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Dog's Life: Lifestyle
The toxic ingredient is showing up in more household products.
It's widely known that xylitol, an ingredient in sugar-free gum, is toxic to dogs. Even small amounts can cause life-threatening hypoglycemia and liver failure. This has led me to be really careful about leaving packs of gum in handbags I leave around the house. I also keep gum packs (and chocolate) in a secure plastic bin in my pantry, just to be sure no hungry dogs get into the dangerous treats.
But I recently discovered that many more household products contain xylitol. In addition to other edible goods, like cookies, cough drops, and medications, the ingredient has been popping up in toothpaste, cosmetics, and mouthwash. The Pet Poison Hotline even found a line of clothing with xylitol embedded in it!
Clearly it's important to check the ingredients of the products you have lying around the house and keep them away from your pets. Xylitol is typically listed in the "Other ingredients" or "Inactive ingredients" section, but it's also been seen in the "Supplement Facts" box, so make sure you read the package closely. Sometimes the ingredients won't be listed as xylitol, but may be included as "sugar alcohols," which encompasses many different sugar alcohols, like xylitol.
If your pet has ingested a product with xylitol in it, immediately call a veterinarian. The ingredient is so toxic that symptoms can show up within 10 minutes of ingestion. This includes weakness, lethargy, loss of coordination, seizures, vomiting, and rapid breathing. Fortunately dogs can recover if treated promptly.
This just shows how important it is to know what's in the products in your home.
Dog's Life: Lifestyle
You Tube videos chronicle awareness around pet food ingredients
When I got my first dog, I spent countless hours pouring over the ingredient of different pet foods. I finally settled on grain free kibble made from human grade ingredients, but even so I don't think I would eat a day's worth of dog food.
Enter Dorothy Hunter, animal lover and owner of Paws Natural Pet Emporium in Kennewick, Washington. Dorothy is so passionate about quality pet food that she just completed a vow to eat only dog, cat, and bird food from her store's shelves for one month. She embarked on this journey to create awareness around pet nutrition, chronicled in a series of You Tube videos.
"You would be surprised how tasty dog and cat food can be when it's made right," says Dorothy. She believes that, in many cases, our pets are eating better than us.
Many people asked Dorothy about her digestion, but she says she felt great on the diet. Her selection couldn't be further from the "supermarket kibble" people picture when they think of pet food. Dorothy's menu consisted of oven baked blueberry treats, freeze dried vegetables, kibble with salmon flakes, and canned food with pieces of succulent chicken.
Dorothy's You Tube videos are a great way to get people thinking about their pets' food while reaching a new audience. There's nothing like eating dog treats and kibble to make you hyper aware of the ingredients inside!
Good Dog: Behavior & Training
A study with insights into welfare
If you think that having dogs who bounce off the walls is problematic for them and for you, you are not alone. "Wall bouncing" is one of the repetitive behaviors that have long been considered indicative of poor welfare and chronic stress in the animals performing them. Other repetitive behaviors that are commonly seen in dogs are pacing, circling and spinning, all of which are generally regarded as stereotypical behavior.
Stereotypical behaviors are those that are not just repetitive, but also pointless and occur because of deficits in animals' housing situation that cause frustration. That is, when animals are performing stereotypies, they are exhibiting behavior that has no function, and doing it over and over because their living environment is inadequate to meet their needs. A recent study in the journal Physiology and Behavior called Repetitive behaviour in kennelled domestic dog: Stereotypical or not? explored whether all the repetitive behaviors observed in kennelled dogs are actually stereotypies. The reason this question matters is that if their repetitive behaviors are stereotypies, it suggests that animals' welfare may be compromised, but if they are performing repetitive behaviors for other reasons, then that conclusion may be suspect.
The researchers studied 30 male German Shepherds who are fully trained Police Dogs in the UK and live in a kennel that can hold as many as 40 dogs. They studied their behavior as well as their cortisol profiles (which indicate stress) before and after veterinary exams. They found that all but two of the dogs performed repetitive behaviors, but that very few of them displayed stereotypies. Repetitive behaviors were most commonly induced by a dog and handler walking past the kennel and by witnessing food preparation, which supports the idea that repetitive behaviors are simply a response to situations of high arousal rather than to stress.
The dogs could be divided into four groups based on the pattern of their repetitive behavior and the eliciting stimuli. Twelve of the dogs only exhibited repetitive behavior in response to husbandry events (including veterinary care) or not at all and showed them in less than half of the observation period. Five additional dogs also only displayed repetitive behavior in those same contexts, but they showed it more than half of the time that they were observed. Eight dogs performed repetitive behaviors in response to husbandry and when a person walked by or stood outside their kennel. The last five dogs displayed repetitive behavior in the absence of these and other specific stimuli.
Though all the groups had similar baseline cortisol profiles, this last group had a cortisol profile following the exam that differed from the other groups. These dogs showed a decrease in cortisol immediately after the exam rather than the increase in cortisol seem in the other groups. This suggests one of two possibilities. One is that these dogs are under chronic stress and lack the physiological ability to respond typically to the additional stress of an exam. The other possibility is that these dogs are so attached to people, including their caregivers and the veterinarian, that being with them after a separation is such a positive experience that it balances out the stress of being removed from the kennel and examined.
The relationship between repetitive behaviors in dogs and their welfare status remains unclear, but this study suggests that there is not just one motivating factor behind the expression of repetitive behaviors. Many questions remain about repetitive behavior in dogs who are kenneled. Is it an indication of poor welfare? Could the repetitive behaviors be a result of reinforcement (food or attention) of these behaviors from people caring for the dogs? Why are the cortisol profiles different in dogs who exhibit repetitive behaviors without specific eliciting stimuli?
Wellness: Healthy Living
Help your pup shed excess weight.
How many times has your veterinarian commented on your dog's weight? How many times have you been told, "Here's a bag of prescription diet food—if you feed your dog this and only this, he will lose weight." But what if he doesn't? And why should you care?
Clinical research has shown that losing just 10 percent of body weight will slow or prevent many life-threatening disease processes, including debilitating osteoarthritis and diabetes, and perhaps even some types of cancers. By taking a few simple measures, you may be able to add more quality time to your dog's life, time the two of you can enjoy together.
Food Watch
Feed higher protein/lower carbohydrate foods (a 3:1 ratio); proteins and fats are converted to usable energy faster than starches and carbs. Think of this as the "puppy Paleo diet"! And even if you're feeding a high-protein, grain-free variety, cut down on kibble. In general, all kibble has 60 percent more starch than canned food because starch is needed to maintain the kibble's shape when it's baked or extruded. Too much dry food equals too much starch, which breaks down to sugars and is stored as body fat. It's easy to overfeed dry foods, especially if you follow the directions on the packaging.
Add water or broth to kibble to make it nicely soupy. The extra liquid will help your dog digest his food more easily and reduce his body's need to pull water from his system to his stomach, which can contribute to dehydration.
Try gradually reducing your dog's kibble ration by half, replacing it with more moisture-based foods such as lean meats, fish or eggs, and low-starch green and orange vegetables and fruits. I've found that companion animals do best with at least 50 percent of their diet fed as fresh foods—cooked, raw, dehydrated or freeze-dried—mixed with a significantly reduced volume of highgrade kibble. This keeps them satisfied and helps with the faster metabolic change that promotes weight loss. Another option is to feed him a low-carbohydrate canned food; these have less starch and more water, and therefore, fewer extra calories to stick around. Or, transition him to a complete and balanced commercial raw diet, which has very little starch.
Decreased fat content also helps with weight loss, but do not eliminate fats entirely, as they satisfy hunger; look for 4 to 7 percent fat content in canned foods. Also, avoid feeding excess insoluble fiber; among other things, it may interfere with nutrient absorption. Roughly 5 to 6 percent fiber is ideal. If stools become soft, add 1/4 teaspoon of psyllium to each meal. Make mealtime more fun with interactive feeding toys. These not only stimulate a dog's mind, they make him work for his supper (or breakfast, or snack). Dogs eat more slowly and expend more calories. Google "how to stuff a dog-feeding toy" for helpful tips. The Kong is the granddaddy of dog-feeding toys, and there are other excellent options on the market as well, among them Nina Ottosson's ingenious products.
Walk It Out
As your dog becomes stronger, try walking in water at the beach, up streams and against gentle currents. (The caveat here is to be aware of water temperature; very cold water can lead to achy joints.) Or, walk on sand, on grassy slopes, and up and down gentle inclines. Finally, when he's ready for it, take him on longer hikes or try a doggie treadmill.
Keep your dog on his feet and improve his balance with some fun exercises. To work his gluteals and hamstrings, have him take several steps backward. Stepping sideways tunes up his adductor and abductor muscles. Navigating cavaletti (small hurdles set at uneven heights); threading through poles or cones; or walking on cushions, an air mattress or a thick foam pad will help him with balance and proprioception (knowing where his feet are). Sit-to-stand and lie-to-stand exercises strengthen hip and knee muscles.
Weight-shifting is another way to help your dog's balance. Hold one of his legs off the ground for three to six seconds at a time, or have him stand with his front feet on a stair step to eat. To loosen his neck, shoulder muscles and upper spine, lure him into stretching his head back toward his body with a carrot or small lean meat treat.
So, here's the proverbial bottom line: One—paraphrasing Michael Pollan—feed your dog real food, feed him less of it, and include a variety of protein sources and dog-safe fruits and vegetables. Two, strengthen and improve his muscle tone, balance and stamina with condition-appropriate activities. He'll have a sleeker physique and you'll thank yourself for making the effort.
Wellness: Healthy Living
Summer maintenance
Ah, summer—a season for rambles, picnics and water fun. Longer days and warm weather inspire us to get ourselves and our dogs outside to soak up some sun (judiciously) and get some exercise.
Maintaining our dogs' grooming routines is also important. It's not all about looking good, though that's certainly one motivator; it's also about keeping a close eye on the condition of our dogs' skin, ears and nails, solving small problems before they become big ones.
While some breeds require the services of a professional groomer, all dogs benefit from a good brushing, and you don't have to be a pro to do that. A dog's best friend is a tool appropriate for his coat type, one that strips out loose hair so air can circulate against his skin. Regular and thorough brushing also prevents mats, which are not only painful but also trap heat and moisture and can result in skin infections.
However, experts tell us to resist the urge to shave down our dogs, particularly those with double coats, who can be quite comfortable as long as those coats are well cared for. Whatever its length and composition, a dog's coat provides built-in climate control as well as a first line of defense against sunburn, twigs and stickers, among other things.
This is also the time of year to be particularly vigilant about ticks and fleas. The former can carry disease and the latter can quickly set up housekeeping on your dog—and in your house—if not managed. Another reason to be conscientious about wielding the brush, rake or comb of your choice. While your dog may or may not agree, adding an extra bath or two is also a good summer strategy. Brush before and after, choose a shampoo that's a good match for his skin and coat type (or make your own), lather once and rinse well.
Check your dog's ears regularly, particularly if swimming is on his play list. Dogs whose ears fold over are prone to ear infections, which wet ears promote. Some groomers pluck hair from a dog's ear canal, but vets advise against this, as the hair pores then secrete extra serum, providing another excellent medium for infection. After your dog takes a dip, wipe the inside earflap gently with a cotton ball; if your vet says it's okay, you can also use drops that contain a drying agent. According to the Dog Owner's Home Veterinary Handbook, a drop of white vinegar will also help prevent "swimmer's ear."
And in the "of course" category, continue to brush your dog's pearly whites and pay attention to his paws. Check between his toes for ticks, foxtails, brambles or other debris, and trim his nails.
None of this is rocket science, just good old-fashioned conscientiousness. And the payoff is so worth it: a dog who feels good and smells good, and far fewer fur-bunnies rolling across the floor and lurking under the couch!
For more on this subject, see the interview with groomer extraordinaire Robyn Michaels at thebark.com/groomed.
Wellness: Healthy Living
… and how to avoid them
In my line of work as a veterinary surgeon, I don't need a weatherman to tell me that summer has officially arrived. One glance at our list of ER admissions is all it takes. Outdoor parties and barbecues are perfect opportunities for flirty, furry, four-legged socialites to work the crowd and make new friends. The downside is that dogs' curiosity, their heightened sense of smell and their gift for the art of scavenging can spell trouble. Use the following list of usual suspects to prepare, educate your guests or consider a change in menu plans.
Yards: With friends coming and going, there's always a risk your dog may become disoriented or run off through an open gate. Make sure the perimeter is secure (and everyone knows to keep it that way), or have your dog stay indoors in a quiet, familiar room. And despite your desire to show off your canine Michael Phelps, if it's a pool party, your dog should stay out of the water, as a crowd of swimmers can create panic and distress.
Bones: It doesn't matter whether they're from chicken wings or pork ribs, cooked meat bones cause all sorts of problems, especially if they get lodged in the mouth, throat or esophagus. Terriers in particular have been proven to be at higher risk (which is probably more behavioral than anatomical, but still true). Make sure your guests have somewhere to dispose of their carnivorous waste rather than using your dog as a trash can.
Skewers: Tasty morsels pierced by a sharp wooden skewer may be a convenient and eye-catching way to serve grilled meat or veggies, but the inedible (though deliciously aromatic) stick can prove irresistible to an inquisitive canine, and is guaranteed to wreak havoc on an unsuspecting intestinal tract. More trash bags, please!
Corn Cobs: There's something about the size and diameter of a corn cob that makes for a snug fit in the canine small intestine, frequently resulting in an obstruction and an expensive trip to the operating room. Be vigilant about picking up leftovers and repositioning plates perched on table edges at the level of a curious snout.
Chocolate: A compound called theobromine found in chocolate can be potentially toxic to dogs, stimulating the heart and nervous system, sometimes with fatal consequences; an overdose is more likely in small breeds. If you know your dog has ingested chocolate, call your vet immediately. If your dog appears excited, or is restless, panting or vomiting, get to your nearest veterinary hospital. If ingestion occurred within two hours and you are seeing none of these signs, vomiting can be induced; administer 3 percent hydrogen peroxide, 1 teaspoon for every 10 pounds [4.5kg] of body weight, by mouth.
Fruit and Nuts: Grapes and raisins (dried grapes) can be extremely toxic to some dogs. In one report, four to five grapes were toxic in an 18-pound dog. If you suspect ingestion, call your veterinarian immediately. Apple cores can become lodged in the canine esophagus; peach pits have a knack for blocking the intestines; and macadamia nuts (plain or in cookies) can cause weakness, clumsiness, vomiting, muscle pain and joint swelling. Fortunately, most cases of macadamia toxicity can be managed with supportive care at home.
Not So Fun Stuff: The combination of a really hot barbecue grill and the desire to get to what's on offer can overwhelm all canine self-control. Keep your dog away from the grill and nearby raw meats and seasonings. Collect trash frequently and secure it in closed containers. Come nighttime, glow sticks are fun … unless your dog chews through to the toxic contents inside. Candles (a safe distance from happy tails) are a better option.
Fireworks: Call me a party-pooper, but if you want to set off fireworks, don't invite the dog.
Wellness: Healthy Living
Simple preventive steps can go a long way toward offsetting their threats
A few months ago, the icy breath of the north that normally tucks itself over the Arctic during the winter blasted into the Northeast, prime tick country. This prompted climate scientists to look for links between a weakened polar vortex and a warming world. But those who study arachnids were interested in other signs … like fewer ticks.
In January, Thomas Mather, PhD, an entomologist known to many as the "tick guy," trudged through thick snow in Kingston, R.I., looking for the spot where he'd buried vials of deer ticks the day before. The overnight temperature had fallen to a tick-numbing three degrees. Locating the vials, he sprinkled the tiny black specks on his palm. They sat there like pepper. Then they began to move.
For ticks, it seems, the ice age was a snowbird's vacation. So don't drop your guard, warns Mather, director of the University of Rhode Island's Center for Vector-Borne Disease and its outreach arm, the TickEncounter Resource Center (TERC). Mather has spent two decades studying the rise of the blacklegged tick—commonly called the deer tick—in Rhode Island.
"I'm pretty certain that we won't really be able to credit winter's serial polar vortices for whatever the ticks are or are not doing in the spring," he says. It's not about the weather, but cycles. In their two-year lifespan, ticks feed on the blood of hosts during three growth stages: larval, nymphal and adult. According to Mather, the deer tick problems we're facing in 2014 were largely decided last August and September by the number of larval ticks that found infected rodent hosts. "That will determine both the summer nymph populations and fall's adult tick abundance," Mather says.
In recent years, those cycles have produced record numbers of nymphs at the sites his team sample each summer. So many, in fact, that he considers it a public health crisis in his state, which is part of the East Coast "tick-belt."
Mather says that human and pet encounters with ticks are skyrocketing, and while ticks don't always carry a disease, they may, and many of those diseases are dangerous.
Between 2006 and 2010, Veterinary Week reported a 30 percent increase in the rate of dogs exposed to tick-transmitted diseases. Among them: The aggressive lone star tick can transmit ehrlichiosis, one of the most common and dangerous tick-borne diseases in dogs. The brown dog tick and American dog tick also spread ehrlichiosis, babesiosis and Rocky Mountain spotted fever (RMSF).
Then there's the deer tick. Although there are hundreds of species of ticks—all of which are relatives of spiders and mites, in the U.S. —the deer tick is number one on the most unwanted list. It spreads several dangerous infections, Mather says, and topping that list is Lyme disease.
Trail of Infection
The deer tick in the East and the related western blacklegged tick are the only known transmitters of Lyme disease in the United States. The trail of infection typically begins with rodents or, in the West, lizards, natural reservoirs of the Lyme bacterium, Borrelia burgdorferi. Ticks need a blood meal to reproduce, and acquire the bacterium when they bite an infected host. The next time they bite, they inject the bacterium into their unlucky meal source.
Where Lyme is found, so are deer, but the "deer tick," as it's commonly called, is actually the blacklegged tick, and it feeds on many different mammals, birds and reptiles. This tick has been on a tear in the Northeast, its range expanding, its pathogens mutating, ever since the disease it spreads—long known in Europe—was recognized in 1975 in Lyme, Conn.
Lyme disease was first diagnosed in a dog about 25 years ago, and now it's one of the most common tick-borne diseases in dogs in the U.S., notes Cornell University's Baker Institute for Animal Health. In several of the most affected states, one out of 15 dogs tested positive for Lyme disease in 2011, according to a study by the Centers for Disease Control and Prevention (CDC). And where dogs test positive, so do humans. In 2012, 95 percent of human cases were reported from 13 states concentrated in the Northeast and upper Midwest.
In parts of the Northeast, up to half of the deer ticks are infected with Lyme disease. In California, where Lyme also exists, the infection rate is far lower, with the disease mainly occurring in four northwestern counties.
A dog's risk in such areas goes up and down. As noted on the Baker Institute's website, even within highly infected regions, there are "hotspots of tick infestation and Lyme disease risk," which "mingle with non-infested areas with much lower risk." Even so, far fewer infected dogs than people develop the disease. Studies suggest that more than 75 percent of dogs in hyperendemic areas may be exposed to infected ticks, yet only about 5 percent develop Lyme. However, Lyme is only one of the diseases deer ticks spread to dogs; among the others are ehrlichiosis, babesiosis and anaplasmosis ("dog tick fever").
There's also a growing list of new diseases involving deer ticks, including one caused by the bacterium Borrelia miyamotoi, which mimics Lyme disease, and the rare but increasing Powassan virus and its variant, deer-tick virus. Powassan hasn't been found in dogs, but dogs with neurological issues aren't commonly tested for this rare disease, and such tests aren't readily available.
In fact, even with available tests, diagnosing Lyme disease in dogs is challenging. Unlike viral diseases such as Powassan, Lyme is a bacterial infection and can be treated with antibiotics. But its symptoms, if any, mimic many other diseases. One common sign, lameness, takes two to five months to appear, according to the Baker Institute, and, unlike people, dogs don't develop the telltale bull's-eye rash around the bite.
A CDC study found that people in areas with a higher-than-average number of dogs with Lyme disease are at greater risk of getting it themselves. There's no evidence that dogs spread it directly, but they may bring infected ticks into homes and yards.
And since dogs have a way of getting people outside, down that trail and—bag in hand—under that bush, it's easy to see why the CDC says that dog owners face an elevated risk for Lyme disease.
Know the Enemy
Going outdoors is not the problem. What increases the risk of being infected is entering tick habitats. Especially if you go in thinking that ticks fall off trees. Or that they pounce, or fly. Surveys find that most people don't know enough about ticks and their habits to ward them off.
"When it comes to tick-bite protection and disease prevention, we've learned that people tend to only focus on it after the fact," Mather says.
That's why TERC, which Mather heads, came into existence. Its goal is to entice people to learn more than they ever wanted to know about Ixodes scapularis (blacklegged or deer ticks)—ticks that carry the Lyme disease pathogen—and other species as well.
The idea for TERC began around 2004, when Mather decided to start "an aggressive, grassroots, tick-bite prevention program." The tally wasn't nearly as appalling back then, but by 2013, CDC estimates of the number of Americans diagnosed with Lyme disease each year hovered around 300,000, a whopping 10 times higher than anyone thought.
Although Mather felt that scientists already had solutions, "the link between science and people's lived experiences with ticks was largely missing." To fill this gap, his team took their fieldwork in a new direction: into tick-afflicted neighborhoods and to meetings with stakeholder groups. "People kept asking if we had a brochure or website," he says. "After hearing that, oh, like 50 times, we started brainstorming." They knew that brochures usually end up in the trash, but could a website reach people? "TickEncounter is what we came up with," he says. It launched in 2006.
Today, the Internet teems with tick-related websites and information, and Mather believes it's more important than ever to promote "a common core message" so the facts are clear to people. TickEncounter aspires to be the place people turn to for reliable and up-to-date information. The site isn't soft on the facts; many people are susceptible, even likely to fall victim to tick-borne disease, which can be devastating. But simple preventive behaviors work. Before people can take action, Mather says, they need to believe in their own ability to successfully use those practices.
TERC's unique graphic interface empowers users to snitch on the tiny army, ratting on its whereabouts and force-strength by season and region. The TickSpotters program, which includes crowd-sourced surveillance, recently added veterinary clinic reporting. Every two weeks, participating clinics send in patients' ticks for identification. "These data are informing our 'Current Tick Activity' databases," he says. Posts are updated every two weeks for nine U.S. regions. They plan to add an online dashboard with a map of results to show tick trends across America.
In February 2014, the TickSpotters page reflected the effects of the frigid weather, showing low tick activity in New England. Things were heating up on the West Coast, however, home to the western blacklegged tick. In fact, it's always tick season somewhere, and people and pets can get Lyme disease even in winter.
"Pet owners seem most [affected] by adult ticks because they can see them," Mather says, but the nymphs "are potentially more dangerous." Nymph season is May through August, months during which people and dogs tend to spend the most time outside. Nymphs lurk in moist leaf litter in or near the edge of wooded areas. Because they're so tiny at this stage, nymphs attach to small mammals near ground level, such as mice, which often carry Lyme. According to the Baker Institute, only repeated exposure to nymphs causes infection in dogs.
Adults, being larger, tend to bump into their hosts at higher altitudes. They wait aboard grasses and bushes, closest to animals' largest body surface. They're mainly a threat to dogs in fall and early spring. In winter, they only seek hosts when temperatures rise above freezing. Adults also transmit Lyme, babesiosis and anaplasmosis.
Despite the threats ticks pose, it's not easy designing public education programs that work for everyone, health officials say. The problem is different for places in which ticks are entrenched and those with an emerging infestation. The bad news is, the number of the latter is definitely growing.
More Ticks, More Diseases
According to the U.S. Geological Survey, the temperate, humid, northeastern U.S. is a favorable place for ticks. More so all the time, it seems.
Ninety percent of canine Lyme cases now occur in the Northeast, according to the Companion Animal Parasite Council, whose website includes a "parasite prevalence" map by state, with confirmed canine cases by county. Lyme disease has also shown up in Northern California and on the Oregon coast, but there isn't much evidence of spread.
The deer tick has even moved into Canada, where average temperatures have increased by 2.5º F over the past 60 years. One study suggests that tick-inhabitable regions in Eastern Canada will expand from 18 percent to more than 80 percent by 2020.
A 2013 study by researchers at the University of Toronto found that in the U.S., Lyme disease is shifting northward; the study noted large increases in 21 states between 1992 and 2007. This may be due "at least in part to the effects of climate change," wrote the researchers. A Yale study also found links between Lyme disease outbreaks and milder weather in the Northeast. The 2004–2007 survey found the greatest risk in southern Maine through Washington, D.C., Minnesota and Wisconsin. Newer hotspots appeared to be cropping up in Illinois, Indiana, Michigan and North Dakota.
Warmer winters, which allow ticks to breed throughout the year, may be a factor, the researchers say. Warm, moist air may also extend their life cycle. They dismissed the Southeast as a location for Lyme disease, only acknowledging the lone star tick. But some say there's growing evidence of a Lyme or Lyme-like infection there, too. In North Carolina, Lyme disease is up slightly, with a few cases diagnosed per year, but other diseases are being reported. RMSF cases rose 50 percent in 2012 compared to 2011. In June 2013, a child died from RMSF.
In 2009, the Ixodes affinis tick, native to South America and previously seen only in coastal Florida and Georgia, was found in North Carolina. Recently, the more southerly Gulf Coast tick, which transmits canine hepatozoonosis, was spotted there as well. This disease affects muscle cells and results in a debilitating and usually fatal condition. The aggressive lone star tick, historically found in southern and south-central states such as Texas and Florida, has been marching north and east for decades, scientists say. It has even worked its way into Maine and Ontario, Canada.
According to the CDC, cases of RMSF, mainly found in the Southeast, cropped up in an area of eastern Arizona where it had never before been seen—mostly in communities with many free-roaming dogs, who likely carried the brown dog tick. Newer deer tick pathogens are expanding their range, as well.
Tipping Points
Many things are tipping the balance, scientists say, and they're all wrapped together. They include the prevalence of deer, invasive plants, bird migration and traveling pets. Then there's the sprawl of suburbs into woodlands, which exposes more people and pets to tick-borne diseases.
Some point to dwindling biodiversity, as animals that keep tick numbers down are increasingly shut out of their habitats by development and other human activities. Though ticks aren't known to be any animal's food source, opossums—rarely welcomed in the suburban landscape—groom themselves meticulously, and in the process, kill ticks by the thousands. As Rick Ostfeld, senior scientist at the Cary Institute of Ecosystem Studies, remarked, "Many ticks try to feed on opossums, and few survive the experience."
Warmer weather and drought may be causing oaks to overproduce acorns some years, creating a boom in the white-footed mouse population. More acorns, more mice; more mice, more ticks. When the acorn crop crashes, fewer mice reproduce, and ticks are driven to seek fresh blood.
Some scientists think ticks migrate, following animal hosts that may be moving with the shift of plants.
And they may find perfect habitat in a dog's backyard.
Tools to Stem the Tide
Farmers who take a sustainable approach often use a technique known as integrated pest management (IPM) to control pests and avoid toxic chemicals. Pet owners can learn from these farmers' practices, which combine a range of methods and as few synthetic chemicals as possible. The U.S. Environmental Protection Agency's website describes IPM as "an effective and environmentally sensitive approach" that can be applied in homes and gardens.
In fact, surveys find that homeowners in suburban neighborhoods in the Northeast are reluctant to spray chemicals to kill ticks. And at any rate, ticks are adapting to traditional pesticides. A recent CDC study found that spraying bifenthrin in a suburban area failed to reduce tick bites. Homeowners do widely accept methods such as brush and leaf-litter control or landscape barriers, which experts say offer medium levels of control.
TERC doesn't rule out pesticides to control deer ticks, but suggests careful targeting to limit their use. Their recommended approach combines host-specific "Tick Tubes" and habitat-specific perimeter sprays. They also discuss many other ways to keep ticks in check, including their web-based TickEncounter Risk Calculator. By answering questions about their landscaping and other factors, people can use it to help determine the risks their yards offer, and can receive customized action plans.
At a 2013 EPA conference on tick-borne disease and IPM, Mather discussed his work, including the top protective actions people can take. Among them are knowing the ticks in your area and how to identify their life stages and seasonal patterns; taking protective actions, such as daily tick checks; and, of course, including pets in the plan. Even when a tick finds a dog, it has to be embedded for 24 to 48 hours to spread infection; quick removal drastically reduces the risk. TERC is also working on a vaccine for people, pets and wildlife.
So, the key to successful tick control lies in your own back yard, where about 75 percent of tick bites are said to occur. Seeing one tick is not enough to launch weapons. Signs of deer near your home, though, may be an important clue. To discourage ticks and their hosts, mow regularly, remove weeds and leaves, and make sure garbage and composting containers are rodent-proof. Prevention might also mean removing exotic vegetation or other welcoming habitat. Invasive bush honeysuckle and Japanese barberry, for example, attract white-tailed deer and mice (and thus, their ticks), a study found. Managing the growth of these plants significantly reduced the abundance of infected ticks. Paving or laying down gravel in heavily used areas also helps limit tick turf.
There is no one perfect solution to what seems to be nature's new normal. Come heat or hail, ticks are on the march. As summer unfolds, they're sure to be out in force, seeking the most inviting habitats and hosts. Dog owners just have to think more like farmers … and tick guys.
Wellness: Health Care
A new treatment holds promise
Weekend hikes gradually turn into strolls around the block. Joyful games of fetch or Frisbee are rare. Even standing up after a nap becomes a daunting task for your faithful friend.
Anyone who has had a lifelong canine companion has also had the difficult experience of watching that companion age, becoming increasingly stiff and less interested in play. The cause is usually osteoarthritis, which affects nearly one in every five dogs. The progressive, chronic degeneration of cartilage characteristic of this condition can occur in various joints and at almost any age, and the pain that results can be debilitating.
Geriatric pets most commonly develop it in the hip, stifle (knee) or elbow; however, it is also often seen in dogs with hip or elbow dysplasia as early as one to two years of age. Treatments range from supplements and antiinflammatory medications to surgical intervention and, increasingly, stem cell therapy.
Over the last decade, regenerative medicine, which has been around in the human sphere for nearly a quarter of a century, has become more common in veterinary medicine, and stem cell therapy is at the forefront. Stem cells are the body's way of regenerating itself. Biological "blank slates," they have the potential to specialize into one of many types of cells—skin, muscle, nerve, bone, tendon or ligament—and virtually any organ, and can be found in every organ in the body.
According to Dr. Samuel Franklin, assistant professor of small animal orthopedic surgery at the University of Georgia, a good candidate for the therapy "has failed treatment with less invasive and less expensive treatment and has arthritis that does not benefit from surgery." Franklin also notes that while stem cell therapy helps modulate inflammation, "stem cells do not regenerate cartilage."
In 2005, Dr. Brian Voynick of the American Animal Hospital in Randolph, N.J., was the first U.S. veterinarian to use stem cell therapy in dogs. He recommends it for young dogs with early signs of hip dysplasia and lameness because it is less invasive and more proactive than surgery.
"In cases of hip dysplasia, we see [improvement in] greater than 90 percent of cases—better mobility, less or no lameness, and increased quality of life. Sometimes, we see improvement on radiographs," says Voynick. These results are typical when the therapy is used in conjunction with platelet rich plasma (PRP), a concentrated mix of platelets and growth factors taken from the patient's own blood. According to Voynick, PRP turbocharges the cells' activation. Once injected, stem cells have an anti-inflammatory effect within the joint and contribute to the reformation and architectural organization of the tissues.
Voynick recalls a case of a dog with severe hip osteoarthritis treated with stem cell therapy and PRP. "[Before treatment] she could not stand up from a lying position. Three days later, she was walking and wagging her tail."
Normally, however, the response is not quite so dramatic. Though improvement in lameness and pain is sometimes seen within the first week, it more commonly comes within a period of about 90 days. The exact duration of the injection's effectiveness is not known, but it is thought that, at least initially, monthly injections are most beneficial. Patients are rechecked at 30, 60 and 90 days post-treatment, and injections may be repeated if lameness returns.
Stem cell therapy is also being used for osteoarthritis resulting from cranial cruciate ligament (CCL) injuries. This common injury of the canine knee is more often seen in large-breed dogs but can affect dogs of all sizes. CCL injuries may be treated medically with rest and medication, or they may require surgery.
"With a full [CCL] tear, we want the stabilization of surgery," says Voynick, adding that stem cell therapy can be beneficial post-operatively during rehabilitation, especially if the injury is accompanied by muscle loss.
Franklin warns that more research is needed to support the results of stem cell therapy. "There is no evidence that [stem cell therapy] is any more beneficial than other treatments that are less invasive and less expensive." Among these treatments are injections of hyaluronic acid, steroids or PRP. And, says Voynick, "Stem cell therapy should not be used in patients with infections or cancer. Stem cells target inflammation and can exacerbate disease in these cases."
The process itself is relatively straightforward. Stem cells are either embryonic or somatic (adult), the latter of which can be retrieved from bone marrow or adipose tissue (fat). Due to the ease of collection, fat is usually the source of stem cells for use in companion animals. Fat-derived stem cells do not need to be cultured and can, therefore, be sent for processing and returned in as little as 48 hours.
Harvesting the fat is much less invasive than a spay. It is commonly taken from the shoulder, lumbar region or falciform ligament (a fatty ligament attaching the liver to the body wall). The 20-minute surgery is performed under general anesthesia and the fat is then sent to a laboratory, where it yields a product called stromal vascular fraction (SVF).
Once the SVF is in hand, the veterinarian will sedate the dog and inject SVF into the affected joint(s); it may also be injected into the bloodstream intravenously. Any remaining SVF is usually stored for future treatments. Although as with any surgery, there is risk when undergoing anesthesia to harvest the fat tissue, stem cell therapy is generally very safe. And, since SVF is derived from the dog's own cells, the rate of immune reactions is extremely low.
Treatment with stem cell therapy isn't easy on the wallet, however. Surgery, processing and the initial injection can range between $2,000 and $3,000, close to the cost of some surgical treatments. There are also no guarantees, and surgery may still be required if stem cell therapy fails. As Franklin, who recommends a case-by-case assessment on the value of stem cell therapy to an individual dog, notes, "It's all about pros and cons—[deciding] what will be best for the patient."
News: Guest Posts
The danger of foxtails grows
The season of ripgut and painful vet bills is here. Foxtails, a longtime scourge in the West, can now be a problem in every state. And climate change may add a twist. Studies find that weeds grow faster under elevated atmospheric carbon dioxide; will migrate northward and are less sensitive to herbicides. A botanist who researched their effects on dogs also warns about a deadly disease.
Sporting dog owners may know it best since field dogs routinely charge into thick brush, where they easily inhale or swallow foxtails, and spend hours in grassy hotspots. But dogs playing in the park or yard, hiking, at a roadside stop; any dog, wherever foxtails live, can develop grass awn migration disease.
It begins with a jagged seed. Of the many kinds of foxtails, both native and non-native, only some have harmful barbs. Among them: foxtail barley, found nationwide except in the South Atlantic and Gulf Coast states, according to the U.S. Forest Service; cheatgrass; giant foxtail, and ripgut brome, named for its effects on livestock. The spring through fall season often starts in May, when the green, bushy awns turn brown and seeds disperse. Their spikes help them burrow into soil or be spread by animals. They can also dig down in fur and puncture skin. The foxtail, which carries bacteria, may then keep tunneling into tissue, carving the dangerous path of infection that marks grass awn disease.
The disease is very difficult to diagnose, says University of Wyoming botanist William K. Lauenroth, who studied its occurrence in ten Midwestern states, where field dog owners believe there's been a sharp rise in cases. One reason it's hard to pinpoint is that the infection occurs behind the migrating seed.
Many infections show up as an acute illness, according to the findings of Wisconsin resident Cathy Lewis, whose website meanseeds.com provides case histories and information about foxtails and grass awn disease. In 2013, her Springer Spaniel "XL" developed a mysterious respiratory ailment that required draining fluid from his lungs. It began during an outing in January; not the time of year when foxtails come to mind. But the website of Atascadero Pet Hospital in California says they've seen pets with "a recurrent abscess that is ongoing for 2 years and once the foxtail is removed the abscess goes away."
In fact, no plant material was found to confirm XL's condition. But Lewis has had several other dogs with grass awn infections and recognized the signs, however vague. Today XL is "doing fine," Lewis says. "He's back to running field trials, and placing." That may be due to how quickly she acted on his symptoms: labored breathing, high temperature and lethargy.
Vets say the dog's body can't break down the plant material. Sometimes, a foxtail lodges and causes a localized infection. But when it migrates, its barbs keep it moving on a one-way journey to almost anywhere, even the brain. Organs can be pierced, fungal infection can arise, and bacteria pack an extra punch deep inside the body. Head shaking or muscle movement propels it onward. Breathing can draw it further into nasal passages. Inhaled foxtails can travel from the nasal cavity to the lungs; a common site in working field dogs.
But what about the urban hound or beach bum pup? One study of grass awn migration found the most common site in all dogs was the external ear canal. Others were feet, eyes, nose, lumbar area, and thoracic cavity. Warning signs, if any, include extreme sneezing, head-shaking; coughing; excessive licking of a skin puncture, and a high temperature.
According to Dr. Jeffrey Horn's veterinary blog, "foxtails are very hard to find due to their small size and because they're covered with infection and scar tissue, and are completely invisible on X-Rays."
Sporting dog owners hope to make it easier to diagnose and treat grass awn. Lauenroth, who trains retrievers, pursued the matter with a grant from the AKC and sporting dog groups. They suspect barbed grasses, especially Canada wild rye, planted in the U.S. Department of Agriculture's Conservation Reserve Program have caused more cases. The grasses occur on lands where field dogs train and trial. The program pays farmers to let idle cropland provide ecological services, such as erosion control and wildlife habitat. The farmers plant approved native grasses and comply with mowing restrictions.
Lauenroth found that plenty of Canada wild rye has been planted in the Midwest, and its sharp awn makes it dangerous for dogs. Canada wild rye is also common along the east coast, he says. But the study dried up due to a dearth of definitive diagnoses to draw on. For vets, finding a foxtail seed in a dog is like searching for a needle in a haystack. Lauenroth says he was unable to extract numbers of cases over the past 20 years from the records of veterinary hospitals.
What he found were many "foreign body" cases without resolution. Many of those may have been grass awn disease. A study in 1983 found that grass awn migration in dogs and cats accounted for 61 percent of all foreign body-related cases. Most involved dogs.
To make foxtails more visible, vets often suggest giving dogs a close shave called a foxtail haircut. Others swear by headgear that is truly a pup tent: foxtail hoodies, designed to keep mean seeds out of eyes, ears and mouths.
Lauenroth's advice is to thoroughly brush and comb after outings. The seeds don't instantly disappear into the body. Also, get to know the few dangerous grass plants in your area.
In foxtail zones like California, it can also mean getting to know other dog owners: many outings at park and beach end with a festive foxtail-pulling party.
Wellness: Healthy Living
It's time to get out, kick back and have fun with dogs—safely!
Homework: Before you set off on your summer road trip, check out rules and regs and make a list of dog parks, vets and doggie hang-outs at your destination (and stops along the way). There are apps for that—BringFido (bringfido.com), for example.
Be Ready: Put together a "go-bag" for your dog, which can also serve as an emergency kit; include basic first-aid supplies, an extra collar with ID tags, a leash, bowls, a couple of old towels or a blanket, and perhaps food with a good shelf life.
Overheating: It's nice to have company when you're running around doing errands, but this time of the year, it's best to let your co-pilot snooze at home rather than in your car. Even if it's "not that hot," even with the windows down, even in the shade, cars heat up fast, and heatstroke kills.
Humidity: And it's not just the heat, it's the humidity. Dogs pant to cool off, evaporating body heat by moving it across their wet tongues, and high humidity slows down that process.
Car Safety: If you don't already use one, invest in a canine restraint device for your car. A loose dog can distract you, or worse, become airborne if you suddenly hit the brakes.
Water Safety: Before taking your pooch on the water, be sure she can swim (not all dogs do). Buckle her into a canine lifejacket if you'll be on a fast-moving river or open water. Too much water might also not be a good thing. Swimming, diving for balls or even playing with a water hose can lead to water intoxication that can result in life threatening hyponatremia (excessively low sodium levels).
Splash: A rigid kiddie pool is a perfect place for a hot dog to cool off. A floating toy or two will make it even more irresistible.
Frosty Treats: Or cool her down with frozen treats. Some dogs like plain ice cubes, but practically any food your dog likes can be frozen (try easy-release silicone ice trays or cupcake pans). More recipes online;
Fear Less: Tis the season of thunderstorms and fireworks. If your dog is upset by their noise and flash, get good advice from dog-behavior pro Patricia McConnell at thebark.com/fear. Or check out Thundershirt.
Stung: Some dogs love chasing bees— until they catch one. Be prepared; before that happens, review thebark.com/stings.
Good Host: Doing some outdoor entertaining? Plan ahead with your dog in mind. Start with keeping the yard gate closed and secured, then make sure that all those tasty picnic classics—bones, skewers, corn cobs—don't make their way into Fido's stomach.
Copyright © 1997-2016 The Bark, Inc. Dog Is My Co-Pilot® is a registered trademark of The Bark, Inc


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Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here we report that p38γ MAPK regulates breast cancer cell motility and metastasis, in part by controlling expression of the metastasis-associated small GTPase RhoC. This p38γ-RhoC regulatory connection was mediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we demonstrated that p38γ-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, which were experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38γ associated with lower overall survival of breast cancer patients. Taken together, our results offer a detailed characterization of how p38γ contributes to breast cancer progression, presents a new mechanics-based analysis of cell motility, and discovers a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38γ as a candidate therapeutic target.
Breast cancer (BC) presents as a dysplastic disease of mammary epithelial cells, which can grow uncontrollably for years yet remain confined within mammary ducts or lobules. If diagnosed at this early stage BC responds well to therapeutic intervention (1). BC becomes much more severe once the cancer cells exit the mammary ducts and metastasize to vital organs. Understanding the molecular alterations that confer metastatic properties to otherwise benign cells is therefore essential to controlling the disease and improving patient survival.
p38 MAPK is a serine/threonine kinase that integrates extracellular stimuli and translates them into cellular responses by phosphorylating a network of downstream effector proteins (2). The p38 arm of the MAPK pathway is effected by four isoforms: p38 α, β, γ and δ. Despite their sequence similarity and shared upstream kinases, the p38 isoforms can have unrelated, and even antagonistic, roles in development and disease (3–7).
p38γ (also known as MAPK12, ERK6, or SAPK3) is expressed predominantly in muscle tissue where it promotes myoblast differentiation into myotubes (8–11). p38γ mRNA is overexpressed in several cancers (12, 13) and helps increase Ras-induced cancer invasion (14, 15). Viewing p38γ function from the developmental perspective led us to hypothesize that p38γ enables mesenchymal-like behavior in BC cells by controlling their motility properties.
Using multiple mechanisms of inhibition we reveal that p38γ is a crucial mediator of BC cell motility and metastasis. Our computational model demonstrates the central role of stress fiber orientation in p38γ-mediated cell motility. Through this in silico experimentation, and subsequent in vitro validation, we discover a novel leading edge behavior in motile BC cells. Mechanistically, p38γ elicits its effects at least in part through RhoC GTPase by affecting RhoC ubiquitination and degradation—a regulatory mechanism never before observed for RhoC. Clinically, high p38γ expression is associated with the basal-like BC subtype and confers a worse prognosis. This work establishes that p38γ is a metastasis-enabling gene responsible for mediating BC cell motility and metastasis, in part by regulating cytoskeletal architecture and modulating RhoC.
Untransfected cell lines were cultured in RPMI 1640 (MDA-MB-231, BT549) or DMEM (Hs578t) supplemented with 10% fetal bovine serum, or DMEM/F12 (MCF-10A) supplemented with 10% horse serum. Selection media for shRNA-transfected MDA-MB-231 cells ("scrambled" or "shp38γ") was standard cell line media containing 1μg/ml puromycin. MDA-MB-231 stably transfected with both shRNA and RhoC/RhoC G14V were cultured in standard cell line media containing 1μg/ml puromycin and 350μg/ml G418. All cell lines were grown at 37°C in a humidified 5% CO2 incubator.
Protein was extracted from 70% confluent cells with RIPA buffer. Total protein extracts were incubated with primary antibody (anti-p38γ or anti-phospho-p38) overnight at 4°C. The following morning protein-antibody complexes were captured by incubation with protein A/G beads (Santa Cruz Biotechnology). Immunoprecipitates were run on an SDS-PAGE gel, transferred to a nitrocellulose membrane, and probed with the appropriate reciprocal antibody (anti-p38γ or anti-phospho-p38). All immunoprecipitation and western blot data represent at least 3 independent experiments.
Fresh and formalin-fixed, paraffin-embedded tissue blocks of BC were obtained from the files of the Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI. IRB approval was obtained and the diagnosis was confirmed by morphology. After pathological review, a tissue microarray was constructed from the most representative area using the methodology of Nocito et al. (16). Survival data was obtained from the The University of Michigan's Cancer Registry.
Triple immunofluorescence staining was performed as previously described (17) and the AQUA system (HistoRx, New Haven, Connecticut) was used for automated image acquisition and analysis. See Supplemental Methods for the detailed staining and imaging procedure.
All mouse work was compliant with the University's standards for animal use. 231 scrambled and shp38γ cells were diluted 1:1 with Matrigel (BD Biosciences) to a final concentration of 3 × 106 cells/ml. Athymic nude mice were anesthetized and 1.5 × 105 cells (50 μl) were injected directly into the fourth mammary gland. Tumors were monitored weekly and mice were euthanized once tumor volume approached 2 cm3. Tumors were resected at euthanization, fixed in 10% formalin, and subsequently paraffin embedded. Hematoxylin and eaosin-stained tumor sections were scored for lymphatic metastasis in a single-blind manner by Dr. J. Erby Wilkinson at the ULAM Pathology Core. Lymphatic metastasis was defined as the presence of tumor cells in the inguinal lymph node of the uninjected fourth mammary gland (the contralateral gland, relative to injection site), thus indicating the tumor cells' ability to exit the primary tumor and metastasize to distant sites through the vasculature. The number of mice presenting with lymphatic metastases were compared using Fisher's exact test. Images were captured at room temperature using an Olympus BX-51 upright light microscope with Olympus UPlanApo 10×/0.4 NA and 40×/0.85 NA objectives and an Olympus DP-70 high resolution digital camera with DP controller software.
All data is representative of at minimum three independent experiments, and all error bars are ± s.e.m. unless otherwise indicated. All p-values were calculated by Student's two-tailed t-test unless otherwise noted. Expression levels of p38γ and RhoC in TMA samples were compared using Spearman's rank coefficient. Association between p38γ and BC subtype, and the prevalence of lymphatic metastasis between scrambled and shp38γ cells were determined by Fisher's exact test. The relationship between p38γ expression and patient survival was calculated by Kaplan Meier analysis, with surviving patients censored. The log-rank test statistic was used for significance.
p38 is activated by dual phosphorylation of the Thr and Tyr residues of the conserved TGY motif (3, 18). To assess p38γ functional relevance in aggressive BC, we assayed phospho-p38γ levels in a representative and widely used aggressive BC cell line, MDA-MB-231 ("231 cells"). Compared to the nontumorigenic mammary epithelial cell line MCF-10A, 231 cells have increased levels of phosphorylated p38γ, despite similar levels of total p38γ (Fig. 1A).
To investigate the role of p38γ on the metastatic features of 231 cells we used small hairpin RNA ("shRNA") to stably knock down p38γ expression (Fig. 1B). Importantly, the shRNA did not affect expression of the other three p38 isoforms (Supplementary Fig. S1A). Since there is no p38γ-specific pharmacologic inhibitor, we overexpressed dominant negative p38γ (19) ("DNp38γ") in MDAMB-231 cells as an additional inhibition method (See Supplementary Methods and Supplementary Fig. S2).
Immediately apparent in the p38γ knockdown cells ("shp38γ cells") was an altered cell morphology compared to scrambled control cells ("scrambled cells"). While scrambled cells exhibited the elongated morphology characteristic of 231 cells and mesenchymal cells in general, shp38γ cells adopted a more rounded shape (Fig. 1C), as did DNp38γ cells (Supplementary Fig. S2C). This change was quantified by the cells' aspect ratio (see Methods). As depicted in Fig. 1C (right), shp38γ cells are significantly less elongated than scrambled cells.
We further asked whether the actin cytoskeleton was modified in shp38γ cells. Immunofluorescent confocal microscopy revealed that shp38γ cells have a strikingly disorganized actin cytoskeleton (Fig. 1D), as do DNp38γ cells (Supplementary Fig. S2E). Scrambled cells exhibit mesenchymal-like polarization with cell-length stress fibers oriented at 3.42° ± 1.89° (mean ± std. dev.) on either side of the normal to the leading edge (Fig. 1D). shp38γ cells retain thick actin bundles resembling stress fibers, but primarily confined to the leading edge and with a bimodal orientation distribution at 61.08° ± 3.94° (mean ± std. dev.) (Fig. 1D). This cluster of actin bundles forms the lamellipodia-like structure present in shp38γ cells (Figs. 1C and D) but shows little similarity to classic lamellipodial cytoskeletal architecture, which normally consists of thin, branched actin filaments forming a protrusive meshwork (20).
Elongated cell shape is one factor that delineates both the mode of motility used by a cell and metastatic from non-metastatic cancer cells in vitro (21, 22). To determine whether the shp38γ cells' rounded shape and modified cytoskeletal architecture indicated a change in metastatic properties we first analyzed cell motility—specifically unstimulated random walk—using time lapse microscopy.
p38γ knockdown profoundly affected the quality of cell motility (Fig. 1E, left) and their speed (Fig. 1E, right). Scrambled control cells had a mesenchymal-like motility, consistent with their appearance and cytoskeletal structure, using long pseudopodial projections to "pull" themselves along in alternating cycles of protrusion and contraction (Fig. 1E, top left, and Movie 1). shp38γ cells, however, remained un-polarized and were unable to form long pseudopodia (Fig. 1E, bottom left, and Movie 2). The cells moved inefficiently using broad lamellipodia-like structures and exhibited detachment anomalies at the rear of the cell. Quantitatively, p38γ knockdown significantly reduced cell speed (Fig. 1E, right).
We also investigated p38γ function in cancer cell invasion and aggressive 3D growth and found that p38γ knockdown significantly impaired both properties (Supplementary Figs. S1B–C). These data demonstrate that p38γ knockdown affects the in vitro metastasis-related properties of aggressive BC cells, and specifically inhibits efficient mesenchymal-like motion in a qualitative and quantitative manner.
We observed that p38γ knockdown had functional (impaired motility and other metastasis-related properties) and structural (actin cytoskeleton and cell shape) effects on MDA-MB-231 cells. However, there remained the question of whether the change in actin cytoskeletal structure is sufficient to explain the observed impairment of motility. Since it remains inaccessible to experiments, this central question was addressed by computational modeling.
Our computational models use the finite element method to solve the partial differential equations governing the mechanics of cell motility (see Supplementary Materials and Methods for details). We hypothesized that the strikingly different cytoskeletal architectures--polarized stress fibers in scrambled versus bimodal bundles of fibers in shp38γ cells--underlies the observed differences in motility.
To test this hypothesis we first created a computational model of scrambled cell motility. Using the typical dimensions of scrambled cells (Supplementary Table S2/Fig. 1C), their observed cytoskeletal morphology of ±3.42° (Fig. 1D), and the mechanical properties of actin fibers and cell membranes of mammalian cells (Supplementary Table S1) we varied the rates of actin filament protrusion and retraction as model inputs to successfully recreate the observed locomotion of live scrambled cells (Fig. 1F, top, and Movie 3).
To determine whether actin cytoskeletal architecture delineates the motility of the two MDA-MB-231 phenotypes we next created a computational model of shp38γ cells, using the dimensions reported in Supplementary Table S2 and Fig. 1C, the cytoskeletal morphology of actin bundles at ±61.08° (Fig. 1D and Supplementary Fig. S3) and the same mechanical properties of actin fibers and cell membrane as for the scrambled cells (Supplementary Table S1). We further conjectured, and computationally demonstrated, that the observed oscillations in motion of shp38γ cells that are evident in Movie 2 were only possible if the two families of actin bundles at ±61.08° alternate (are out of phase) in their protrusion and retraction (data not shown). When incorporated, these alternating dynamics, albeit not precisely timed, produced a disjoint crawling motion with oscillations of the cell body of the computational shp38γ cell. This motility was remarkably similar to our live shp38γ cell motility (Fig. 1E, bottom, and Movie 3), suggesting that actin cytoskeletal architecture is important for defining shp38γ cell motility. However, further experiments were necessary to separate the influence of actin fiber orientation from actin protrusion/retraction dynamics.
The computational shp38γ cell motility thus revealed the possibility of a previously unobserved aspect of cellular dynamics, namely waves of oscillating left- and right-of-center protrusion at the leading edge of a migrating cell. To test this model prediction we studied in detail the dynamic behavior of the leading edge of scrambled and shp38γ cells stably transfected with RFP-actin.
Using time-lapse microscopy and image edge detection techniques (Supplementary Materials and Methods), we observed remarkable differences in leading edge protrusion between scrambled and shp38γ cells (Figs. 2A and 2C). At first observation, scrambled cells appeared to protrude in one continuous motion while shp38γ cells had alternating left- and right-of-center protrusions, corresponding to the two families of actin bundles at ±61.08° (Fig. 2A). Upon closer analysis, leading edge protrusion in both cell lines actually manifested alternations between left- and right-of-center leading edge regions (Figs. 2B and 2C). (In the case of scrambled cells these regions correspond to the stress fibers at ±3.42°.) However, the cell lines were distinguished by the time half-period between left and right protrusions being much longer (4.83 ± 1.09 minutes) in shp38γ cells than in scrambled cells (1.75 ± 0.14 minutes) (Fig. 2D). This periodicity is evident in the time lapse movies as the disjoint crawling motion of shp38γ cells (Movie 2), contrasting the coordinated protrusion/retraction cycle of scrambled cells (Movie 1). Also note the larger amplitudes of leading edge protrusions in shp38γ cells (Fig. 2C).
These live cell results confirmed the computational model predictions. We repeated our computational cell motility studies with the mean left/right leading edge protrusion amplitudes and time periods, and trailing edge retraction rates (Supplementary Fig. S4A) which we measured via time-lapse microscopy now used as targets to be met by controlling the actin fiber extension/contraction rates in the model (Supplementary Materials and Methods). Incorporating these experimentally-measured dynamics further refined our computational models, showed good agreement between the live and computational cells, and importantly did not fundamentally alter the refined computational cell model results from the initial ones in a qualitative sense (compare Figs. 1F and and2E;2E; Movie 4). Through a series of additional control computational simulations (Supplementary Fig. S4 and Supplementary Results) we determined that, other parameters remaining the same, modifications in cytoskeletal architecture alone are sufficient to influence cell motility in the manner observed experimentally: from creating effective locomotion in live scrambled cells to ineffective locomotion of shp38γ cells.
Rho-family GTPases (Rac, Rho, and cdc42) are the classic regulators of actin cytoskeletal dynamics driving cell motility (23). Based on the actin cytoskeletal changes and motility defects we observed, we hypothesized that p38γ knockdown affected members of the Rho GTPase family. Interestingly, we found that RhoC GTPase protein levels were downregulated in both shp38γ and DNp38γ cells (Fig. 3A and Supplementary Fig. S2F), with no change in the close homolog RhoA (data not shown). Surprisingly, RhoC mRNA levels were unaffected by p38γ knockdown (Fig. 3B), suggesting p38γ influences RhoC expression at the translational or post-translational level.
To determine whether p38γ affects RhoC expression at the translational or post-translational level we treated scrambled and shp38γ cells with the translation inhibitor cycloheximide and observed the effect on protein expression. Cycloheximide treatment caused RhoC protein levels to rapidly decrease in shp38γ cells with no corresponding decrease in scrambled cells (Fig. 3C), indicating that RhoC protein is less stable in shp38γ cells.
Upon observing this change in stability we asked whether RhoC was ubiquitinated in shp38γ cells—a common marker of proteins slated for degradation. Upon assaying RhoC ubiquitination we found that levels of ubiquitinated RhoC were increased in shp38γ compared to scrambled cells (Fig. 3D).
To elucidate the RhoC degradation mechanism, we treated cells with either proteasome inhibitors (MG132 or lactacystin) or lysosome inhibitors (ammonium chloride or chloroquine) and observed the effect on RhoC protein levels. Lysosome inhibition caused an increase in RhoC protein (Fig. 3E) whereas proteasome inhibitors had no effect on RhoC expression (Supplementary Fig. S1D), indicating that ubiquitinated RhoC is degraded by the lysosome. Taken together, these data support the conclusion that p38γ affects RhoC expression by mediating RhoC protein stability through regulation of RhoC ubiquitination and lysosomal degradation.
Based on the established roles of RhoC in cell motility and metastasis (24, 25) we hypothesized that decreased RhoC expression in shp38γ cells directly contributes to the impaired motility of shp38γ cells. To test this hypothesis, we stably transfected either RhoC or a constitutively active variant (RhoC G14V) into shp38γ cells and observed the effect on cell motility (Fig. 3F).
Live cell microscopy revealed that re-expressing RhoC significantly increased motility of the shp38γ cells to levels comparable to scrambled control cells (Fig. 3G). Interestingly, the cell speed increase seemed to have a near-linear relationship with RhoC expression/activity. Combined with our previous observations, these data establish a novel mechanistic link whereby p38γ directs cell motility through stabilization of RhoC protein.
We next asked whether the p38γ-RhoC relationship persists in human BC tissues. To address this question we assayed expression of p38γ and RhoC using AQUA of immunofluorescence signals for each marker in cytokeratin-positive cells from a BC tissue microarray. Analysis of 177 BC specimens revealed a strong positive correlation between p38γ and RhoC expression (Fig. 3H). Taken together with our in vitro results, these data strongly support a p38γ-RhoC relationship in BC, one that likely involves p38γ regulation of RhoC expression.
Because p38γ specifically alters the actomyosin contractile motility of MDA-MB-231 cells by affecting RhoC expression, we asked whether it plays a similar role in other mesenchymal-like BC cell lines. To address this question we used two additional widely-studied BC cell lines – Hs578t and BT549 – both of which have increased levels of phosphorylated p38γ compared to both MCF-10A and HME non-tumorigenic mammary epithelial cells (Fig. 4A). We transiently knocked down p38γ expression in these two cell lines with siRNA (Fig. 4B) and observed the effects on the actin cytoskeleton and cell motility.
siRNA knockdown of p38γ ("sip38γ") dramatically affected the actin cytoskeletal architecture and cell shape of both cell lines in a manner consistent with 231 shp38γ cells (Figs. 4C–D): sip38γ cells moved significantly less than scrambled cells (Figs. 4E–F). p38γ knockdown in these cell lines also reduced RhoC expression (Fig. 4G). Taken together, these results support our conclusion that p38γ plays a crucial role in promoting motility of aggressive BC cells by modulating RhoC expression.
Having discovered that p38γ is associated with mesenchymal-like cell motility and is overactivated in three basal-like BC cell lines, we hypothesized that p38γ is associated with the basal-like BC subtype. To test this hypothesis we assayed p38γ expression in 43 BC patient samples that were previously analyzed for molecular subtype by PAM50 (26). We divided the cohort into "high" (top 25%) and "low" (bottom 75%) p38γ-expressing tumors and examined the association between p38γ expression level and molecular subtype. We found that the basal-like subtype is significantly enriched in the high p38γ-expressing tumors (p = 0.018, Fig. 5A), whereas none of the other subtypes examined showed significant association with p38γ expression (data not shown). Taken together with our in vitro data, this clinical data strongly supports an association between high p38γ expression and the basal-like BC subtype.
Based on our in vitro observations we hypothesized that p38γ knockdown reduces the metastatic potential of MDA-MB-231 BC cells in vivo. To test this hypothesis we orthotopically xenografted athymic nude mice with 231 scrambled and shp38γ cells and allowed tumors to grow for 14 weeks, at which point we resected the tumors and analyzed the contralateral respective lymph node for signs of metastasis (see Materials and Methods). Two-thirds of mice injected with scrambled cells presented with lymphatic invasion and metastasis, compared to one of nine shp38γ-injected mice (Figs. 5B–C). This in vivo data, combined with the extensive body of in vitro data presented here, strongly suggests that p38γ is necessary for metastasis, and that it exerts its effects, at least in part, by promoting cell motility through regulation of RhoC.
As a final determination of the clinical relevance of p38γ expression we assayed p38γ levels in a cohort of 118 BC cases containing patient survival data. Using the same high/low cutoffs as the molecular subtype analysis, we found a significant association between high p38γ expression and lower overall patient survival (p = 0.013, Fig. 5D). This clinical data supports our in vitro and in vivo findings that p38γ is an important mediator of BC cell aggressiveness, establishing that p38γ expression has important implications for BC patient outcome.
As the breast is a non-vital organ, primary tumor burden is very rarely the direct cause of cancer-specific mortality. Instead, metastasis of cells from the primary tumor to vital organs results in patient death. Here we demonstrate that p38γ is a novel metastasis-associated gene, which acts in part by affecting cytoskeletal orientation, cell motility, and RhoC.
The importance of the p38 MAPK pathway in cancer has been appreciated (6, 27), but diverse, and sometimes contradictory, roles have been described for p38 in cancer (13). In agreement with other recent findings (15, 28) we show that at least some of the discrepancy in p38 function may be attributed to the distinct contributions of p38 isoforms. The p38 MAPK pathway is ubiquitously utilized in stress-response., It logically follows that metastasizing cancer cells, which encounter an ever-changing milieu of cellular stresses, may gain survival advantages under stressed conditions upon modulation of the appropriate p38 MAPK isoforms; thus, dissecting the contributions of each p38 isoform would allow more precise targeting of specific subsets of cancer. p38γ is an especially promising drug target as, in addition to the data presented here, it is a kinase, has restricted tissue expression (8, 10, 11), and lacks a phenotype when knocked out in mice (29)—possibly indicating that its inhibition may offer a differential detrimental effect on tumor versus normal cells.
Using a computational cell model in combination with live cell microscopy studies we showed that p38γ promotes BC cell motility at least in part by mediating actin cytoskeletal remodeling to create proper stress fiber orientation. Using the computational cell models, we first noted that whereas the observed whole cell locomotion could be produced by simultaneous action of all stress fibers in scrambled cells, the experimentally-observed ineffective locomotion of shp38γ cells was only possible if the action alternated between the two families of actin bundles seen in this cell phenotype—a result that would prove difficult to demonstrate using cell biological techniques alone.
The computational model predicted, and subsequent biological experiments verified, the presence of left-right leading edge protrusion oscillations in both scrambled and shp38γ cells. We note that other groups have identified oscillations in components of the leading edge (30, 31), however these oscillations all involved forward-backward (protrusion-retraction) movement of the leading edge as a whole. To the best of our knowledge the data presented here is thus the first evidence of left-right oscillations in the leading edge. Interestingly, the principle difference between the two cell types studied here (scrambled and shp38γ) lies in the periodicity of these oscillations. Through detailed in silico experimentation (Fig. 2, Supplementary Fig. S4) we determined that leading edge protrusion oscillation periodicity is influenced by and inseparable from cytoskeletal architecture. This inseparability sharpens the question of exactly how leading edge actin dynamics are linked to cell shape and cytoskeletal morphology. While this is a subject for future investigation, we do speculate on the chain of events: p38γ knockdown results in cytoskeletal architecture changes, which lead to alteration of cell shape, compensatory changes in leading edge protrusion periodicity, and ultimately modified whole cell motility.
Oscillation of other components of cell motility, such as cell shape (32) and trailing edge retraction (33), have been shown to be essential for productive cell motion in Dictyostelium (32) and fish keratocytes (33). We expect further investigations to uncover links between these processes and leading edge protrusion oscillations.
p38γ bears analogies with other mediators of normal mesenchymal differentiation such as twist and snail, which have been shown to also be important promoters of cancer progression (34, 35): p38γ functions in muscle cell differentiation, and thus it is consistent that it functions in mesenchymal-like BC cells. Interestingly, p38γ appears to exert its effects independently of classical cell differentiation markers, as p38γ knockdown does not alter expression of epithelial-tomesenchymal transition markers such as vimentin or E-cadherin (data not shown) despite significantly reverting the mesenchymal-like phenotype of aggressive BC cells. Although many other genes have been shown to drive metastatic transition (36), based on the data presented here we propose that p38γ serves as a crucial regulator of the major cytoskeletal changes necessary for the switch to rapid, mesenchymal-like cell motility—independent of differentiation status—at least in part by modulating RhoC.
RhoC is involved in stress fiber formation and actomyosin contraction (37, 38)— both of which are perturbed by p38γ knockdown—and has previously been linked to the p38 MAPK pathway (39). RhoC also drives metastasis in several types of cancer, including breast (37, 40–42), and plays a larger role in stress fiber formation and contraction than RhoA (43); thus we postulated that changes in RhoC expression influence the shp38γ phenotype. Supporting this hypothesis we found that re-expressing RhoC alone was sufficient to restore motility to shp38γ cells—a surprising feat, given the multitude of proteins involved in cell motility (44, 45), which highlights the importance of RhoC in p38γ-mediated cell motility. Further supporting the p38γ-RhoC link is our finding that expression of the two proteins is concurrently altered in clinical BC specimens (Fig. 5A), suggesting that the p38γ-RhoC axis may be functionally significant—and a potentially druggable target—in the clinic.
We discovered that p38γ regulates RhoC expression by preventing RhoC ubiquitination and subsequent lysosomal degradation. Although other p38 isoforms have been linked to protein ubiquitination (46, 47), ours is the first evidence of p38γ contributing to this process. Ubiquitination and protein degradation have recently emerged as important mechanisms for regulating Rho GTPase expression (48), however this is the first demonstration of modulating RhoC ubiquitination as a relatively fast mechanism to regulate RhoC action within a time domain relevant to cell motion. Further research into the specific proteins and mechanisms regulating ubiquitination of RhoC and other Rho GTPases should have significant impact on our understanding of how cell motility and metastasis are regulated.
We thank the University of Michigan Microscopy and Image Analysis lab for excellent technical support with all microscopy work; Dr. J. Erby Wilkinson and the ULAM Pathology Core for tissue processing and pathologic analysis; and Dr. Dafydd Thomas and the UMCCC Tissue Core for performing the AQUA staining and image acquisition.
Grant Support This work was supported by the Department of Defense Breast Cancer Research Program through a Predoctoral Traineeship award (BC083262) (D.T.R.) and a Multidisciplinary Postdoctoral award (A.C.V.), an NIH Cellular and Molecular Biology Training Grant (T32-GM07315) (D.T.R.), the Burroughs Wellcome Fund (S.D.M.), the Breast Cancer Research Foundation (S.D.M.); and a Department of Energy PECASE award (K.G.). A.C.V. is a member of the Carrera del Investigador Científico (CONICET)
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.

subset: commoncrawl


text:
SYDNEY, 4 November - The Sydney Blue Sox defeated Team New Zealand 10-4 Sunday evening at Blacktown International Sportspark behind three hits and two RBIs from Jacob Younis.
The catcher came to the plate four times and finished with three hits, two runs, two RBIs and a stolen base to lead the Blue Sox to their highest run total of the season, dating back to their season-opening series against Canberra and the three-game series against Team Australia last weekend.
The DiamondBlacks scored in the top of the second inning to take a 1-0 lead but that was the only time they led in the contest as the Blue Sox scored one run in the third inning and two runs in the fifth to take a 3-1 lead.
Team NZ cut the deficit to 3-2 in sixth inning, but in the bottom of the sixth Sydney scored three runs, highlighted by a single from James Robbins, a walk to Zac Shepherd and an RBI-single from Younis for a 6-2 advantage.
However, Team NZ would not go quietly, scoring two more runs in the seventh inning when Max Brown ripped an RBI-single and David Skeels smoked an RBI-double to cut the Blue Sox lead to 6-4. Sydney put the game beyond all doubt in the seventh and eighth innings when they scored two runs in each, closing the scoring at 10-4.
"Today was a good chance for some of our younger players to get some international experience," Blue Sox manager Jason Pospishil said. "Our pitching struggled a little bit but our offence was able to pick them up. It was nice being able to play Team New Zealand which showed they have some quality players."
Luke Wilkins earned the win with three innings of relief pitching, while Nick Dawson suffered the loss for Team NZ.
For the DiamondBlacks, it was their first-ever competitive baseball game as a club, and Moko Moanaroa finished 3-for-4 with a single, double and solo home run. Team NZ first baseman Boss Moanaroa, Moko's brother, will compete for the Blue Sox at the conclusion of the DiamondBlacks' World Baseball Classic qualifying rounds.
The Blue Sox and DiamondBlacks continue their two-game series tomorrow night at Blacktown International Sportspark. First pitch is scheduled for 7:30 p.m.
ABL Headlines
- Baseball Australia reveal Honkbal roster
- Hoskins hits walk-off blast in Double-A
- Baseball closer to 2020 Olympic return
- ACT government to fund Narrabundah renovations
- ABL in MLB: Saupold debuts, Goeddel heats up
- Saupold becomes 32nd Aussie in MLB
- Former MLB-er Snelling coaching high school baseball
- Moylan returns to Majors with Kansas City Royals
- Saupold off to strong start in Triple-A
- Goeddel, Rickard shine on MLB Sunday
MLB Headlines
- Young aces star in NL East clash on MLB.TV
- Dra-Matt-ic finish! Cards top LA in 16
- Awe in the Familia: Met streak elite at 50
- Big names bubble up in trade talks
- Hall of Fame induction weekend FAQ
- Missing Hall of Famers leaving a void
- Yankees stay hot, send Giants to 6th straight loss
- Peers share tales from Griffey's HOF career
- Astros edge Angels, gain ground on Rangers
- Piazza's induction to hold special place with Mets fans


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text: With a stay at Dar Guzeppa Farmhouse in Xaghra (Gozo), you'll be minutes from Ta'Kola Windmill and Ggantija Temple. This hotel is within close proximity of Xerri's Grotto and Calypso's Cave. Make yourself at home in one of the 5 air-conditioned rooms featuring kitchens. Rooms have private balconies. Cable television is provided for your entertainment. Conveniences include phones, as well as ceiling fans and irons/ironing boards. Be sure to enjoy recreational amenities including an outdoor pool and a spa tub. Additional features include babysitting/childcare (surcharge), tour/ticket assistance, and barbecue grills. Getting to nearby attractions is a breeze with the complimentary area shuttle. Featured amenities include multilingual staff and laundry facilities. A roundtrip airport shuttle is provided at no charge. An outdoor pool and a spa tub are on site. The recreational activities listed below are available either on site or nearby, fees may apply.


text:
I had to find a bed here, because it was getting late and the map showed fewer settlements, the further Westward I went. After some searching, I was lucky to find a hot pot of tea and a simple place - no, not this one in the picture. ;))
Ich musste wohl bald ein Bett finden, nicht nur wegen der späten Stunde; denn die Karte zeigte mir, dass, je weiter gegen Westen ich fuhr, umso weniger Gelegenheiten zum Übernachten würde es geben. Nach einigem Suchen fand ich schliesslich ein einfaches B&B mit einem heissen Krug Tee - nein, nein, nicht das Gebäude im Bild. ;))
Hi Swissmay;
Very beautiful scenery, small house, how beautiful, spring has arrived .. Congratulations ..
Wishes, greetings from Turkey .. Ismail
Thank you very much, Ismail! The photo is from June 2008. Best greetings, May
Oh so nice to see pictures from your 2008 venture May...Good you found better lodging than this shed here.... Best wishes, Peter
Lieber Peter, vielen Dank für deine Besuche und Kommentare! I am happy, someone reads my texts below the photos. :) Yes, the lodging I found was a little better than that one. ;) In this region it's not very easy to find an accomodation as a single person. Warm regards, May
I also read your texts below the photos May:)... and in fact it's a part of the picture, sometimes with very interesting information, thank you:) Cheers, Jurgis
Jurgis, I am very pleased, that you are interested in the information as well, thank you very much! This picture above is close to a military airport and a nuclear plant. Besides there are only a few towns and villages on this part of the coast. I enjoyed the long days in June and I guess, Lithuania must be about the same latitude as the North of Scotland. Warm regards, May
Thanks May. I've never been north of Inverness. It's very pretty up there.
Hank, thank you! I love the solitude up in the North, the winds and the bright nights. I went to sleep at midnight, when it was still bright and awoke at 3 am, when it was bright again. :) Best wishes, May
Thanks for your response May, I see this photo is taken at the latitude 58°, Vilnius is at 54°, so there was a little bit brighter. Last year I was in beginning of July near Kuusamo in Finland which is at 65°, that was already impressive, in fact no darkness at all:) Kind regards, Jurgis
Jurgis, thanks for coming back! I found it already impressing in the North of Scotland, how very much more it must be in the higher North. Best regards, May
Cher Domi, je te remercie pour ta visite! Oui, je l'aimais beaucoup, il y avait un vent énorme, parfait pour produire de l'énergie. Amitiés, May
Thank you for your visits to my country have done. I hope you like.
This is wonderful photo !!
Greetings murat
Thank you, Murat! Yes, I like your country very much. I have met very friendly people. Greetings, May
Ma Grannie,s Hieland Hame, May.LOL cheers scally.
:) Hi Scally, thanks!
With the windmills doing their bit to reduce carbon footprints, it suggests the roof patches may be solar panels. The hut may have had hot running water and a warm place to stay, May!! LOL
Dear May,
It really is wonderful to wander through Thurso and along the coasts of Scotland with you, then plunge again into the beauty of Engadin!
LOL! Maybe there would even have been access to the internet and a soft bed of straw, Ian! Those few photos from Scotland are just to tease you. The others will have to wait to be uploaded till maybe next year. I don't know yet exactly, where I will go to this summer. First of all I want to see my two grandchildren in Northengland. One thing I know, there will be some more photos to upload during the next 5 years or so. :)
My warmest regards, May
Photo taken in Highland, UK


text:
Speed Bumps, and an Exit, on Iran's Nuclear Road
Think of Iran's nuclear program as a car chugging down a highway, moving relentlessly ahead but with miles to go before reaching its destination.
Now think of U.S. policy as an effort to slow that car down and make it increasingly expensive to drive—while also building an exit ramp off the highway. The great question to be answered in the next few months is whether Iran has any interest at all in taking that exit ramp.
Right now, the effort to increase the cost of Iran's nuclear journey is going reasonably well. International sanctions to stop Iran before it can develop nuclear weapons are having a deeper bite than skeptics expected when the United Nations Security Council imposed a new round of them in early June. The European Union and Canada have since joined the U.S. in imposing additional restrictions on doing business with Iran; American officials say Japan and South Korea will follow suit shortly. Most notably, the sanctions seem to be limiting Iran's ability to import badly needed refined gasoline. So Tehran's drive is getting more costly.
But are the U.S. and its allies also succeeding in slowing it down? That's harder to tell.
Iran's enrichment effort certainly seems to be hitting some technical problems. At the big uranium-enrichment facility at Natanz, U.S. officials say, only about half the installed enrichment centrifuges appear to be operating, with others broken or held in reserve.
Whether that's the result of technical deficiencies or sabotage is anybody's guess. In either case, the pace of enrichment isn't what was once feared. Iran probably has enough low-level uranium to produce two nuclear weapons, if it were to clear the considerable hurdles to turning raw material into arms—something Tehran insists, of course, it isn't interested in doing anyway.
So there's some good news on making Iran's journey slower and costlier. That's where the exit ramp comes into play.
U.S. and European officials realize that if the economic pressure now being applied has any chance of succeeding in changing the game, Iran needs to be given a face-saving way to back away from its current nuclear program into one more clearly designed for peaceful purposes. Much of the conversation in coming weeks with America's allies in this effort—the other four permanent members of the Security Council, plus Germany—will be devoted to this topic.
The latest Security Council sanctions resolution starts to sketch out what this exit ramp would look like. Iran would suspend enrichment activity and its work on a heavy-water nuclear research reactor, and cooperate with the International Atomic Energy Agency to answer a host of questions about its previous, often secretive nuclear activities. Then sanctions would be lifted.
But the U.S. and its allies know that, if only to retain the diplomatic high ground, they will need to offer something more to make it clear that a truly peaceful nuclear program will be acceptable. That was the point of the offer the allies made to Tehran last fall, proposing to take a good chunk of its low-enriched uranium, process it further for use in a medical-research reactor in Tehran, and then ship it back to Iran strictly for that purpose.
Look for further offers to show Iran, and the world, that the world would accept a legitimate nuclear-energy program, and that Tehran has no need to enrich uranium to have one. That's why Russia's move this month to provide the fuel to start a new nuclear power plant at Bushehr wasn't all bad. By providing the fuel, and taking away spent fuel, the Russians have undercut Iran's argument that it has to do its own enrichment.
Beyond calling Iran's bluff, there's a genuine need to find out whether Iran's leaders—at least some of them— might actually be interested in a way out. Nobody thinks the odds are very good, but the economic pressure now is real enough to test the possibility.
Signals from Iran are typically mixed. Last week, President Mahmoud Ahmadinejad said he was interested in talks with the West this fall, while supreme religious leader Ali Khamenei promptly ruled them out until sanctions are lifted. Then, over the weekend, President Ahmadinejad said in a Japanese newspaper interview that he was ready for talks with no preconditions.
Meantime, an important new IAEA report on the status of Iran's program is only weeks away. As they wait, U.S. officials console themselves with the knowledge that Iran's dithering serves at least one useful purpose.
"If they refuse to talk," says Gary Samore, the White House official in charge of nuclear issues, "that obviously makes it easier for us to make the case that Iran is the obstacle, and that there is a need to increase the pressure."
Write to Gerald F. Seib at firstname.lastname@example.com


text:
I'm looking for a fast way to interconvert between linear and multidimensional indexing in Numpy.
To make my usage concrete, I have a large collection of N particles, each assigned 5 float values (dimensions) giving an Nx5 array. I then bin each dimension using numpy.digitize with an appropriate choice of bin boundaries to assign each particle a bin in the 5 dimensional space.
ndims = 5
p = numpy.random.normal(size=(N,ndims))
for idim in xrange(ndims):
bbnds[idim] = numpy.array([-float('inf')]+[-2.,-1.,0.,1.,2.]+[float('inf')])
binassign = ndims*[None]
for idim in xrange(ndims):
binassign[idim] = numpy.digitize(p[:,idim],bbnds[idim]) - 1
binassign then contains rows that correspond to the multidimensional index. If I then want to convert the multidimensional index to a linear index, I think I would want to do something like:
linind = numpy.arange(6**5).reshape(6,6,6,6,6)
This would give a look-up for each multidimensional index to map it to a linear index. You could then go back using:
mindx = numpy.unravel_index(x,linind.shape)
Where I'm having difficulties is figuring out how to take binassign (the Nx5 array) containing the multidimensional index in each row, and coverting that to an 1d linear index, by using it to slice the linear indexing array linind.
If anyone has a one (or several) line indexing trick to go back and forth between the multidimensional index and the linear index in a way that vectorizes the operation for all N particles, I would appreciate your insight.


text:
Chinese shares tumbled 3.80 percent by the break on Tuesday, extending the previous day's hefty losses as dealers fret over a liquidity crisis in the country's banking system that has squeezed lenders.
The benchmark Shanghai Composite Index dived 74.56 points to 1,888.68, following a 5.30 percent dive on Monday.
Investors have been spooked as cash dries up and the interbank rate -- the interest banks charge to lend to each other -- has jumped, raising fears they will cut back on loans, which would in turn drag on the economy.
The central People's Bank of China added to those worries on Monday when it ruled out providing any fresh cash to bolster markets and ordered banks to get their own houses in order.
"We are likely to see the stock market under more downward pressure if the central bank doesn't make any policy stance, explicitly or implicitly," Minsheng Securities analyst Zhang Lei said.
However, despite the growing discomfort the seven-day repurchase agreement rate -- a benchmark for interbank borrowing costs -- fell to 6.50 percent from Monday's close of 7.53 percent. It is also well down from the 11.62 percent seen on Thursday.
Banking stocks fell across the board.
China Minsheng Bank tumbled 9.87 percent to 7.67 yuan, Industrial Bank lost 5.69 percent to 13.10 yuan and China Merchants Bank dropped 4.94 percent to 10.39 yuan.
-- Dow Jones Newswires contributed to this story --