who love to dig, bury a toy in in a bag of kibble for a day and then hide the toy in a child’s pool full of sand so your dog must use his sense of smell to find it. Scent hounds may enjoy following trails of kibble hidden around the yard. Certain types of scents can be also calming to dogs such as lavender.
Dogs are known for not having very developed taste buds compared to us, but they benefit from working for their food. Hide portions of your dogs meals around the house, stuff a Kong in different layers made a various types of treats and in the summer make frozen treats. For instance, you can place some water in an ice cube tray and insert in the middle one of your dog’s favorite treat or a couple of kibble. Once the water freezes, the treat will be suspended inside the ice cube so your dog will need to lick the ice-cube to get to it. This is a great way to keep your dog hydrated and entertained!
Veterinary behaviorist Lore Haug also suggests placing vegetables or fruits safe for dogs (apples, carrots, melon, celery) out in the yard or allowing them to float in a wading pool. She warns though to avoid grapes or raisins as they’re toxic to dogs.
Diamond MC, Krech D, Rosenzweig MR (August 1964). “The Effects of an Enriched Environment on the Histology of the Rat Cerebral Cortex”. J. Comp. Neurol.123: 111–20.
Briones TL, Klintsova AY, Greenough WT (August 2004). “Stability of synaptic plasticity in the adult rat visual cortex induced by complex environment exposure”. Brain Res.1018 (1): 130–5.
Livingston R.B. (1966). “Brain mechanisms in conditioning and learning”. Neurosciences Research Program Bulletin4 (3): 349–354.
Texas Veterinary Behavior Specialist, Environmental Enrichment for Dogs, retrieved from the web on July 24th, 2016.
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"Electrophysiological response to omitted stimulus in sentence processi" by Hiroko Nakano, Mari-Anne Rosario et al.
The current study provides evidence that the absence of a syntactically expected item leads to a sustained cognitive processing demand. Event-related potentials were measured at the omission of a syntactically expected object argument in a speech sequence. English monolingual adults listened to paired sentences. The first sentence in the pair established a context. The second sentence provided a response to the first sentence that was either grammatically correct by containing an overt object argument in the form of a pronoun, or was syntactically unacceptable by omitting the expected object pronoun. Event-related potentials measured at the omission of the object argument showed a prolonged positivity for 100–600 ms with a broad scalp distribution, and for 600–1000 ms with a focus in the anterior region. This observed omitted stimulus potential may contain characteristics of the P300 component, associated with the detection of the deviation of an expected stimulus, and the classical P600 related to syntactic reanalysis. Further, the late anterior P600 may indicate an increased memory demand in sentence comprehension. Thus, this linguistic omitted stimulus potential is a cognitive indicator of language processing that can be used to investigate the organization of linguistic knowledge.
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Music in Anglo Saxon England was a fairly significant part of social life. Two distinct types of music existed in Anglo-Saxon society, namely music associated with religious services, and secular music played on other occasions. The first type of music was usually composed and played by church composers at different religious occasions.
This was also the type of music to which most of the commoners had access to and would occasionally enjoy carol dancing in churchyards. The secular type of music was most typically played at the frequent feasts which were thrown by the Anglo-Saxon nobility. Music was also played by the poets in Anglo-Saxon England. Extant historical sources reveal that a wide range of musical instruments were used in the Anglo-Saxon society.
During the Anglo-Saxon rule in Britain which lasted from the 5th century until the 11th century, a wide range of instruments were used in England. During the early Anglo-Saxon days, more rudimentary instruments were used which had native Breton-Celt origins or Germanic origins. Towards the subsequent centuries, Anglo-Saxons came to admit significant influence from Continental Europe and consequently, many contemporary European musical instruments reached Anglo-Saxon England as well.
According to extant sources, a quadrangular instrument with multiple strings called crot or cytere by the Anglo-Saxons was popular in England. Towards the 9th and 10th centuries, this instrument was replaced by a harp. Both harps and cyteres have been found in the discovered Anglo-Saxon burials, underlining their significance.
Wind instruments such as horn were being used in Anglo-Saxon England by the 10th century. And by the 11th century, Anglo-Saxon music utilised a vast variety of instruments including the rebec, flutes, drums, bells and panpipes.
Music was a regular part of Anglo-Saxon feasts where soft music was played during dining to aid in digestion while more jovial music was later played by the guests assembled. In fact, it was a common tradition among the Anglo-Saxons for all guests on a feast to come together and then play the harp one after the other. Male members of the Anglo-Saxon nobility were expected to know how to play the harp and their failure to do so occasioned embarrassment at events such as a feast.
Anglo-Saxon music was produced between 5th and 11th centuries in England.
Two types of Anglo-Saxon music existed in medieval England: religious music and secular music.
The golden age of Anglo-Saxon music arrived in the 10th and 11th centuries when Anglo-Saxon poetry flourished and many instruments became available.
Secular Anglo-Saxon music utilised a wide range of stringed, percussive and wind instruments.
Secular Anglo-Saxon music was frequently played at the grand feasts thrown by Anglo-Saxon nobles.
There is some evidence in historical sources that like the music traditions in many other parts of the medieval world, poets in Anglo-Saxon England frequently made use of an instrument to accompany their poetry recitals. Poetry comprising of heroic ballads and epic historical narratives was common in Anglo-Saxon England and the poets probably used harp’s or some other stringed instruments when reciting their compositions to a crowd.
Once the Church began to exercise significant influence over the Anglo-Saxon society, music became more and more associated with religious services. As a result, secular music especially one which could induce different emotional states was looked upon with suspicion by the Anglo-Saxon ecclesiastical offices. Despite this, music remained strongly associated with Anglo-Saxon tradition of feasting as well which ensured that secular music would survive despite the Church’s disapproval.
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Pernichev Welcome! Nice talking to people who develop solutions.
Could you briefly explain what differentiate your product from f.lux which I am currently using?
Also, there is a lot of talking about temporal dithering. I cannot find the discussion now, but I recall reading that f.lux could potentially exacerbate eyestrain from dithering. Is there any effect of Iris on dithering? Thanks.
Pernichev I've never used Iris, but I think the product itself is good (an improved software based blue-light filter, with it's own trade offs), but I'm not a fan of your licensing scheme. $15 isn't bad but I have multiple computers across several operating systems that I use on a daily basis.
My 2 cents: I am not sure blue light filtering is the best direction to go in, as flux already does this for free, and PWM free monitors are now common place - though a laptop solution would be welcomed. If you want to get my money, software that stops temporal dithering for AMD or Nvidia graphics cards, or android phones would do it.
Are you familiar with Suguru Kawamoto's work? he created software that prevents modern intel integrated GPUs from dithering, something I rely on to use computers comfortably. However I understand that without recognition that such things are problem, marketing this software would be difficult.
Item 7-9 are applicable to everyone, but I believe most of us are here is because of 1-6.
To complicated matters, a smartphone/laptop/PC that is causing eye strain, it could have a combination of items from the list. For example, one laptop could have multiple sources of eye strain e.g. PWM, intel graphics driver, dithering etc, while another laptop only has PWM.
To further complicate matters, a person may get eye strain from one, or from multiple items from the above list. Plus a person may know some of the items in the list causes them eye strain, but may not know if others items causes them eye strain or not.
So to solve an eye strain problem for someone, say Person A, first need to know how many items from the list would Person A get eye strain from. Then need to look at the device (smartphone/laptop/PC). The device has how many of the items in the list? Then need to eliminate the cause of the eye strain one by one.
Take me for example, I get eye strain and headaches from item 1, 2, 5 and 6. These are what I know. So if I use a laptop that has PWM, and newer intel graphics driver, then I would get eye strain. For me to use a laptop without eye strain, I need to choose a laptop that has no PWM, has older intel graphics driver, and older version of Windows 10. If I buy a laptop with just no PWM, I will still get eye strain if the laptop is using newer version of intel graphics driver. The laptop still have other causes of eye strain that is affecting me.
So if a person says to you, hey I tried your Iris software on my PC but it still giving me eye strain. Maybe that person is effected by other causes of eye strain in the list. Getting rid of just one cause of eye strain (e.g. blue light), will not get rid of the eye strain if that PC still has other causes of eye strain such as PWM, dithering etc. Need to get rid of all the causes of eye strain from the device that that particular person has, before the eye strain can be eliminated.
PWM is mostly hardware. But dithering is software and hope you can find a way to get rid of it. Other things like intel graphics driver, we still dont know what exactly in these drivers that is causing the eye strain. Intel investigated for over 2 years+, then gave up and stopped investigating. So unknown factor x still remains unknown.
Any efforts you and your company can do to find the root cause of these eye strain, and find ways to solve it, would be greatly appreciated. Right now you already have a solution for one of the items in the list, which is blue light. If you can find the solution for one or two of other items in the list, that would give a huge positive impact to many of us here.
Something that'd be great would be to disable temporal dithering (especially Intel's) for all Windows, Linux, and Mac.
I'd love to hear how ... software ... can remove PWM and blue light.
Gurm I've heard of Intel PWM Control software before where the PWM is raised very high. I think some people are affected even when PWM is high, but less so, so that is one possible software change.
AGI Also, there is a lot of talking about temporal dithering. I cannot find the discussion now, but I recall reading that f.lux could potentially exacerbate eyestrain from dithering. Is there any effect of Iris on dithering? Thanks.
I'd assume so because it's altering the displayed colors, and the colors that f.lux/Iris use are outside of the standard color gamuts.
AGI I personally find Iris more advanced, for example, it can auto change your blue light value based on time of day/night in where you live in by using approximation (basically taking the city/country you live in), while flux is only locked to the position of the sun and uses geolocation which takes your exact coordinates and feels like a privacy issue for me.
Guys this product in it's current form is not going to solve our eyestrain. Blue light is not causing eye strain. It's possibly messing up circadian rhythm based on some studies and common sense. This application is likely just changing tint like F.lux and Redshift, and messing with brightness to stop PWM. Most likely by running the true backlight at 100% so no PWM is present and then using overlays/gamma games or some other thing to software dim. I have seen other people talk about doing this with other products but cannot remember their names. The general public is just now becoming aware of the "blue light" scare so we can expect to hear more and more about it. It can definitely affect your sleep cycle with late exposure, but its not causing eyestrain or else sunlight would be making people have strain all day long, and is without a doubt a red herring for overuse, dithering or whatever else is at the root for that person.
@AGI F.lux/Redshift mess with gamma settings and some people have said doing so HELPS and some HURTS so no idea what that is about. Maybe IF dithering is an issue those changes trigger/block it in certain instances. Personally it doesn't effect me either way and a bad device is still bad. This product likely fiddles with gamma as well because anything affecting color or color profiling will, but they can speak to that.
hpst I mentioned it at a previous reply but right now we are trying to solve the temporal dithering. I wouldn't say that our company is about following the money and ripping off clients, as a matter of fact, we try to help every client and make them happy.
Seagull I'm doing some of my own research at the moment related to this. Don't have anything to share yet and I'm busy with university as well.
Pernichev Thanks on reply and link.
I found out about dithering on this website. From the little I understand it is not universally acknowledged to be a problem, as flickering or blue light. The big guys in the electronics industry would probably say ours are just speculations. You are working on eliminating such a feature though. Could you disclose why you believe it is a source of eyestrain?
Well that is certainly good news. Is your dithering solution going to be available for Linux? What is the basic theory you are chasing to toggle dithering? As I have been told it would require drivers for each vender to be altered. Do you have a time frame?
My comments were born of cynicsm and lots of negative experiences combined with misery from this problem. My apologies if it felt personal. That said many of us are desperate enough to be held ransom and pay whatever one might charge, but if there is a solution forthcoming I'd prefer to see it be open sourced and not a proprietary product. I have no problem donating, paying, or putting up bounties...but I do not like closed software that makes me dependent on you forever since companies come and go and this matter is too important of an accessibility issue to hinge on one "secret sauce" that may or may not be there long term for us if nobody can fork it, continue development etc. Personally the dithering solution is the only bit I am interested in and I wouldn't use the other existing features.
Pernichev If you could do a lifetime multi PC subscription (I think $50 is reasonable given how there is a trial and all) I think that would be a better product.
JTL can you message me over at [email protected] so we can talk?
I actually think that with the PWM Flicker removal you eliminate most of the eye strain anyway, enough to make it a pleasant experience. What we want from Iris is to be the best possible when it comes to saving eyes so that's why we are going to try adding it right now.
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Context. Dust grains forming in the extended atmospheres of AGB stars are critical for the heavy mass loss of these cool luminous giants, as they provide radiative acceleration for the stellar winds. Characteristic mid-IR spectral features indicate that the grains consist mainly of silicates and corundum. The latter species seems to form in a narrow zone within about 2 stellar radii, preceding the condensation of silicate dust, which triggers the outflow. Recent high-angular-resolution observations show clumpy, variable dust clouds at these distances.
Aims. We explore possible causes for the formation of inhomogeneous dust layers, using 3D dynamical simulations.
Methods. We modeled the outer convective envelope and the dust-forming atmosphere of an M-type AGB star with the CO5BOLD radiation-hydrodynamics code. The simulations account for frequency-dependent gas opacities, and include a time-dependent description of grain growth and evaporation for corundum (Al2O3) and olivine-type silicates (Mg2SiO4).
Results. In the inner, gravitationally bound, and corundum-dominated layers of the circumstellar envelope, a patchy distribution of the dust emerges naturally, due to atmospheric shock waves that are generated by large-scale convective flows and pulsations. The formation of silicate dust at somewhat larger distances probably indicates the outer limit of the gravitationally bound layers. The current models do not describe wind acceleration, but the cloud formation mechanism should also work for stars with outflows. Timescales of atmospheric dynamics and grain growth are similar to observed values. In spherical averages of dust densities, more easily comparable to unresolved observations and 1D models, the variable 3D morphology manifests itself as cycle-to-cycle variations.
Conclusions. Grain growth in the wake of large-scale non-spherical shock waves, generated by convection and pulsations, is a likely mechanism for producing the observed clumpy dust clouds, and for explaining their physical and dynamical properties.
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Except for Harold Washington's 1983 - 1987 tenure until his untimely death, Chicago never had populist mayors, notably under father Richard J. (April 20, 1955 - December 20, 1976) and son Richard M. Daley (April 24, 1989 - May 16, 2011).
However, after two months in office, Emanuel looks likely to be Chicago's worst, based on policy initiatives he supports.
As White House chief of staff, he was criminally part of Obama's war cabinet. As Chicago's mayor, he's waging it against labor.
Candidate Emanuel, in fact, promised draconian anti-worker cuts "in attacking our budget deficit, (so) there must be no sacred cows....Chicago will have to make tough choices, (forcing) more than 0 million in efficiencies" on the backs of working Chicagoans already struggling to get by when they need help, not greater sacrifices they can't afford.
No matter, slash and burn now is policy, including layoffs, wage freezes, and benefit cuts, notably targeting healthcare and pensions. Then in June, Emanuel rescinded a contractual 4% raise owed 30,000 teachers, indicating the same policy would follow for other Chicago Public Schools (CPS) employees as part of his war on public education and Chicago workers.
In late June, it continued with 1,000 teachers fired, besides 4,000 since 2009, school closures, larger class sizes, and other draconian measures. Reassigned teachers retain salaries and benefits for one year as "interim" substitute staff. If not kept after 10 months, they're "honorabl(y) terminated."
In other words, fired, no matter their qualifications, tenure, or student needs. In fact, many other teachers were sacked without temporary pay or benefits, according to union officials, who have little to boast about after endorsing Illinois Senate Bill 7 (SB 7).
Its provisions include using standardized tests to fire teachers, regardless of seniority, tenure, qualifications, or how students respond to effective classroom practices, what rote memory tests can't measure. It also lets school districts increase hours per day, and add extra school weeks, with no additional compensation. In addition, teacher strikes are prohibited until after four months of negotiations plus a special arbitration panel's ruling.
Even then, the Chicago Teachers Union (CTU) must give 10 days notice backed by 75% of its members to approve a walkout. In other words, SB 7 empowers state and city authorities over their right to demand equity or walk out.
At the same time, CPS executives got salary increases up to 30% over their predecessors. Emanuel's new CPS head, Jean-Claude Brizard, earns 0,000 plus a 15% incentive package. Earlier as Rochester, New York public schools superintendent, 95% of teachers deplored his policies in office.
Moreover, he's named in two federal lawsuits regarding improper handling of budget cuts and school closures. Earlier, he attended the notorious Superintendents' Academy of the Broad Center for the Management of School Systems, founded by corporate predator Eli Broad to train administrators on restructuring and privatizing public education at the expense of educating kids.
Nonetheless, Emanuel wants him to replicate what he did in Rochester. Elizabeth Swanson is his deputy chief of staff, formerly (billionaire Penny) Pritzker Traubert Family Foundation executive director.
-- destroying public education by creating another business profit profit center.
Emanuel plans more of it for Chicago, including weakening collective bargaining and teachers' right to strike, the same core issues Wisconsin state workers tried and so far failed to save, perhaps heading for the chopping block in Chicago.
"As we (prohibit strikes by) police and firefighters, I would have it for teachers because they provide an essential service."
Of course, so do all public and private workers, entitled to rights like everyone, including to bargain collectively and strike if treated inequitably.
Since taking office, however, Emanuel waged war on Chicago workers, implementing austerity like Obama's doing nationally at a time massive stimulus is needed.
Sworn in on May 16, his 25-minute address mimicked Obama, calling for "shar(ing) the necessary sacrifices fairly and justly." In other words, make working Chicagoans sacrifice so corporate interests and city elites share, the same cancer metastasizing across America, destroying an earlier time long gone.
Saying "Chicago is ready for change," he omitted hard truths he began implementing on the backs of struggling working households. They need help, not greater hardships with lots more coming to close a 0 million budget gap and resolve .6 billion in underfunded pension liabilities perhaps by expunging them and cheating retirees.
While campaigning, in fact, he told city unions he planned pension cuts for all city employees, privatizations of many city services, selling Chicago incrementally to corporate favorites, and restructuring of revenue, finance, fleet management, and general service systems.
-- improving Chicago's business climate in collaboration with complicit unions, betraying their rank and file for a seat at the table plus high salaries, excellent benefits, and generous perks.
On July 15, Emanuel announced laying off 625 city workers. Affected are custodians, water department call center operators, and transportation department seasonal workers.
He also announced new privatizations. In addition, cost-cutting work rules are being discussed with union bosses, including unpaid days off, paid holidays reduced from 12 to nine, and new hoisting engineer wage differentials, based on machines they operate.
-- union apprenticeship cost saving programs will be enhanced.
Moreover, city workers no longer will provide airport and library custodial services. Private companies will replace them at greater cost.
In addition, seasonal transportation department workforces will be cut 75%. As a result, 61 fewer blocks of curb and gutter improvements will be made, as well as 76 fewer sidewalk blocks repaired.
Henceforth, a professional benefits management company, not public staff, will handle city benefit services at greater cost to the city and taxpayers.
Chicago's water bill call center will also be privatized, again at greater cost.
Overall, hundreds of city workers will be sacked to allegedly save millions of dollars. In fact, costs will be increased, not cut, making Chicagoans pay for privatized services public workers can do as well cheaper.
"Mayor Emanuel's announced intention to lay off 625 employees will diminish the availability and quality of city services on which Chicago residents depend. It will also" increase already high city unemployment.
"We are surprised and disappointed at (his) scattershot approach to the city's budget shortfall. We are paricularly disappointed that most of his bullets are aimed at frontline employees who do the real work of city government."
"Contrary to (his) claim, neither he nor his representatives have ever made any attempt to meet with our union to negotiate changes to work rules....If the mayor were serious about (instituting positive changes), he would have taken the appropriate measures to engage in such discussions." Not doing so shows "blaming union work rules for (Chicago's) massive deficit is mere public relations gimmickry."
"In that spirit, we call on the Mayor to rescind his layoff threat and work collaboratively to reduce costs while protecting city services and jobs."
In fact, AFSCME, CTU, and other city union bosses collaborate with city management, furthering their own interests over rank-and-file members they pretend to represent. As a result, Bayer's statement rings hollow, common practice to make workers think he's on their side when, in fact, he and other union heads fall short.
In Chicago, Illinois and across America, government and corrupted union bosses collaborate against workers, agreeing on wage freezes, benefit cuts, and layoffs, making already dire conditions worse.
As a result, harder than ever hard times deepen to assure corporate favorites and wealthy elites benefit at the expense of troubled working households being scammed.
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What was the benefit to your company?
We also help clients increase their productivity through the use of workplace tools such as gmail, docs, and cloud-based storage. We move companies to the cloud with initial setup,configuration, and data migration services.
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The Director of National Intelligence Open Source Center (OSC) is a U.S. Central Intelligence Agency (CIA) intelligence center located in Reston, Virginia, which provides analysis of open-source intelligence materials, including gray literature, through OSC's headquarters and overseas bureaus. Established on November 1, 2005, by the Office of the Director of National Intelligence, OSC is tasked with improving the availability of open sources to intelligence officers and other government officials. OSC provides material to the National Technical Information Service (NTIS) and other government officials through the online news service World News Connection.
In the fall of November 1992, Senator David Boren, then Chairman of the Senate Select Committee on Intelligence, sponsored the National Security Act of 1992, attempting to achieve modest reform in the U.S. Intelligence Community. His counterpart on the House Permanent Select Committee on Intelligence was Congressman Dave McCurdy. The House version of the legislation included a separate Open Source Office, at the suggestion of Larry Prior, a Marine Reservist with Marine Corps Intelligence Command experience then serving on the House Permanent Select Committee on Intelligence staff.
The Aspin-Brown Commission stated in 1996 that US access to open sources was "severely deficient" and that this should be a "top priority" for both funding and DCI attention.
In issuing its July 2004 report, the 9/11 Commission recommended the creation of an open source intelligence agency, but without further detail or comment. Subsequently, the WMD Commission (also known as the Robb-Silberman Commission) report in March 2005 recommended the creation of an Open Source Directorate at the CIA.
Following these recommendations, in November 2005 the Director of National Intelligence announced the creation of the DNI Open Source Center. The Center was established to collect information available from "the Internet, databases, press, radio, television, video, geospatial data, photos and commercial imagery." In addition to collecting openly available information, it would train analysts to make better use of this information. The OSC absorbed the CIA's previously existing Foreign Broadcast Information Service (FBIS), originally established in 1941, with FBIS head Douglas Naquin named as director of the Center.
In response to the Cuban Missile Crisis and START Treaty, FBIS was tasked with monitoring for clandestine and encoded messages from all nations and coordinating broadcast media contact points who could instantly broadcast urgent messages on "All Channels" and "All Calls" and mutually receive messages in all languages and codings from any foreign broadcast station. This task continues despite the Open Source Center's DNI reorganization.
The OSC is located in the Reston Town Center development in Reston, Virginia, in the former headquarters of the FBIS. The construction of the facility sparked some controversy in Reston, a planned community, due to the presence of a chained linked and barbed wire fence surrounding the buildings. In the late 1980s, the CIA agreed to install a more aesthetically pleasing fence around the buildings.
^ "Centers in the CIA". Central Intelligence Agency. December 30, 2011. Archived from the original on November 24, 2013. Retrieved April 5, 2013.
^ Peak, Douglas. (October 1, 2005) Military Intelligence Professional Bulletin. DOD and the DNI Open Source Center -Building the Partnership. Volume 31; Issue 4; Page 15.
^ a b "About World News Connection". Archived from the original on 2012-07-01. Retrieved 2007-07-14.
^ "DNI Press Release". Archived from the original on 2006-07-19. Retrieved 2006-07-19.
^ "Other Public Citations". Archived from the original on 2006-09-04. Retrieved 2006-07-04.
^ See page 413 of the 9-11 Commission Report (pdf).
^ Office of the Director of National Intelligence. "ODNI Announces Establishment of Open Source Center Archived 2006-06-23 at the Wayback Machine". Press release, 8 November 2005.
^ Ensor, David. "The Situation Report: Open source intelligence center". CNN, 8 November 2005.
^ "High-Tech, Secure & Laboratory Environments". DNC Architects. Archived from the original on 2013-07-29. Retrieved April 4, 2013.
^ "CIA Scraps Plan for More Reston Offices". Washington Post. July 20, 1989. p. V15.
The Assistant Deputy Director of National Intelligence for Open Source (ADDNI/OS) is a senior-level position within the Office of the Director of National Intelligence, responsible for developing strategic direction, establishing policy and managing fiscal resources for Open Source Intelligence, providing oversight for the DNI Open Source Center, as well as document and media exploitation for the United States Intelligence Community.
Foreign Broadcast Information Service (FBIS) was an open source intelligence component of the Central Intelligence Agency's Directorate of Science and Technology. It monitored, translated, and disseminated within the U.S. government openly available news and information from media sources outside the United States. Its headquarters was in Rosslyn, Virginia 38.8959°N 77.0727°W / 38.8959; -77.0727, later Reston, Virginia 38.955°N 77.359°W / 38.955; -77.359, and it maintained approximately 20 monitoring stations worldwide. In November 2005, it was announced that FBIS would become the newly formed Open Source Center, tasked with the collection and analysis of freely available intelligence.
The Government of the Islamic Republic of Iran (Persian: نظام جمهوری اسلامی ایران, translit. Neẓām-e jomhūrī-e eslāmi-e Irān, known simply as Neẓām (Persian: نظام, lit. 'the system') among its supporters, and "the regime" among its dissidents) is the ruling state and current political system in Iran, in power since the revolution and fall of Pahlavi dynasty in 1979.Its constitution, adopted by a referendum, uses separation of powers model with Executive, Legislative, and Judicial systems, while the Supreme Leader is the country's head of state and commander-in-chief of the armed forces.It is currently one of the four governments using the title Islamic republic.
Giovanni "John" Gambino (August 22, 1940 – November 16, 2017), was an American mobster. Born in Palermo, Sicily, he became a made member of the Gambino crime family in 1975 and a capodecina or captain, and head of the crime family's Sicilian faction, appointed by family boss John Gotti in 1986, according to Mafia turncoat Sammy Gravano.
Kahoku Shimpō (河北新報) is a Japanese language daily newspaper which is published in Sendai, Japan.
L'Express (French pronunciation: [lɛksˈpʁɛs]) is a French weekly news magazine headquartered in Paris. The weekly stands at the political centre in the French media landscape, and has a lifestyle supplement, L'Express Styles, and a job supplement, Réussir.
La Tribune (French pronunciation: [la tʁiˈbyn]) is a French weekly financial newspaper founded in 1985 by Bruno Bertez. It's main competitor is the French newspaper Les Échos, which is currently owned by LVMH.
From 1993 to 2007 La Tribune was part of LVMH. In 2010, Alain Weill, the Chairman and CEO of NextRadioTV sold 80% of La Tribune to Valérie Decamp for €1 and he still owns 20%.In 2000 had a circulation of 531,000 copies. In 2008 it switched from tabloid to berliner. It was rescued from bankruptcy in 2011. In 2012, the newspaper switched to a weekly format.
Marianne (French pronunciation: [maˈʁjan], ISSN 1275-7500) is a weekly Paris-based French news magazine.
Morteza Heidari (Persian: مرتضی حیدری) (born 17 June 1968 in Tehran) is an Iranian TV presenter. His surname is also spelled Heydari.
Army General Nikolai Yegorovich Makarov (Russian: Никола́й Его́рович Мака́ров, IPA: [nʲɪkɐˈlaj jɪˈgorəvʲɪtɕ mɐˈkarəf]; born 7 October 1949) was Chief of the General Staff of the Armed Forces of Russia and First Deputy Minister of Defence from 2007 to 2012 when he was replaced by Valery Gerasimov.
Présent is a French newspaper (published five days a week). The paper was founded in 1982. It is close to the French Front National, and follows a traditionalist Catholic editorial line. Jean Madiran was for long its editor in chief and is still involved in it.
Reston Town Center (preliminary name Reston Parkway) is a planned rapid transit station on the Silver Line of the Washington Metro in Reston, an unincorporated area in Northern Virginia. Expected to open in late 2019 or 2020, it will be part of the second phase of the Silver Line project, extending the line westwards to Dulles International Airport and eastern Loudoun County.
VSD is a French weekly news, celebrity and leisure magazine, published on Thursdays in France. The name is formed from the first letters of the French names for Friday (Vendredi), Saturday (Samedi) and Sunday (Dimanche).
Vladislav Yuryevich Surkov (Russian: Владислав Юрьевич Сурков; born 21 September 1964) is a Russian businessman and politician of Chechen descent. He was First Deputy Chief of the Russian Presidential Administration from 1999 to 2011, during which time he was widely seen as the main ideologist of the Kremlin who proposed and implemented the concept of sovereign democracy in Russia. From December 2011 until May 2013 Surkov served as the Russian Federation's Deputy Prime Minister. After his resignation, Surkov returned to the Presidential Executive Office and became a personal adviser of Vladimir Putin on relationships with Abkhazia, South Ossetia and Ukraine.Surkov is perceived by many to be a key figure with much power and influence in the administration of Vladimir Putin. According to The Moscow Times, this perception is not dependent on the official title Surkov might hold at any one time in the Putin government. BBC documentary filmmaker Adam Curtis credits Surkov's blend of theater and politics with keeping Putin, and Putin's chosen successors, in power since 2000.Journalists in Russia and abroad have speculated that Surkov writes under the pseudonym Nathan Dubovitsky, although the Kremlin denies it.
World News Connection was a compilation of current international news translated into the English language. The United States Department of Commerce National Technical Information Service compiled and distributed it from non-U.S. media sources, usually within 24–72 hours from the time of the original publication or broadcast.
It provided the full text of newspaper articles, television and radio broadcasts, online sources, conference proceedings, periodicals, and non-classified technical reports. This information was collected and translated to aid decision makers at the highest levels of the executive and legislative branches of the U.S. Government who needed to know what was happening abroad and how it was being reported locally. WNC was especially useful for access to local thoughts and perceptions for those who didn't know the local language. It covered 130 countries, including many out of the way places not generally covered by other news services. It also contained news analyses by OSC specialists.World News Connection was the online offering from the Open Source Center (OSC) (formerly the Foreign Broadcast Information Service (FBIS)) that replaced the hard-copy regionally oriented "pink books" that used to be published. Due to a shift in the 1990s toward copyright compliance, the online version was a limited rendition (about half) of what is available for internal government use.
DIALOG, a commercial search service under ProQuest, offered a fee-based means of accessing WNC content. WNC material was also available from Acquire Media, Country Watch, East View Information Services, NISC Pty Ltd (South Africa), and Westlaw.The World News Connection shut down on December 31, 2013.
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Birth injury is a term used to refer any injury that occurs to the baby before, during, or right after the birthing process. An injury can occur due to many reasons including oxygen deprivation, neonatal infections, mechanical force, and more.
Birth injuries usually lead to disabilities such as cerebral palsy, intellectual impairment, hypoxic-ischemic encephalopathy, seizure disorders, and more. This may sound very traumatic to soon-to be parents, but the good news is that nearly all birth injuries are preventable.
The medical professionals involved in the birthing process can prevent birth injuries by monitoring the health of the mother and the baby, and taking prompt action when necessary.
While there are many reasons that can lead to a birth injury, most common problems occur during labor, especially when it is delayed or the nursing staff take too long.
In order to ensure that no complications occur during the birthing process, doctors should recommend various prenatal tests which will help them access the health of both the mother and the child. These tests can reveal in-depth information about different maternal conditions that can help medical professionals recognize fetal issues in a timely manner.
Throughout the pregnancy, medical professionals should keep monitoring the baby and the mother for any sort of fetal distress. This can be found by various signs such as decreased fetal movement, abnormal amniotic fluid volume, and more.
Medical professionals work closely with the mother throughout the pregnancy to ensure that the delivery of the baby is as smooth and free of injury as possible. But sometimes, due to ignorance, or any other mistakes by these professionals, can lead to injury to the mother or child.
What to do when a birth injury occurs due to medical malpractice?
Medical professionals must make sure to follow the standards of care when managing pregnancy. The health of the infant and mother must be closely monitored and the professionals must make important medical decisions with consent from the parents.
When consent is taken from one or both the parents, it means explaining the risks, benefits and any other problems that can occur during the birthing process. If any medical professional such as a doctor, nurse, or the medical institution fails to follow the basic standards of care, and this ends up causing harm to the mother or the baby, it is known as medical malpractice.
Some parents may choose to seek legal action against medical malpractice that caused an injury to their child. This is to ensure that the hospital, doctor, and nursing staff involved are held accountable for their errors.
Moreover, seeking legal help also means that you will receive the financial means to support your child who became a victim of birth injury which resulted in a life-long disability. Should you choose to go down the legal road, Miami FL birth injury attorneys may be able to help. Birth injury attorneys focus specifically on birth injury and have the required legal and medical expertise needed to fight your case.
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book/paper I want to read: "The life-cycle of corporations and long-term equity/debt returns for the small passive investor". Who has written it? If no one, who has written the best book/paper on "The life-cycle of corporations: historical data and theoretical models"? Also interested in discussions comparing the life-cycle of publicly traded corporations versus the life-cycle of private corporations/proprietorships/partnerships.
Deep Thought: Living off the capital feels a lot like living off the income.
Deep Thought: You can't mix sambar with ketchup.
Deep Thought: "Patriotism is not enough, I must have no hatred or bitterness towards anyone."
And it seems to me that for "patriotism" you can substitute "ideals" or "dreams".
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I need a mod which will prevent users of my forum from posting more than 2 image tags into a post. Upon the user submitting their post the mod should check how many image tags are in the post and if there is more than two the script should display a message to the user.
The right programmer for this task should be familiar with the phpbb forum software.
I have done lots of phpBB mods, including translation and other mods. You can see a sample of it here: [login to view URL] I can do this quickly and professionally.
I can do it for you at professional quality. I have a website which provides some free MODs as an example. [login to view URL] You can check the information and services I provided in my forum.
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