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Tai Chi Exercise: Horse Dance – Video


Tai Chi Exercise: Horse Dance
Learn more: http://www.uwhealth.org UW Health Integrative Medicine Mindfulness instructor Kristi Rietz demonstrates a practical Tai Chi exercise called, "Horse Dance." This exercise is intended to help support your well being by encouraging you to become aware of your body and how it feels. When you experience stressful situations, hopefully you will be able to draw on your awareness to feel how stress is affecting you so you can can relax and breathe deep.From:UWHealthWIViews:11 0ratingsTime:03:52More inEducation

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Tai Chi Exercise: Horse Dance - Video

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Simple Ways to Never Age, According to Experts | Eat This Not That – Eat This, Not That

Living to be 100 used to be a novelty, so much so that Willard Scott, the Today Show weatherman, would announce your name on air in awe (Al Roker still does). Yet, these days it's not so uncommon to live that long. We're all living longer than ever. The Centers for Disease Control and Prevention currently pegs 78 years of age as the average life expectancy. That's not too shabby considering a century ago people lived to be around 39 (due to an influenza outbreak).

But what if we could push it 25 years more?

Worldwide, there are nearly 500,000 people who have made, or surpassed, the 100-mark, and this number is projected to grow to 3.7 million by 2050. Here, Eat This, Not That! Health rounds-up the latest research that'll not only help you to live to be triple digits, but ensure you're happy doing so. Read onand to ensure your health and the health of others, don't miss these 19 Ways You're Ruining Your Body, Say Health Experts.

Don't down a bottle of Jgermeister in hopes of a long life ahead. But a glass of red wine, by all means. "Our research shows that light-to-moderate drinking might have some protective effects against cardiovascular disease," says Bo Xi, MD, associate professor at the Shandong University School of Public Health in China and the lead author of a study published in the Journal of the American College of Cardiology, "while heavy drinking can lead to death. A delicate balance exists between the beneficial and detrimental."

The Rx: Red wine contains antioxidants, can lower cholesterol, reduces the risk of stroke and increases bone density. Enjoy one to two glasses a day if you wish.

Eating meat less than once a week may increase longevity by 3.6 years, according to a study published in the American Journal of Nutrition. Another 22-year study out of Finland found increased mortality and disease among individuals with higher animal protein intakes.

The Rx: If you must eat meat, opt for leaner proteins (chicken, turkey, lean cuts of beef) and keep off the bacon and sausages since diets heavy in processed meats are linked to higher risk of cancer and heart disease. Otherwise, explore the exciting new world of plant-based nutrition, with a product like Beyond Meat, made with pea protein.

Be mindful of your surroundings, and what you're breathing in. Everything from Benzene (found in gasoline), smoke, and other toxins can lead to cell degeneration and increase mortality rates, studies show.

The Rx: Don't miss this essential list of 100 Ways Your Home Could be Making You Sick.

Olive oil, veggies, fruits, nuts, seafood and a moderate amount of wine and cheesewe've all heard the Mediterranean diet is the secret to a longer life. In fact, numerous studies have linked the diet to improving brain health and function, lower risk of cancer and other diseases.

The Rx: Now it's time you tried it. Eat almonds, hummus, wild salmon, garlic, lemon, quinoa, cauliflower, chia seeds and olives frequently. Eat eggs, Skyr, and chicken moderately. And eat red meat rarely. Avoid entirely the packaged, processed, store-bought items that are loaded with additives.

RELATED: 9 Everyday Habits That Might Lead to Dementia, Say Experts

Gene variants found in centenarians have been linked to their longer lives. A healthy lifestyle can help people live into old age, but these genes help maintain basic maintenance and function of the body's cells in individuals of advanced age, in their 80s and beyond.

The Rx: You can't outrun genetics but you can learn about yours. Consider taking a DNA test, in which you'll learn about your proclivity to certain diseases.

Japan is doing something right! It currently holds the title of longest life span, according to the World Health Organization. This may have something to do with the size of their plates. When it comes to diet, the Japanese tend to eat smaller portionsspecifically the size of a salad plateand don't overstuff themselves. Centenarians studied in Okinawa stop eating when they are 80 percent full. They also tend to live seven years longer than Americans, according to a study, and have fewer cases of heart disease and cancer.

The Rx: Experiment with the 80% rule. Or at the very least, don't keep eating when you feel full.

Don't work so hard; your life depends on it. A Finnish study followed male businessman born between 1919 and 1934, and found that those who didn't sleep enough, were overworked, and didn't take enough time off (i.e. vacation) were 37 percent more likely to die between the years of 1974 and 2004. By 2015, some of the oldest participants, who always took their vacay, reached 81 to 96 years of age.

The Rx: Our current culture rewards non-stop go-and-do work. But at what cost? If you have vacation days, use them to unplug, and be firm with your boss if you must. He'll value your work more if you're alive than dead.

RELATED: The #1 Reason You Could Get Cancer, According to Science

Each hour you binge Netflix, Hulu, HBOthe list goes onafter the age of 25 may cut your life by 22 minutes, according to research out of the University of Queensland, Australia. Those who spent an average of six hours in front of the tube per day were also likely to die five years earlier than those that didn't watch TV at all.

The Rx: There are other reasons to stop clicking "next episode." They can be addictive and eat up your time. (Robert De Niro is currently suing an ex-employee because he watched 55 episodes of Friends in a row.) Enjoy your One Day at a Timeone episode at a time.

A study out of the University of Naples found that too little or too much sleepsleeping less or more than six to eight hours on averageis linked to a 30 percent higher chance of premature death.

The Rx: Seven to eight hours of shuteye is the sweet spot.

RELATED: This Supplement Can Raise Your Heart Attack Risk, Experts Say

Packed with vitamin C and other nutrients, studies have found mustards, also known as Brassicaceae, will keep you around longer, according to researchers.

The Rx: Enojy cabbage, broccoli, cauliflower, kale, radishes, watercress, Brussels sprouts and a few spices like horseradish, wasabi and, yes, white, Indian and black mustard.

Hey, none of us are getting out of this alive, but that's no reason to keep that sour mug. Researchers examined smile intensity among photos of baseball players from the 1950s. Of the players who had died in the years 2006 to 2009, those who were not smiling in those photos lived an average of 72.9 years, while the big smilers lived nearly 80 years. They concluded that there's a clear link between smiling intensity and longevity.

The Rx: Men, stop telling women to smile. It's demeaning and implies they're subservient. However, given the impact on our health (mental and otherwise), we could all stand to turn that frown upside down.

Old dogs can't learn new tricks but you can. Education, coupled with a healthy weight, leads to a longer life expectancy, revealed a study out of the University of Edinburgh, with almost a year added to your life for each year spent studying beyond school.

The Rx: Pull a Dangerfield and go back to schooleven if it's just an herbalism course, knitting class or continuing ed program.

RELATED: I'm A Doctor And Warn You Never Take This Supplement

Avoid certain jobs, some of the deadliest out there, according to the Bureau of Labor Statistics National Census of Fatal Occupational Injuries, if you want to stick around longer. On the flip side, find a job you love. You'll be happier, longer, which can impact you positively long-term.

The Rx: Truck driver, farmers and construction laborers are among the most dangerous, mainly owing to vehicular accidents.

Country life is serene, but the Milken Institute Center for the Future of Aging found that living in a major city can also support longer life spans because of stronger health systems, and more access to learning, arts, culture, and other healthy stimulants.

The Rx: Eat This, Not That! Health is based in New York City and our editors can attest living here indeed makes you feel young, although struggling to afford it might age you. Weigh the fantasy versus reality before any leaps.

Good relationships, more than money or fame, are what keep people happy throughout their lives, a Harvard study revealed. Another study in Personal Relationships looked at 270,000 people in nearly 100 countries with a strong link to better health in older age among those with strong friend and family connections.

The Rx: Send a "friend request" to someone you'd like to be closer toand meet them in person, not just online.

Compared with persons with a normal body mass index (18.5 to 25), those who are underweight, overweight, and obese have an increased risk of death over a 30-year period. Being too underweight, or at the extreme, obese, can impact health significantly over time, show studies.

The Rx: A book like Zero Belly Diet can help you cut dairy, reduce bloat, stay plant-based and be leaner for life.

Stay away from men. That's what centenarian Jessie Gallan, at one time Scotland's oldest woman, credited for her longevity. "They're more trouble than they're worth," she said in an interview before her death in 2015. Granted, Gallan was a tough woman without or without a man. She started working at the age of 13 and spent her 109 years staying fit and having good people in her life but never walked down the aisle.

The Rx: There's no definitive research supporting a link between marriage and longevity one way or the other, although one study found that "current marriage is associated with longer survival. Among the not married categories, having never been married was the strongest predictor of premature mortality." Our advice: Marry the person you want to spend your life with, and give one another room to grow.

If you want to live longer, make sure you and your spouse are happy. A study published by the Association for Psychological Science found that a happy marriage can lead to a longer life.

The Rx: A good marriage is linked to a more active life and healthier habits, overall. How's your relationship?

RELATED: The #1 Cause of Obesity, According to Science

As stressful as parenthood gets at times, having kids can actually keep you around longer since it encourages a healthier lifestyleyou're more likely to give up smoking and stay active, shows one study.

The Rx: Don't have children just to live longer. But if you do have or want kids, remember that your habits become theirs. Set the example.

Keep a good pace. Brisk walking will keep your heart healthy and add some years to your life, according to a recent Mayo Clinic study. Researchers reported that women who walked more quickly had a life span of about 87 years compared to 72 years for women who walked slowly. Meanwhile, men who walked quickly had a life span of about 86 years compared to 65 years for men who walked more slowly.

The Rx: "Walking is man's best medicine," said Hippocrates. Get steppin'.

A handful of nuts a day may keep the doctor away, according to Harvard University research, which found that people who crunch some nuts daily lived 20 percent longer than those who didn't.

The Rx: Our favorite is almonds. Besides being an easy go-to snack that you can whip out of your bag during a good ol' 9-5 shift, almonds are also chock-full of essential vitamins and minerals, with vitamin E and biotin being the most predominant. Those nutrients enable your skin to remain smooth and gives your lush hair and strong nails the nutrition they need to flourish.

Don't stopever! The moment you become stagnant, things may go downhill. Stay active. A 2016 study found that elderly people who exercised for just 15 minutes a day, at an intensity level of a brisk walk, had a 22 percent lower risk of early death compared to people who don't exercise.

The Rx: "For most healthy adults, the Department of Health and Human Services recommends these exercise guidelines: Get at least 150 minutes of moderate aerobic activity or 75 minutes of vigorous aerobic activity a week, or a combination of moderate and vigorous activity," reports the Mayo Clinic.

To quote Dr. Nelly of Nellyville: It's getting hot in here. Frequent spicy food consumption is linked to a longer life. Those who eat spicy foods nearly every day have a 14 percent chance of living longer, according to a Harvard study. Capsaicin and other compounds in chili peppers have been linked to fighting cancer, obesity, and more.

The Rx: Sprinkle some cayenne pepper into your eggs every morning, for a one-two punch of protein and spice.

RELATED: Signs You're Getting One of the "Most Deadly" Cancers.

Researchers at the Carleton University in Canada say that having a sense of purpose may add more years to your life, because of positive relations and emotions and overall well-being.

The Rx: Start small. Rather than ask yourself, "Why am I here? What is my place in the Universe" ask yourself, "What can I do today that will make me feel like I've enriched my life, or the lives of others?"

Yoga can help improve digestion, calm the nervous system, lower blood sugar, and so many other tangible benefits. It's no wonder researchers say it will help increase your overall life span.

The Rx: Get your chaturanga on! There's no doubt a yoga studio near you, with teachers who will welcome first-timers. For long-timers, consider a retreat.

Taking care of your teeth and gums isn't just about preventing cavities or bad breath. The mouth is the gateway to the body's overall health. Not flossing allows plaque to build up, which then turns into tartar that can eventually irritate the gums, which can lead to various infections and disease over time. Researchers followed more than 5,400 people for 18 years and found that those who did not brush their teeth daily had a 22 to 65 percent greater risk of dementia than those who brushed three times a day.

The Rx: The American Dental Association recommends brushing your teeth twice a day. Use fluoride toothpaste, and brush for two minutes.

Coffee is packed with tons of healthy compounds, including antioxidants, which can protect the body against cellular damage that can lead to disease, studies show.

The Rx: Drinking four to five cups daily is also associated with a reduced risk of early death.

This one is pretty self explanatory. An active lifestyle will keep you around longer. Exercising at a moderate level for at least 150 minutes can add on 3.4 years to your life, according to the National Institute of Health.

The Rx: Try one of these 25 Easy Exercises That Boost Your Health Fast. They really work.

Helping others can only make you feel good, and it helps boost overall mental health throughout time, which impacts the body's immunity to fight disease, according to a study published in BMC Public Health.

The Rx: Animal rescue shelters, national parks, Habitat for Humanity, local libraries, political campaigns and the YMCA are a few places that rarely say no to help.

RELATED: Sure Signs You Had COVID and Didn't Know It

Studies show sex releases endorphins and hormones in the body, which can help combat feelings of loneliness and depression, keep you physically active, reduce stress relieving, and boost mental wellness.

The Rx: Take this advice seriously. Having sex is one of theSimplest Ways to Avoid a Heart Attack, Say Doctors.

Are there stairs nearby? Good. Use them. The European Society of Cardiology released a study showing how brisk movement, particularly being able to climb three flights quickly, can reduce your risk of early death from cardiovascular and oncologic, and other diseases.

The Rx: Skip the elevators and escalators, and track your steps with a fitness watch, if you need more motivation.

The sweet stuff won't get you far in lifeliterally. Too much sugar is linked to shorter life spans, according to one study. Sugar has even been linked to reprogramming how our genes function. The Centers for Disease Control and Prevention (CDC) reports that about 14% of the daily calories the average Ameican consumes comes from added sugars. And it shows. According to a Population Health Management publication, the number of Americans diagnosed with diabetes increased more than three times between 1990 and 2010. This just so happens to be the same years sugar starting becoming more prevalent in our food.

The Rx: A book like Sugar Free 3 can teach you how to identify added sugarsand how to give them up.

Get in touch with your spiritual side. People who attend religious services, or have some spiritual connection, typically experience lower levels of anxiety, depression, have lower blood pressure, and are generally in better health. An 18-year study published in PLOS One found that regular service attendance was linked to reductions in the body's stress responses, and worshippers were 55 percent less likely to die.

The Rx: You read that right: 55 percent less likely to die. Start by defining what spirituality means to you, and then see if there's a community that supports that common interest.

If you're not connected to a particular religion, you can still find your spiritual balance through meditation. Not only does it improve mental health, but meditating has been linked to a lower risk of cancer and other diseases, according to a study from the University of California-Davis, which found that regular meditation produces higher levels of telomerase, an enzyme that helps lengthen the telomeres in our chromosomes, which impact aging.

The Rx: Apps like Insight Timer, Headspace and Calm have taken meditating mainstream; try one. One of our favorite apps is 10% Happier, from ABC News man-turned-meditator Dan Harris.

If you know how to laugh at things, you'll live longer. A 15-year study out of Norway assessed the link between a sense of humor and mortality rates among 53,556 men and women and found that women who had a good sense of humor lived longer, despite illnesses, including cardiovascular disease; cheerful men faired just as well with laughter protecting them from infection.

The Rx: We've been obsessed with the funniest lines from HBO's Successionand aren't even sure it's a comedy!

RELATED: Everyday Habits That Make You Look Older, According to Science

Want to live to 85 or longer? Optimistic thinking can add years on to your life, say researchers at Boston University School of Medicine. Optimistic people can better regulate emotions so we can bounce back from stressors and difficulties more effectively.

The Rx: Technically, the glass is always half full. The other half is air.

Creativity keeps the brain healthy and may decrease mortality rates. Researchers agree. Creative people just tend to live longer.

The Rx: Remember this, if something's blocking you: You don't have to be "creative" to create.

Be good to yourself. Self compassion goes a long way, say researchers. It's associated with better moods, can improve body image, and is linked to happiness, optimism, wisdom, personal initiative, and more. Overall, it improves our entire mental health, which keeps our body more resilient to stress and illnesses.

The Rx: Did we mention we love that thing you said today? So smart! So funny! So wise.

People who eat fiber-rich foods, including some good 'ole oatmeal or porridge, cut their risk of dying from cardiovascular, infectious, and respiratory diseases by 24 to 56 percent in men and by 34 percent to 59 percent in women, shows one study.

The Rx: Buy "regular" oatmeal and add berries for sweetness. Anything else may be loaded with dangerous added sugars.

Owning a dog is linked to a longer life, according to researchers out of Uppsala University in Sweden, who reviewed national registry records of 3.4. million men and women, ages 40 to 80.

If you're a cat person, you'll get some extra years from kitties as well. A study by the Minnesota Stroke Institute found that people who owned cats were 30 percent less likely to suffer a heart attack.

The Rx: We mentioned volunteering at the ASPCA. If you feel truly capable of caring for a pet, discuss taking one home. We like these questions from Nylabone:

Get back to basics with food. Those who incorporate more whole grains, vegetables, fruits, and fish and limiting too much sodium, unhealthy fats, excess red meat, sugar, and processed foods, improved their overall health and life expectancy.

The Rx: For the web's #1 nutrition resource, and to make the right food choice every time, head to Eat This, Not That!

Does longevity run in your family? Dig deeper into your family history, including lifestyle habits, illnesses, deaths, and beyond. It may help us tap into how long we ultimately have here.

The Rx: Put together a family treewith dates of birth, death, and causes.

Tea contains flavonoids, a compound that works to boost health. One study found that 88 percent of women were 40 percent more likely to live longer because they drank two cups of tea per day.

The Rx: Go green. The most potent catechin in green tea is EGCG, the powerhouse compound that's responsible for most of green tea's weight loss properties. In addition to revving your metabolism and boosting the breakdown of fat, EGCG can also block the formation of new fat cells.

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2020 in Neuroscience, Longevity, and AIand What’s to Come – Singularity Hub

Covid-19 sucked most of the oxygen out of science this year. But we still had brilliant wins.

The pandemic couldnt bring rockets or humans down: multiple missions blasted off to the red planet in the summer of Mars. Two astronauts launched to the International Space Stationand made it safely backin a game-changer for commercial space travel. NASA released dozens of findings on how space travel changes our bodies, paving the way to keep us healthy in orbitor one day, on Mars and beyond.

Back on Earth, scientists scoured mud ponds and fished out a teeny-tiny CRISPR enzyme that packs a massive punch for genome editing. AI and neuroscience became even more entwinedsometimes literally. Biological neurons got hooked up to two silicon-based artificial neurons, across multiple countries, into a fully-functional biohybrid neural network. Others tapped dopaminethe main messenger for the brains reward systemto unite electricity and chemical computing into a semi-living computer. While still largely a curiosity, these studies take brain-inspired computers to another level by seamlessly incorporating living neurons into AI hardware. Now imagine similar circuits inside the brainNeuralink sure is.

More abstractly, biological and artificial brains further fed into each other in our understandingand craftingof intelligence. This year, scientists found mini-computers in the input tree-like branches of neurons. Like entire neural networks, these cables were capable of performing complex logical calculations, suggesting our brain cells are far brainier than we previously thoughtsomething AI can learn from. On the flip side, a hotshot algorithm inspired by the brain called reinforcement learning pushed neuroscientists to re-examine how we respond to feedback as we learn. AI also helped build the most dynamic brain atlas to date, a living map that can continuously incorporate new data and capture individual differences.

As we leave 2020 behind, two main themes percolate in my mind, not just for what theyve accomplished, but as indicators of what lies ahead. These are the trends Ill be keeping my eyes on in the coming year.

Why we age is extremely complex. So are methods that try to prevent age-related diseases, or slow the aging process itself. This nth-dimensional complexity almost dictates that longevity research needs to self-segregate into lanes.

Take probing the biological mechanisms that drive aging. For example, our cells energy factory spews out bullet-like molecules that damage the cell. The genome becomes unstable. Cells turn zombie-like. Working stem cells vanish. Tissue regeneration suffers. Scientists often spend entire careers understanding one facet of a single hallmark of aging, or hunting for age-related genes. The lucky ones come up with ways to combat that one foefor example, senolytics, a family of drugs that wipe out zombie cells to protect against age-related diseases.

But aging hallmarks dont rear their heads in isolation. They work together. An increasing trend is to unveil the how of their interactions workcrosstalk, in science-speakwith hopes of multiple birds with one stone.

This year, longevity researchers crossed lanes.

One study, for example, took a stem cell playbook to rejuvenate eyesight in aged mice with vision loss. They focused on a prominent aging hallmark: epigenetics. Our DNA is dotted with thousands of chemical marks. As we age, these marks accumulate. Using gene therapy, the team introduced three superstar genes into the eyes of aged mice to revert those marks and reprogram cells to a younger state. Youve probably heard of those genes: theyre three of the four factors used to revert adult skin cells into a stem-cell-like state, or iPSCs (induced pluripotent stem cells). Resetting the epigenetic clock was so powerful it improved visual acuity in old mice, and the team has now licensed the tech to Life Biosciences in Boston to further develop for humans.

Another study combined three main puzzle pieces in agingzombie cells, inflammation, and malfunctioning mitochondriainto a full picture, with the surprise ending that senolytics has multiple anti-aging powers in cells. Talk about killing two birds with one stone. Finally, one team (which I was a part of) combined two promising approaches for brain rejuvenationexercise and young bloodto begin pushing the limits of reigniting faltering memory and cognition due to aging.

Longevity research has long been fragmented, but its starting to coalesce into a multidisciplinary field. These crossovers are just the start of a rising trajectory to combat the multi-headed Hydra thats aging. More will come.

If youre looking for a sign that AI is leaving the digital realm of Atari games and heading into the real world, this year was it.

In biotech, theres no doubt of AIs promise in drug discovery or medical diagnoses. In late 2019, a team used deep learning and generative modelssimilar to AlphaGo, the DeepMind algorithm that trounced humans at Go and wiped the Atari libraryto conjure over 30,000 new drug molecules, a feat chemists could only dream of. This year, the viral hurricane thats Covid-19 further unleashed AI-based drug discovery, such as screening existing drugs for candidates that may work against the virus, or newlydesigned chemicals to fight off SARS-CoV-2 infectionthe virus that causes Covid-19.

For now, we dont yet have an AI-designed drug on the market, an ultimate test for the technologys promise. However, although AI wasnt able to make a splash in our current pandemic battle, the scene is set for tackling the next oneand drug discovery as a whole.

In contrast, AI-based medical diagnosis had a resounding win. This year, the FDA approved a software that uses AI to provide real-time guidance for ultrasound imaging for the heart, essentially allowing those without specialized training to perform the test. The approval brings a total of 29 FDA-approved AI-based medical technologies to date. Even as the debate on trust, ethics, and responsibility for AI doctors cranked up in temperature, the Pandoras box has been opened.

Medicine aside, deep learning further honed its craft in a variety of fields. The neuroscience-AI marriage is one for the ages with no signs of fracture. Outside the brain, AI also gave synthetic biology a leg up by parsing the interactions between genes and genetic networksa mind-bending, enormously complex problem previously only achieved through trial and error. With help from AI, synthetic biologists can predict how changes to one gene in a cell could affect others, and in turn, the cells biochemistry and behavior. Bottom line: it makes designing new biological circuits, such as getting yeast to pump out green fuels or artificially hoppy beer, much easier.

But the coup de grce against AI as an overhyped technology is DeepMinds decimation of a 50-year-long challenge in biology. With a performance that shocked experts, DeepMinds AlphaFold was able to predict a proteins 3D structure from its amino acid sequencethe individual components of a proteinmatching the current gold standard. As the workhorses of our bodies, proteins dictate life. AlphaFold, in a sense, solved a huge chunk of the biology of life, with implications for both drug discovery and synthetic biology.

One more scientific brilliance this year is the use of light in neuroscience and tissue engineering. One study, for example, used lasers to directly print a human ear-like structure under the skin of mice, without a single surgical cut. Another used light to incept smell in mice, artificially programming an entirely new, never-seen-in-nature perception of a scent directly into their brains. Yet another study combined lasers with virtual reality to dissect how our brains process space and navigation, mentally transporting a mouse to a virtual location linked to a reward. To cap it off, scientists found a new way to use light to control the brain through the skull without surgerythough as of now, youll still need gene therapy. Given the implications of unauthorized mind control, thats probably less of a bug and more of a feature.

Were nearing the frustratingly slow, but sure, dying gasp of Covid-19. The pandemic defined 2020, but science kept hustling along. I cant wait to share what might come in the next year with youmay it be revolutionary, potentially terrifying, utterly bizarre* or oddly heart-warming.

* For example, Why wild giant pandas frequently roll in horse manure. Yes thats the actual title of a study. Yes, its a great read. And yes, its hilarious but has a point.

Image Credit: Greyson Joralemon on Unsplash

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Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat dietinduced obesity – Science Advances

Abstract

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

Osteoarthritis (OA) is a multifactorial family of diseases, characterized by cartilage degeneration, joint inflammation, and bone remodeling. Despite the broad impact of this condition, there are currently no disease-modifying drugs available for OA. Previous studies demonstrate that obesity and dietary fatty acids (FAs) play a critical role in the development of OA, and metabolic dysfunction secondary to obesity is likely to be a primary risk factor for OA (1), particularly following joint injury (2, 3). Furthermore, both obesity and OA are associated with a rapid loss of muscle integrity and strength (4), which may contribute directly and indirectly to the onset and progression of OA (5). However, the mechanisms linking obesity, muscle, and OA are not fully understood and appear to involve interactions among biomechanical, inflammatory, and metabolic factors (6). Therefore, strategies that focus on protecting muscle and mitigating metabolic inflammation may provide an attractive target for OA therapies in this context.

A few potential interventions, such as weight loss and exercise, have been proposed to reverse the metabolic dysfunction associated with obesity by improving the quantity or quality of skeletal muscle (7). Skeletal muscle mass is modulated by myostatin, a member of the transforming growth factor (TGF-) superfamily and a potent negative regulator of muscle growth (8), and myostatin is up-regulated in obesity and down-regulated by exercise (9). While exercise and weight loss are the first line of therapy for obesity and OA, several studies have shown difficulty in achieving long-term maintenance of weight loss or strength gain, particularly in frail or aging populations (10). Thus, targeted pharmacologic or genetic inhibition of muscle-regulatory molecules such as myostatin provides a promising approach to improving muscle metabolic health by increasing glucose tolerance and enhancing muscle mass in rodents and humans (8).

Follistatin (FST), a myostatin- and activin-binding protein, has been used as a therapy for several degenerative muscle diseases (11, 12), and loss of FST is associated with reduced muscle mass and prenatal death (13). In the context of OA, we hypothesize that FST delivery using a gene therapy approach has multifactorial therapeutic potential through its influence on muscle growth via inhibition of myostatin activity (14) as well as other members of the TGF- family. Moreover, FST has been reported to reduce the infiltration of inflammatory cells in the synovial membrane (15) and affect bone development (16), and pretreatment with FST has been shown to reduce the severity of carrageenan-induced arthritis (15). However, the potential for FST as an OA therapy has not been investigated, especially in exacerbating pathological conditions such as obesity. We hypothesized that overexpression of FST using a gene therapy approach will increase muscle mass and mitigate obesity-associated metabolic inflammation, as well as the progression of OA, in high-fat diet (HFD)induced obese mice. Mice fed an HFD were treated with a single dose of adeno-associated virus 9 (AAV9) to deliver FST or a green fluorescent protein (GFP) control, and the effects on systemic metabolic inflammation and post-traumatic OA were studied (fig. S1).

Dual-energy x-ray absorptiometry (DXA) imaging of mice at 26 weeks of age (Fig. 1A) showed significant effects of FST treatment on body composition. Control-diet, FST-treated mice (i.e., Control-FST mice) exhibited significantly lower body fat percentages, but were significantly heavier than mice treated with a GFP control vector (Control-GFP mice) (Fig. 1B), indicating that increased muscle mass rather than fat was developed with FST. With an HFD, control mice (HFD-GFP mice) showed significant increases in weight and body fat percentage that were ameliorated by FST overexpression (HFD-FST mice).

(A) DXA images of mice at 26 weeks of age. (B) DXA measurements of body fat percentage and bone mineral density (BMD; 26 weeks) and body weight measurements over time. (C) Serum levels for adipokines (insulin, leptin, resistin, and C-peptide) at 28 weeks. (D) Metabolite levels for glucose, triglycerides, cholesterol, and FFAs at 28 weeks. (E) Serum levels for cytokines (IL-1, IL-1, MCP-1, and VEGF) at 28 weeks. (F) Fluorescence microscopy images of visceral adipose tissue with CD11b:Alexa Fluor 488 (green), CD11c:phycoerythrin (PE) (red), and 4,6-diamidino-2-phenylindole (DAPI; blue). Scale bars, 100 m. Data are presented as mean SEM; n = 8 to 10; two-way analysis of variance (ANOVA), P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. For IL-1 and VEGF, P < 0.05 for diet effect and AAV effect. For MCP-1, P < 0.05 for diet effect.

In the HFD group, overexpression of FST significantly decreased serum levels of several adipokines including insulin, leptin, resistin, and C-peptide as compared to GFP-treated mice (Fig. 1C). HFD-FST mice also had significantly lower serum levels of glucose, triglycerides, cholesterol, and free FAs (FFAs) (Fig. 1D), as well as the inflammatory cytokine interleukin-1 (IL-1) (Fig. 1E) when compared to HFD-GFP mice. For both dietary groups, AAV-FST delivery significantly increased circulating levels of vascular endothelial growth factor (VEGF) while significantly decreasing IL-1 levels. Furthermore, obesity-induced inflammation in adipose tissue was verified by the presence of CD11b+CD11c+ M1 pro-inflammatory macrophages or dendritic cells (Fig. 1F).

To determine whether FST gene therapy can mitigate injury-induced OA, mice underwent surgery for destabilization of the medial meniscus (DMM) and were sacrificed 12 weeks after surgery. Cartilage degeneration was significantly reduced in DMM joints of the mice receiving FST gene therapy in both dietary groups (Fig. 2, A and C) when compared to GFP controls. FST overexpression also significantly decreased joint synovitis (Fig. 2, B and D) when compared to GFP controls. To evaluate the local influence of pro-inflammatory cytokines to joint degeneration and inflammation, synovial fluid (SF) was harvested from surgical and ipsilateral nonsurgical limbs and analyzed using a multiplexed array. The DMM joints from mice with FST overexpression exhibited a trend toward lower levels of pro-inflammatory cytokines, including IL-1, IL-1, and IL-6, and a higher level of interferon- (IFN-)induced protein (IP-10) in the SF of DMM joints as compared to contralateral controls (Fig. 2E).

(A) Histologic analysis of OA severity via Safranin O (glycosaminoglycans) and fast green (bone and tendon) staining of DMM-operated joints. (B) Histology [hematoxylin and eosin (H&E) staining] of the medial femoral condyle of DMM-operated joints. Thickened synovium (S) from HFD mice with a high density of infiltrated cells was observed (arrows). (C) Modified Mankin scores compared within the diet. (D) Synovitis scores compared within the diet. (E) Levels of proinflammatory cytokines in the SF compared within the diet. (F) Hot plate latency time and sensitivity to cold plate exposure, as measured using the number of jumps in 30 s, both for non-operated algometry measurements of pain sensitivity compared within the diet. Data are presented as mean SEM; n = 5 to 10 mice per group; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis.

To investigate the effect of FST on pain sensitivity in OA, animals were subjected to a variety of pain measurements including hot plate, cold plate, and algometry. Obesity increased heat withdrawal latency, which was rescued by FST overexpression (Fig. 2F). Cold sensitivity trended lower with obesity, and because no significant differences in heat withdrawal latency were found with surgery (fig. S2), no cold sensitivity was measured after surgery. We found that FST treatment protected HFD animals from mechanical algesia at the knee receiving DMM surgery, while Control-diet DMM groups demonstrated increased pain sensitivity following joint injury.

A bilinear regression model was used to elucidate the relationship among OA severity, biomechanical factors, and metabolic factors (table S1). Factors significantly correlated with OA were then selected for multivariate regression (Table 1). Both multivariate regression models revealed serum tumor necrosis factor- (TNF-) levels as a major predictor of OA severity.

, standardized coefficient. ***P < 0.001.

We analyzed the effects of FST treatment on muscle structure and mass, and performance measures were conducted on mice in both dietary groups. Both Control-FST and HFD-FST limbs exhibited visibly larger muscles compared to both AAV-GFP groups (Fig. 3A). In addition, the muscle masses of tibialis anterior (TA), gastrocnemius, and quadriceps increased significantly with FST treatment (Fig. 3B). Western blot analysis confirmed an increase in FST expression in the muscle at the protein level in FST-treated groups compared to GFP-treated animals in Control and HFD groups (Fig. 3C). Immunofluorescence labeling showed increased expression of FST in muscle (Fig. 3D) and adipose tissue (Fig. 3E) of the AAV-FST mice, with little or no expression of FST in control groups.

(A) Photographic images and (B) measured mass of tibialis anterior (TA), gastrocnemius (GAS), and quadriceps (QUAD) muscles; n = 8, diet and AAV effects both P < 0.05. (C) Western blot showing positive bands of FST protein only in FST-treated muscles, with -actin as a loading control. Immunolabeling of (D) GAS muscle and (E) adipose tissue showing increased expression of FST, particularly in skeletal muscle. (F) H&E-stained sections of GAS muscles were measured for (G) mean myofiber diameter; n = 100 from four mice per group, diet, and AAV effects; both P < 0.05. (H) Oil Red O staining was analyzed for (I) optical density values of FAs; n = 6. (J) Second-harmonic generation imaging of collagen in TA sections was quantified for intensity; n = 6. (K) Western blotting showing the level of phosphorylation markers of protein synthesis in GAS muscle. (L) Functional analysis of grip strength and treadmill time to exhaustion; n = 10. Data are presented as mean SEM; two-way ANOVA, P < 0.05. Groups not sharing the same letter are significantly different with Tukey post hoc analysis. Photo credit: Ruhang Tang, Washington University.

To determine whether the increases in muscle mass reflected muscle hypertrophy, gastrocnemius muscle fiber diameter was measured in H&E-stained sections (Fig. 3F) at 28 weeks of age. Mice with FST overexpression exhibited increased fiber diameter (i.e., increased muscle hypertrophy) relative to the GFP-expressing mice in both diet treatments (Fig. 3G). Oil Red O staining was used to determine the accumulation of neutral lipids in muscle (Fig. 3H). We found that HFD-FST mice were protected from lipid accumulation in muscles compared to HFD-GFP mice (Fig. 3I). Second-harmonic generation imaging confirmed the presence of increased collagen content in the muscles of HFD mice, which was prevented by FST gene therapy (Fig. 3J). We also examined the expression and phosphorylation levels of the key proteins responsible for insulin signaling in muscles. We observed increased phosphorylation of AktS473, S6KT389, and S6RP-S235/2369 and higher expression of peroxisome proliferatoractivated receptor coactivator 1- (Pgc1-) in muscles from FST mice compared to GFP mice, regardless of diet (Fig. 3K). In addition to the improvements in muscle structure with HFD, FST-overexpressing mice also showed improved function, including higher grip strength and increased treadmill running endurance (Fig. 3L), compared to GFP mice.

Because FST has the potential to influence cardiac muscle and skeletal muscle, we performed a detailed evaluation on the effect of FST overexpression on cardiac function. Echocardiography and short-axis images were collected to visualize the left ventricle (LV) movement during diastole and systole (fig. S3A). While the Control-FST mice had comparable LV mass (LVM) and left ventricular posterior wall dimensions (LVPWD) with Control-GFP mice (fig. S3, B and C), the HFD-FST mice have significantly decreased LVM and trend toward decreased LVPWD compared to HFD-GFP. Regardless of the diet treatments, FST overexpression enhanced the rate of heart weight/body weight (fig. S3D). Although Control-FST mice had slightly increased dimensions of the interventricular septum at diastole (IVSd) compared to Control-GFP (fig. S3E), there was significantly lower IVSd in HFD-FST compared to HFD-GFP. In addition, we found no difference in fractional shortening among all groups (fig. S3F). Last, transmitral blood flow was investigated using pulse Doppler. While there was no difference in iso-volumetric relaxation time (IVRT) in Control groups, HFD-FST mice had a moderate decrease in IVRT compared to HFD-GFP (fig. S3G). Overall, FST treatment mitigated the changes in diastolic dysfunction and improved the cardiac relaxation caused by HFD.

DXA demonstrated that FST gene therapy improved bone mineral density (BMD) in HFD compared to other groups (Fig. 1B). To determine the effects of injury, diet intervention, and overexpression of FST on bone morphology, knee joints were evaluated by microcomputed tomography (microCT) (Fig. 4A). The presence of heterotopic ossification was observed throughout the GFP knee joints, whereas FST groups demonstrated a reduction or an absence of heterotopic ossification. FST overexpression significantly increased the ratio of bone volume to total volume (BV/TV), BMD, and trabecular number (Tb.N) of the tibial plateau in animals, regardless of diet treatment (Fig. 4B). Joint injury generally decreased bone parameters in the tibial plateau, particularly in Control-diet mice. In the femoral condyle, BV/TV and Tb.N were significantly increased in mice with FST overexpression in both diet types, while BMD was significantly higher in HFD-FST compared to HFD-GFP mice (Fig. 4B). Furthermore, AAV-FST delivery significantly increased trabecular thickness (Tb.Th) and decreased trabecular space (Tb.Sp) in the femoral condyle of HFD-FST compared to HFD-GFP animals (fig. S4).

(A) Three-dimensional (3D) reconstruction of microCT images of non-operated and DMM-operated knees. (B) Tibial plateau (TP) and femoral condyle (FC) regional analyses of trabecular bone fraction bone volume (BV/TV), BMD, and trabecular number (Tb.N). Data are presented as mean SEM; n = 8 to 19 mice per group; two-way ANOVA. (C) 3D microCT reconstruction of metaphysis region of DMM-operated joints. (D) Analysis of metaphysis BV/TV, Tb.N, and BMD. (E) 3D microCT reconstruction of cortical region of DMM-operated joints. (F) Analysis of cortical cross-sectional thickness (Ct.Cs.Th), polar moment of inertia (MMI), and tissue mineral density (TMD). (D and F) Data are presented as mean SEM; n = 8 to 19 mice per group; Mann-Whitney U test, *P < 0.05.

Further microCT analysis was conducted on the trabecular (Fig. 4C) and cortical (Fig. 4E) areas of the metaphyses. FST gene therapy significantly increased BV/TV, Tb.N, and BMD in the metaphyses regardless of the diet (Fig. 4D). Furthermore, FST delivery significantly increased the cortical cross-sectional thickness (Ct.Cs.Th) and polar moment of inertia (MMI) of mice on both diet types, as well as tissue mineral density (TMD) of cortical bones of mice fed control diet (Fig. 4F).

To elucidate the possible mechanisms by which FST mitigates inflammation, we examined the browning/beiging process in subcutaneous adipose tissue (SAT) with immunohistochemistry (Fig. 5A). Here, we found that key proteins expressed mainly in brown adipose tissue (BAT) (PGC-1, PRDM16, thermogenesis marker UCP-1, and beige adipocyte marker CD137) were up-regulated in SAT of the mice with FST overexpression (Fig. 5B). Increasing evidence suggests that an impaired mitochondrial oxidative phosphorylation (OXPHOS) system in white adipocytes is a hallmark of obesity-associated inflammation (17). Therefore, we further examined the mitochondrial respiratory system in SAT. HFD reduced the amount of OXPHOS complex subunits (Fig. 5C). We found that proteins involved in OXPHOS, including subunits of complexes I, II, and III of mitochondria OXPHOS complex, were significantly up-regulated in AAV-FSToverexpressing animals compared to AAV-GFP mice (Fig. 5D).

(A) Immunohistochemistry of UCP-1 expression in SAT. Scale bar, 50 m. (B) Western blotting of SAT for key proteins expressed in BAT, with -actin as a loading control. (C) Western blot analysis of mitochondria lysates from SAT for OXPHOS proteins using antibodies against subunits of complexes I, II, III, and IV and adenosine triphosphate (ATP) synthase. (D) Change of densitometry quantification normalized to the average FST level of each OXPHOS subunit. Data are presented as mean SEM; n = 3. *P < 0.05, t test comparison within each pair.

Our findings demonstrate that a single injection of AAV-mediated FST gene therapy ameliorated systemic metabolic dysfunction and mitigated OA-associated cartilage degeneration, synovial inflammation, and bone remodeling occurring with joint injury and an HFD. Of note, the beneficial effects were observed across multiple tissues of the joint organ system, underscoring the value of this potential treatment strategy. The mechanisms by which obesity and an HFD increase OA severity are complex and multifactorial, involving increased systemic metabolic inflammation, joint instability and loss of muscle strength, and synergistic interactions between local and systemic cytokines (4, 6). In this regard, the therapeutic consequences of FST gene therapy also appear to be multifactorial, involving both direct and indirect effects such as increased muscle mass and metabolic activity to counter caloric intake and metabolic dysfunction resulting from an HFD while also promoting adipose tissue browning. Furthermore, FST may also serve as a direct inhibitor of growth factors in the TGF- family that may be involved in joint degeneration (18).

FST gene therapy showed a myriad of notable beneficial effects on joint degeneration following joint injury while mitigating HFD-induced obesity. These data also indirectly implicate the critical role of muscle integrity in the onset and progression of post-traumatic OA in this model. It is important to note that FST gene therapy mitigated many of the key negative phenotypic changes previously associated with obesity and OA, including cartilage structural changes as well as bone remodeling, synovitis, muscle fibrosis, and increased pain, as compared to GFP controls. To minimize the number of animals used, we did not perform additional controls with no AAV delivery; however, our GFP controls showed similar OA changes as observed in our previous studies, which did not involve any gene delivery (2). Mechanistically, FST restored to control levels a number of OA-associated cytokines and adipokines in the serum and the SF. While the direct effects of FST on chondrocytes remains to be determined, FST has been shown to serve as a regulator of the endochondral ossification process during development (19), which may also play a role in OA (20). Furthermore, previous studies have shown that a 2-week FST treatment of mouse joints is beneficial in reducing infiltration of inflammatory cells into the synovial membrane (15). Our findings suggest that FST delivery in skeletally mature mice, preceding obesity-induced OA changes, substantially reduces the probability of tissue damage.

It is well recognized that FST can inhibit the activity of myostatin and activin, both of which are up-regulated in obesity-related modalities and are involved in muscle atrophy, tissue fibrosis, and inflammation (21). Consistent with previous studies, our results show that FST antagonizes the negative regulation of myostatin in muscle growth, reducing adipose tissue content in animals. Our observation that FST overexpression decreased inflammation at both serum systemic and local joint inflammation may provide mechanistic insights into our findings of mitigated OA severity in HFD-fed mice. Our statistical analysis implicated serum TNF- levels as a major factor in OA severity, consistent with previous studies linking obesity and OA in mice (22). Although the precise molecular mechanisms of FST in modulating inflammation remain unclear, some studies postulate that FST may act like acute-phase protein in lipopolysaccharide-induced inflammation (23).

In addition to these effects of skeletal muscle, we found that FST gene therapy normalized many of the deleterious changes of an HFD on cardiac function without causing hypertrophy. These findings are consistent with previous studies showing that, during the process of aging, mice with myostatin knockout had an enhanced cardiac stress response (24). Furthermore, FST has been shown to regulate activin-induced cardiomyocyte apoptosis (1). In the context of this study, it is also important to note that OA has been shown to be a serious risk factor for progression of cardiovascular disease (25), and severity of OA disability is associated with significant increases in all-cause mortality and cardiovascular events (26).

FST gene therapy also rescued diet- and injury-induced bone remodeling in the femoral condyle, as well as the tibial plateau, metaphysis, and cortical bone of the tibia, suggesting a protective effect of FST on bone homeostasis of mice receiving an HFD. FST is a known inhibitor of bone morphogenetic proteins (BMPs), and thus, the interaction between the two proteins plays an essential role during bone development and remodeling. For example, mice grown with FST overexpression via global knock-in exhibited an impaired bone structure (27). However, in adult diabetic mice, FST was shown to accelerate bone regeneration by inhibiting myostatin-induced osteoclastogenesis (28). Furthermore, it has been reported that FST down-regulates BMP2-driven osteoclast activation (29). Therefore, the protective role of FST on obesity-associated bone remodeling, at least in part, may result from the neutralizing capacity of FST on myostatin in obesity. In addition, improvement in bone quality in FST mice may be explained by their enhanced muscle mass and strength, as muscle mass can dominate the process of skeletal adaptation, and conversely, muscle loss correlates with reduced bone quality (30).

Our results show that FST delivery mitigated pain sensitivity in OA joints, a critical aspect of clinical OA. Obesity and OA are associated with both chronic pain and pain sensitization (31), but it is important to note that structure and pain can be uncoupled in OA (32), necessitating the measurement of both behavioral and structural outcomes. Of note, FST treatment protected only HFD animals from mechanical algesia at the knee post-DMM surgery and also rescued animals from pain sensitization induced by HFD in both the DMM and nonsurgical limb. The mitigation in pain sensitivity observed here with FST treatment may also be partially attributed to the antagonistic effect of FST on activin signaling. In addition to its role in promoting tissue fibrosis, activin A has been shown to regulate nociception in a manner dependent on the route of injection (33, 34). It has been shown that activin can sensitize the transient receptor potential vanilloid 1 (TRPV1) channel, leading to acute thermal hyperalgesia (33). However, it is also possible that activin may induce pain indirectly, for example, by triggering neuroinflammation (35), which could lead to sensitization of nociceptors.

The earliest detectable abnormalities in subjects at risk for developing obesity and type 2 diabetes are muscle loss and accumulation of excess lipids in skeletal muscles (4, 36), accompanied by impairments in nuclear-encoded mitochondrial gene expression and OXPHOS capacity of muscle and adipose tissues (17). PGC-1 activates mitochondrial biogenesis and increases OXPHOS by increasing the expression of the transcription factors necessary for mitochondrial DNA replication (37). We demonstrated that FST delivery can rescue low levels of OXPHOS in HFD mice by increasing expression PGC-1 (Fig. 3H). It has been reported that high-fat feeding results in decreased PGC-1 and mitochondrial gene expression in skeletal muscles, while exercise increases the expression of PGC-1 in both human and rodent muscles (38, 39). Although the precise molecular mechanism by which FST promotes PGC-1 expression has not been established, the infusion of lipids decreases expression of PGC-1 and nuclear-encoded mitochondrial genes in muscles (40). Thus, decreased lipid accumulation in muscle by FST overexpression may provide a plausible explanation for the restored PGC-1 in the FST mice. These findings were further confirmed by the metabolic profile, showing reduced serum levels of triglycerides, glucose, FFAs, and cholesterol (Fig. 1D), and are consistent with previous studies, demonstrating that muscles with high numbers of mitochondria and oxidative capacity (i.e., type 1 muscles with high levels of PGC-1 expression) are protected from damage due to an HFD (4).

In addition, we found increased phosphorylation of protein kinase B (Akt) on Ser473 in the skeletal muscle of FST-treated mice as compared to untreated HFD counterparts (Fig. 3K), consistent with restoration of a normal insulin response. A number of studies have demonstrated that the serine-threonine protein kinase Akt1 is a critical regulator of cellular hypertrophy, organ size, and insulin signaling (41). Muscle hypertrophy is stimulated both in vitro and in vivo by the expression of constitutively active Akt1 (42, 43). Furthermore, it has been demonstrated that constitutively active Akt1 also promotes the production of VEGF (44).

BAT is thought to be involved in thermogenesis rather than energy storage. BAT is characterized by a number of small multilocular adipocytes containing a large number of mitochondria. The process in which white adipose tissue (WAT) becomes BAT, called beiging or browning, is postulated to be protective in obesity-related inflammation, as an increase in BAT content positively correlates with increased triglyceride clearance, normalized glucose level, and reduced inflammation. Our study shows that AAV-mediated FST delivery serves as a very promising approach to induce beiging of WAT in obesity. A recent study demonstrated that transgenic mice overexpressing FST exhibited an increasing amount of BAT and beiging in subcutaneous WAT with increased expression of key BAT-related markers including UCP-1 and PRDM16 (45). In agreement with previous reports, our data show that Ucp1, Prdm16, Pgc1a, and Cd167 are significantly up-regulated in SAT of mice overexpressing FST in both dietary interventions. FST has been recently demonstrated to play a crucial role in modulating obesity-induced WAT expansion by inhibiting TGF-/myostatin signaling and thus promoting overexpression of these key thermogenesis-related genes. Together, these findings suggest that the observed reduction in systemic inflammation in our model may be partially explained by FST-mediated increased process of browning/beiging.

In conclusion, we show that a single injection of AAV-mediated FST, administered after several weeks of HFD feeding, mitigated the severity of OA following joint injury, and improved muscle performance as well as induced beiging of WAT, which together appeared to decrease obesity-associated metabolic inflammation. These findings provide a controlled model for further examining the differential contributions of biomechanical and metabolic factors to the progression of OA with obesity or HFD. As AAV gene therapy shows an excellent safety profile and is currently in clinical trials for a number of conditions, such an approach may allow the development of therapeutic strategies not only for OA but also, more broadly, for obesity and associated metabolic conditions, including diseases of muscle wasting.

All experimental procedures were approved by and conducted in accordance with the Institutional Animal Care and Use Committee guidelines of Washington University in Saint Louis. The overall timeline of the study is shown in fig. S1A. Beginning at 5 weeks of age, C57BL/6J mice (The Jackson Laboratory) were fed either Control or 60% HFD (Research Diets, D12492). At 9 week of age, mice received AAV9-mediated FST or GFP gene delivery via tail vein injection. A total of 64 mice with 16 mice per dietary group per AAV group were used. DMM was used to induce knee OA in the left hind limbs of the mice at the age of 16 weeks. The non-operated right knees were used as contralateral controls. Several behavioral activities were measured during the course of the study. Mice were sacrificed at 28 weeks of age to evaluate OA severity, joint inflammation, and joint bone remodeling.

Mice were weighed biweekly. The body fat content and BMD of the mice were measured using a DXA (Lunar PIXImus) at 14 and 26 weeks of age, respectively.

Complementary DNA synthesis for mouse FST was performed by reverse transcriptase in a reverse transcription quantitative polymerase chain reaction (RT-qPCR) ( Invitrogen) mixed with mRNAs isolated from the ovary tissues of C57BL/6J mouse. The PCR product was cloned into the AAV9-vector plasmid (pTR-UF-12.1) under the transcriptional control of the chicken -actin (CAG) promoter including cytomegalovirus (CMV) enhancers and a large synthetic intron (fig. S1B). Recombinant viral vector stocks were produced at Hope Center Viral Vectors Core (Washington University, St. Louis) according to the plasmid cotransfection method and suspension culture. Viral particles were purified and concentrated. The purity of AAV-FST and AAV-GFP was evaluated by SDSpolyacrylamide gel electrophoresis (PAGE) and stained by Coomassie blue. The results showed that the AAV protein components in 5 1011 vector genomes (vg) are only stained in three major protein bands: VR1, 82 kDa; VR2, 72 kDa; and VR3, 62 kDa. Vector titers were determined by the DNA dot-blot and PCR methods and were in the range of 5 1012 to 1.5 1013 vector copies/ml. AAV was delivered at a final dose of 5 1011 vg per mouse by intravenous tail injection under red light illumination at 9 weeks of age. This dose was determined on the basis of our previous studies showing that AAV9-FST gene delivery by this route resulted in a doubling of muscle mass at a dose of 2.5 1011 vg in 4-week-old mice or at 5 1011 vg in 8-week-old mice (46).

At 16 weeks of age, mice underwent surgery for the DMM to induce knee OA in the left hindlimb as previously described (2). Briefly, anesthetized mice were placed on a custom-designed device, which positioned their hindlimbs in 90 flexion. The medial side of the joint capsule was opened, and the medial meniscotibial ligament was transected. The joint capsule and subcutaneous layer of the skin were closed with resorbable sutures.

Mice were sacrificed at 28 weeks of age, and changes in joint structure and morphology were assessed using histology. Both hindlimbs were harvested and fixed in 10% neutral-buffered formalin (NBF). Limbs were then decalcified in Cal-Ex solution (Fisher Scientific, Pittsburgh, PA, USA), dehydrated, and embedded in paraffin. The joint was sectioned in the coronal plane at a thickness of 8 m. Joint sections were stained with hematoxylin, fast green, and Safranin O to determine OA severity. Three blinded graders then assessed sections for degenerative changes of the joint using a modified Mankin scoring system (2). Briefly, this scoring system measures several aspects of OA progression (cartilage structure, cell distribution, integrity of tidemark, and subchondral bone) in four joint compartments (medial tibial plateau, medial femoral condyle, lateral tibial plateau, and lateral femoral condyle), which are summed to provide a semiquantitative measure of the severity of joint damage. To assess the extent of synovitis, sections were stained with H&E to analyze infiltrated cells and synovial structure. Three independent blinded graders scored joint sections for synovitis by evaluating synovial cell hyperplasia, thickness of synovial membrane, and inflammation in subsynovial regions in four joint compartments, which were summed to provide a semiquantitative measure of the severity of joint synovitis (2). Scores for the whole joint were averaged among graders.

Serum and SF from the DMM and contralateral control limbs were collected, as described previously (2). For cytokine and adipokine levels in the serum and SF fluid, a multiplexed bead assay (Discovery Luminex 31-Plex, Eve Technologies, Calgary, AB, Canada) was used to determine the concentration of Eotaxin, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IFN-, IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-15, IL-17A, IP-10, keratinocyte chemoattractant (KC), leukemia inhibitory factor (LIF), liposaccharide-induced (LIX), monocyte chemoattractant protein-1 (MCP-1), M-CSF, monokine induced by gamma interferon (MIG), macrophage inflammatory protein1 (MIP-1), MIP-1, MIP-2, RANTES, TNF-, and VEGF. A different kit (Mouse Metabolic Array) was used to measure levels for amylin, C-peptide, insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, glucagon, insulin, leptin, protein phosphatase (PP), peptide yy (PYY), and resistin. Missing values were imputed using the lowest detectable value for each analyte.

Muscles were cryopreserved by incubation with 2-methylbutane in a steel beaker using liquid nitrogen for 30 s, cryoembedded, and cryosectioned at 8 m thickness. Tissue sections were stained following standard H&E protocol. Photomicrographs of skeletal muscle fiber were imaged under brightfield (VS120, Olympus). Muscle slides fixed in 3.7% formaldehyde were stained with 0.3% Oil Red O (in 36% triethyl phosphate) for 30 min. Images were taken in brightfield (VS120, Olympus). The relative concentration of lipid was determined by extracting the Oil Red O with isopropanol in equally sized muscle sections and quantifying the OD500 (optical density at 500 nm) in a 96-well plate.

To determine spatial expression of FST in different tissues, cryosections of gastrocnemius muscles and adipose tissue were immunolabeled for FST. Tissue sections were fixed in 1.5% paraformaldehyde solution, and primary anti-FST antibody (R&D Systems, AF-669, 1:50) was incubated overnight at 4C after blocking with 2.5% horse serum (Vector Laboratories), followed by labeling with a secondary antibody (Alexa Fluor 488, Invitrogen, A11055) and with 4,6-diamidino-2-phenylindole (DAPI) for cell nuclei. Sections were imaged using fluorescence microscopy.

Second-harmonic generation images of TA were obtained from unstained slices using backscatter signal from an LSM 880 confocal microscope (Zeiss) with Ti:sapphire laser tuned to 820 nm (Coherent). The resulting image intensity was analyzed using ImageJ software.

To measure bone structural and morphological changes, intact hindlimbs were scanned by microCT (SkyScan 1176, Bruker) with an 18-m isotropic voxel resolution (455 A, 700-ms integration time, and four-frame averaging). A 0.5-mm aluminum filter was used to reduce the effects of beam hardening. Images were reconstructed using NRecon software (with 10% beam hardening and 20 ring artifact corrections). Subchondral/trabecular and cortical bone regions were segmented using CTAn automatic thresholding software. Tibial epiphysis was selected using the subchondral plate and growth plate as references. Tibial metaphysis was defined as the 1-mm region directly below the growth plate. The cortical bone analysis was performed in the mid-shaft (4 mm below the growth plate with a height of 1 mm). Hydroxyapatite calibration phantoms were used to calibrate bone density values (mg/cm3).

Fresh visceral adipose tissues were collected, frozen in optimal cutting temperature compound (OCT), and cryosectioned at 5-m thickness. Tissue slides were then acetone-fixed followed by incubation with Fc receptor blocking in 2.5% goat serum (Vector Laboratories) and incubation with primary antibodies cocktail containing anti-CD11b:Alexa Fluor 488 and CD11c:phycoerythrin (PE) (BioLegend). Nuclei were stained with DAPI. Samples were imaged using fluorescence microscopy (VS120, Olympus).

Adipose tissues were fixed in 10% NBF, paraffin-embedded, and cut into 5-m sections. Sections were deparaffinized, rehydrated, and stained with H&E. Immunohistochemistry was performed by incubating sections (n = 5 per each group) with the primary antibody (antimUCP-1, U6382, Sigma), followed by a secondary antibody conjugated with horseradish peroxidase (HRP). Chromogenic substrate 3,3-diaminobenzidine (DAB) was used to develop color. Counterstaining was performed with Harris hematoxylin. Sections were examined under brightfield (VS120, Olympus).

Proteins of the muscle or fat tissue were extracted using lysis buffer containing 1% Triton X-100, 20 mM tris-HCl (pH 7.5), 150 mM NaCl, 1 mm EDTA, 5 mM NaF, 2.5 mM sodium pyrophosphate, 1 mM -glycerophosphate, 1 mM Na3VO4, leupeptin (1 g ml1), 0.1 mM phenylmethylsulfonyl fluoride, and a cocktail of protease inhibitors (Sigma, St. Louis, MO, USA, catalog no. P0044). Protein concentrations were measured with Quick Start Bradford Dye Reagent (Bio-Rad). Twenty micrograms of each sample was separated in SDS-PAGE gels with prestained molecular weight markers (Bio-Rad). Proteins were wet-transferred to polyvinylidene fluoride membranes. After incubating for 1.5 hours with a buffer containing 5% nonfat milk (Bio-Rad #170-6404) at room temperature in 10 mM tris-HCl (pH 7.5), 100 mM NaCl, and 0.1% Tween 20 (TBST), membranes were further incubated overnight at 4C with antiUCP-1 rabbit polyclonal antibody (1:500, Sigma, U6382), anti-PRDM16 rabbit antibody (Abcam, ab106410), anti-CD137 rabbit polyclonal antibody (1:1000, Abcam, ab203391), total OXPHOS rodent western blot (WB) antibodies (Abcam, ab110413), anti-actin (Cell Signaling Technology, 13E5) rabbit monoclonal antibody (Cell Signaling Technology, 4970), followed by HRP-conjugated secondary antibody incubation for 30 min. A chemiluminescent detection substrate (Clarity, Western ECL) was applied, and the membranes were developed (iBrightCL1000).

The effects of HFD and FST gene therapy on thermal hyperalgesia were examined at 15 weeks of age. Mice were acclimatized to all equipment 1 day before the onset of testing, as well as a minimum of 30 min before conducting each test. Thermal pain tests were measured in a room set to 25C. Peripheral thermal sensitivity was determined using a hot/cold analgesia meter (Harvard Apparatus, Holliston, MA, USA). For hot plate testing, the analgesia meter was set to 55C. To prevent tissue damage, a maximum cutoff time of 20 s was established a priori, at which time an animal would be removed from the plate in the absence of pain response, defined as paw withdrawal or licking. Animals were tested in the same order three times, allowing each animal to have a minimum of 30 min between tests. The analgesia meter was cleaned with 70% ethanol between trials. The average of the three tests was reported per animal. To evaluate tolerance to cold, the analgesia meter was set to 0C. After 1-hour rest, animals were tested for sensitivity to cold over a single 30-s exposure. The number of jumps counted per animal was averaged within each group and compared between groups.

Pressure-pain tests were conducted at the knee using a Small Animal Algometer (SMALGO, Bioseb, Pinellas Park, FL, USA). Surgical and nonsurgical animals were evaluated over serial trials on the lateral aspect of the experimental and contralateral knee joints. The average of three trials per limb was calculated for each limb. Within each group, the pain threshold of the DMM limb versus non-operated limb was compared using a t test run on absolute values of mechanical pain sensitivity for each limb, P 0.05.

To assess the effect of HFD and AAV-FST treatments on neuromuscular function, treadmill running to exhaustion (EXER3, Columbus Instruments) was performed at 15 m/min, with 5 inclination angle on the mice 4 months after gene delivery. Treadmill times were averaged within groups and compared between groups.

Forelimb grip strength was measured using Chatillon DFE Digital Force Gauge (Johnson Scale Co.) for front limb strength of the animals. Each mouse was tested five times, with a resting period of 90 s between each test. Grip strength measurements were averaged within groups and compared between groups.

Cardiac function of the mice was examined at 6 months of age (n = 3) using echocardiography (Vevo 2100 High-Resolution In Vivo Imaging System, VisualSonics). Short-axis images were taken to view the LV movement during diastole and systole. Transmitral blood flow was observed with pulse Doppler. All data and images were performed by a blinded examiner and analyzed with an Advanced Cardiovascular Package Software (VisualSonics).

Detailed statistical analyses are described in methods of each measurement and its corresponding figure captions. Analyses were performed using GraphPad Prism, with significance reported at the 95% confidence level.

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

Acknowledgments: Funding: This study was supported, in part, by NIH grants AR50245, AR48852, AG15768, AR48182, AG46927, AR073752, OD10707, AR060719, AR074992, and AR75899; the Arthritis Foundation; and the Nancy Taylor Foundation for Chronic Diseases. Author contributions: R.T. and F.G. developed the concept of the study; R.T., N.S.H., C.-L.W., K.H.C., and Y.-R.C. collected and analyzed data; S.J.O. analyzed data; and all authors contributed to the writing of the manuscript. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat dietinduced obesity - Science Advances

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10 Habits to Transform Your Mindset During Lockdown – Thrive Global

With an unprecedented proportion of the worlds population in self-isolation, many of us feel uneasy (to say the least) about the sudden, strange upheaval to regular life as we know it. There is no doubt that, on top of the serious physical respiratory health pandemic, a tsunami of associated mental health issues is rapidly sweeping the globe.

It is totally normal and understandable to flip between a multitude of mental and emotional statesduringtheCOVID-19outbreak. Researchers recorded feardepression, anxiety and post traumatic stress disorder in China during the outbreak. Other studies found depression and anxiety levels to rise in the UK, following the announcement of the governments lockdown policy.

As health-optimizing, best-selling author Aubrey Marcus recently shared:

Its okay to feel what you are feeling, whatever that is. Dont feel ashamed if you arent positivePeople misunderstand what being strong really is. Strength is the courage to be vulnerable, be real. Some days I feel empoweredsome days I feel helplessThis week Ive had heaping doses of both polarities. Most people Ive spoken to have felt similar. Its all okay. Aubrey Marcus

Although we might not go actively looking for them , lifes toughest challenges also provide the opportunity to shake up our lives and realise what matters most. After struggling with several big life changes myself a few years ago, I focused on what seemed to help keep me emotionally stable and happy even in the midst of external turmoil.

The pandemic is like a collective challenging life-change the world is battling serious illness; anxiety; financial woes; separation from loved ones; grief; a temporary loss of freedom instability in multiple areas en masse.

Healthy relationshipsare key for our well-being. The 80-year Harvard Study of Adult Development found that close personal connections are key for our happiness and longevity throughout life. Research also suggests that people who engage in supportive, positive relationships produce more oxytocin, which can: boost our immune system, allow us to physically heal quicker, and mean we are less likely to experience stress, anxiety, and depression.

Technology is often blamed for making us feel more socially isolated (more on that later on); but most of us are using it now to build a sense of real-life community that we might miss at the moment. Commit to speaking to at least one person who uplifts you on a phone or video call every day. You can arrange to share meals, play online games, or have creative sessions with loved ones using apps like Zoom or Houseparty. You can even host virtual dinner parties by eating meals at the same time as those we miss; or have virtual book or movie clubs where you discuss a book you are all reading, or film youve watched, on scheduled calls.

Social media self-isolation support groups (global on Facebook, local on Nextdoor, or you can make your own using Whatsapp) are popping up to help members stay positive. These groups can help us pool resources and knowledge; share how we feel; and find the support we need.

As well as contacting those we trust and feel positive with when we are struggling, reaching out to others who might be feeling alone, anxious or overwhelmed can also help us get through hard times together. Every morning when you wake up, try to think of two people you could check in with that day with a message, call or supportive voice note . Helping others is also known to help boost our own mental well-being.

Supporting small businesses online can help those struggling with low in-person footfall. We can also donate to local food banks, homeless shelters, services for the elderly or COVID-19 appeals like the UKs National Emergencies Trust, or volunteer to help the NHS support those most in need.

If you live with other people, keep in mind that we all deal with stress differently, and all have up and down days. In general, try to take a few breaths before reacting to someone elses emotionally-triggering behavior, and to be open about how you feel and your needs perhaps using the Nonviolent Communication method to build understanding rather than resentment.

This recent Freakonomics podcast episode discusses the effects of the pandemic on urban populations and marriages. Tim Ferriss COVID-19-related podcasts have been super-insightful, and his recent interview with acclaimed relationship therapist Esther Perel is packed with useful lockdown coping strategies. There is more practical advice for isolating with your family in this LBC Radio interview.

Healthy relationshipsare key for our well-being. The 80-year Harvard Study of Adult Development found that close personal connections are key for our happiness and longevity throughout life. Research also suggests that people who engage in supportive, positive relationships produce more oxytocin, which can: boost our immune system, allow us to physically heal quicker, and mean we are less likely to experience stress, anxiety, and depression.

Technology is often blamed for making us feel more socially isolated (more on that later on); but most of us are using it now to build a sense of real-life community that we might miss at the moment. Commit to speaking to at least one person who uplifts you on a phone or video call every day. You can arrange to share meals, play online games, or have creative sessions with loved ones using apps like Zoom or Houseparty. You can even host virtual dinner parties by eating meals at the same time as those we miss; or have virtual book or movie clubs where you discuss a book you are all reading, or film youve watched, on scheduled calls.

Social media self-isolation support groups (global on Facebook, local on Nextdoor, or you can make your own using Whatsapp) are popping up to help members stay positive. These groups can help us pool resources and knowledge; share how we feel; and find the support we need.

As well as contacting those we trust and feel positive with when we are struggling, reaching out to others who might be feeling alone, anxious or overwhelmed can also help us get through hard times together. Every morning when you wake up, try to think of two people you could check in with that day with a message, call or supportive voice note . Helping others is also known to help boost our own mental well-being.

Supporting small businesses online can help those struggling with low in-person footfall. We can also donate to local food banks, homeless shelters, services for the elderly or COVID-19 appeals like the UKs National Emergencies Trust, or volunteer to help the NHS support those most in need.

If you live with other people, keep in mind that we all deal with stress differently, and all have up and down days. In general, try to take a few breaths before reacting to someone elses emotionally-triggering behavior, and to be open about how you feel and your needs perhaps using the Nonviolent Communication method to build understanding rather than resentment.

This recent Freakonomics podcast episode discusses the effects of the pandemic on urban populations and marriages. Tim Ferriss COVID-19-related podcasts have been super-insightful, and his recent interview with acclaimed relationship therapist Esther Perel is packed with useful lockdown coping strategies. There is more practical advice for isolating with your family in this LBC Radio interview.

Just a few minutes of meditation day has been shown to have a multitude of positive effects on our mental and physical well-being, and now might be a great time to start. Over the medium-term, research has shown that meditation can help calm down anxious racing minds; decrease stress and depressive feelings; give us new perspectives; and find inner stillness even when the outer world seems tumultuous.

Set up a comfortable, quiet space with a cushion, blanket, candle or other elements which make your spot enjoyable to go to. Head there at a regular time for example at 8am; before you go to bed; or after you brush your teeth to make it more likely that you keep going back.

There is an ever-growing treasure trove of free and paid-for meditation material online. Insight Timer is my favorite meditation app for variety and the community aspect; the Calm app has a free Lets meet this moment together section to soothe COVID-19-related anxiety; and Australian Smiling Mind also has this dedicated Thrive Inside resources page.

Many of the worlds best-known meditation guides (such as Jay Shetty) are busy sharing positive-mindset content on social media; and studios like Unplug Meditaton in California are streaming classes online to help us calm down too. Alchemy of Breath also runs free online breath-work meditation classes every Sunday which can be particularly transformative to our mood.

Megan Monohans book Dont Hate Meditate is a great practical introduction to building a practice; and Deepak Chopras Hope in Uncertain Times site is offering a free 21-Day Meditation Experience.

To be mindful means staying non-judgmentally aware of the present moment rather than mind-wandering into thoughts about the past or the future (which is believed to make us less happy). During difficult times its easy for our attention to drift to worries about worst-case scenarios that may never happen. The fact is, no one really knows what the future holds. It is prudent to be practically prepared, but after that it is helpful to remember that we are safe in the present moment, rather than diving into negative thought spirals.

Meditation is a concentrated, dedicated period of mindfulness, but we can also practice staying mindful or to keep bringing our full attention to during other tasks.

A few easy ways to practice mindfulness include:

Some of my favorite books further exploring mindfulness, consciousness and living in the present moment include the beautifully written The Untethered Soul by Michael A. Singer; the esoteric The Power of Now by Eckhard Tolle; and mind-blowing Freedom From The Known by J. Krishnamurti. You can watch Tolles recent Staying conscious in the state of adversity video here.

Try to build some kind of routine at home you might decide to wake up, go to sleep and eat at regular times; take up exercise on certain days; or diarize blocks of your calendar for work and other tasks. This can help to help maintain our sleep patterns, to eat more healthily and stress less.

Its useful to list things youd like to achieve tomorrow (highlighting three top priorities), as well as the week ahead in your journal, carrying any unfinished tasks forward to the next time period. You can find tips on productively working from home online, like in these articles by the BBC and CNN.

If youve wanted to read a book (here are 10 books that totally transformed my life); learn a new skill (like a language); or take an online course (you can check many affordable or free ones out on Udemy or Coursera) but havent prioritized it take this extra time indoors as an opportunity. Hal Elrods easy read The Miracle Morning suggests activities to start our day off right, including exercise, meditation, reading, journaling and visualization. I personally like to meditate each morning, exercise in the afternoon, and read before I go to bed this structure helps me to stay grounded. I also like to mix up how I exercise, books I read and my self care routine, depending how I feel that day.

To work on forming good habits, or getting rid of old ones, James Clears Atomic Habits is a great guide to getting started. Using a journal, a highly-visible habit tracker, app or having an accountability buddy also helps us stay on track. To help my focus levels, I like listening to calming background music such as this on YouTube, or you can check out scientifically-backed Brain.fm.

Being at home all day means that many of us are spending more time than ever socializing, working, informing and entertaining ourselves through our online devices. The majority of Brits use their smartphones right up until bedtime and, in 2019, the average American checked theirs 96 times per day. Studies have linked heavy smartphone use to stress, depression and anxiety, with too much social media particularly found to affect our mood. Most of us have also likely noticed the associated effects of overuse on on our sleep, focus and productivity at home.

We can use usage-tracker apps like iPhones Screen Time, or Digital Wellbeing for Android to see how much time we spend on our devices usually its way more than we consciously realize! Then its down to simple hacks like having a phone-free room at home (like your bedroom) or times of day (like 9pm to 9am); turning off all but essential notifications; keeping your phone of arms reach when you are working; and deleting social media or other potentially time-wasting apps to declutter your home screen.

Check out the brilliant book How to Break Up With Your Phone by Catherine Price for more tips. Many of us are also enjoying digging out paper books, board games, gardening, baking or exercise equipment for offline entertainment.

Its important to stay up-to-date with key developments, but if you start to feel overwhelmed by negative news, follow the CDCs advice and take a break from it. Over half of participants in a 2018 study by the American Psychological Association said that the news causes them stress, with many experiencing anxiety or sleep loss as a result. Try not to have news on in the background check once a day for updates, rather than constantly, and set a time limit on how late youll consume it at night. Notice how you feel before and after you check the news. If you feel like you are compulsively checking, give someone you care about a call, or do something productive, like picking up a book, instead. Alternatively you can even check out Positive News for pandemic respite. The Centre for Evidence-Based Medicine also has a dedicated COVID-19 page that is updated daily to debunk related fake news.

At a Flying with Confidence course a few years ago, my fellow flight-phobic attendees and I were recommended to avoid watching fictional, Aircraft Investigation-style, TV shows about plane crashes the human brain has a tendency to normalize the catastrophes and outliers we see on TV. It can be tempting to consume all of the apocalyptic Netflix programming we can, in an attempt to understand all of the unknowns. In the same, I am avoiding watching this too, and focusing on uplifting or funny shows (my current favorite is Bojack Horseman) instead.

Laughter is known to make us feel better, and can soothe physical tension, strengthen our immune system and give us pain relief. Notice the small things that make you smile, and make sure you are regularly having fun doing things you enjoy like baking, drawing, dancing, singing, speaking to friends who cheer you up, watching or reading something that makes you smile. Think about what lit you up as a child, and dedicate at least 3060 minutes a day to activities that make you feel most happy and alive instead of consuming anxiety-inducing content.

Studies show that spending time in nature can have positive effects on our health like lowering our blood pressure and boosting happiness; and, for those of us in the Northern Hemisphere, Spring has sprung.

Try to spend time outside in your garden or patio every day, or go for a socially-distanced walk or run in the park or a natural space near you (as permitted by your local governments recommendations). Take the time to mindfully notice your surroundings any trees, flowers or birds you spot. Focusing on distant views can also give our eyes a break from all of the screen time at home.

You can connect with nature without leaving the house, too. Commit to noticing how the sky, or other natural phenomena like trees, look outside each day research suggests a window view of nature can even shorten the recovery time of patients. Owning a houseplant has also been shown to improve our mood; and listening to recorded nature sounds (I love hearing the ocean whilst I work) or looking at images of green environments are thought to also have calming effects on us. You could also install a bird feeder you can see from inside, and try to spend a significant proportion of your day in a room with adequate sunlight.

With all of the upheaval and uncertainty, many of us are finding it harder to nod off, with some reporting vivid dreams or nightmares once they do manage to. The American National Sleep Foundation recommends that adults get seven to nine hours of sleep per night; while the NHS explains here how being chronically under-rested can lead to serious health conditions including anxiety and depression.

For now, try developing a regular relaxing bedtime routine such as having three things you regularly do, like reading a book, having a herbal tea, a bath, journaling, meditating or moisturizing. Make sure your bedroom is as quiet and dark as possible, and avoid mental over-stimulation and blue light from our screens in bed which affect our sleep cycles by charging your phone outside of the bedroom. You could also try putting tech on airplane-mode at 9pm (and not checking your messages until 9am), or using free desktop tool F.lux which aims to keep the light levels coming from our screens with that of our natural environment according to the time of day.

Calms sleep stories have helped millions of people already, and HuffPost has some great tips here on sleeping better during pandemic-related anxiety. If you are interested in finding out more about our sleep qualitys effect on our health, Matthew Walkers book Why We Sleep is full of practical information and tips based on cutting-edge sleep-science.

The UK government recommends healthy adults do at least 2.5 hours of moderate exercise every week. Physical activity has many mental benefits such as improving cognitive function, boosting our perceived quality of life, and reducing anxiety and depression. If youre used to feeling the positive effects of going to the gym or playing sports, which you cant do right now, do not fear! Many of the worlds top fitness studios like Barrys Bootcamp, and instructors like Joe Wicks The BodyCoach TV, have moved to streaming regular free or paid-for classes online during lock down.

Research has found that lower intensity, strengthening movement like yoga (which also often includes a meditation section) can help calm us down during stressful times. Some of my favorite yoga teachers are also recording frequent classes from their social media accounts (like Ted McDonald on Instagram). I also love online ecstatic dance classes with URUBU or Rise Up basically, an excuse to dance like no one else is watching from the comfort of your living room, whilst connecting online to people from all over the world.

As well as dancing, singing has multiple health benefits too, and listening to music we enjoy is known to uplift our mood. There is a proliferation of DJ live streams and concerts going on check out this list of ideas if you are looking for something new.

We can all be guilty of being harsher to ourselves than we would be to anyone else learn to treat yourself like a best friend instead. If youre not feeling as productive as usual do what you can and know that youre trying your best during an unprecedented, stressful situation. This could also be an opportunity to rest a little from normal busy life, and to learn to forgive yourself if you are not feeling 100% (or failing to meet unrealistic standards).

As spiritual thought-leader Sadhguru recently half-joked to his 2.9m followers during his daily Instagram talk, the general public are saving lives just by staying home for once by doing nothing, we are doing something.

If you are comparing yourself with other peoples attitudes or achievements notice, and then try to put a stop to, doing that. We all handle things differently at different times, and we never really know what someone else is going through.

Acknowledging difficult feelings such as anxiety, grief, or boredom by sitting quietly with them and feeling where they come up in the body, and maybe sharing them with someone we trust, or a mental health professional can help us process and move through them, rather than repressing and paying for it later on. We can tell ourselves Ok, Im anxious/grieving/bored now, but that is normal and fine, and this too will pass after all these are not usual times!

Journalling or freewriting committing to writing whatever comes up for a set time duration (such as five minutes) or number of pages (three, for example) without editing or censoring ourselves can help us to get clearer on whats going on in our heads, and so make them feel less cluttered. Recording feelings can also be interesting to reflect on in future.

Keep in mind and check in with what feels useful to your own physical and mental state before and after you practice, then you will learn what works for you. You can find further COVID-19 mental health resources here:

If you are feeling unable to cope or overwhelmed, and speaking to someone close to you who you trust doesnt help you feel better, contact your family doctor or seek a professional counselor or therapist its often possible to have sessions remotely, over the phone or online.

These are uncertain times where many of us face grief, financial pressure, loss of freedom and anxiety so it is imperative to look after the physical and mental well-being of ourselves and others well during this period.

To summarize, try to regularly: meditate and practice mindfulness; build social connections; prioritize sleeping well; practice movement and a hobby you enjoy every day; regulate your tech use and consumption of negative content; and help others who are vulnerable, lonely or in particular need.

We can decide to not only survive and get through this period, but maybe learn to come out the other side as improved beings with a better understanding of how to tend to the needs and feelings of ourselves and others, and a renewed realization of our connectedness to nature and the rest of the world, as well as of what is truly most important to us.

Jessica Warren is co-founder of Mind: Unlocked a mental well-being business that provides practical tools, courses and workshops to help people cope with the stress of everyday modern life. She has been featured as a wellness speaker on BBC Radio and at conferences like Wanderlust and Eurekafest; and writes for Thrive Global, Economia Magazine, and the StartUp and P.S. I Love You publications on Medium. Jessica trained as a Chartered Accountant and worked in corporate finance, before deciding to dedicate her time to exploring and sharing how to live more fulfilling lives we love.

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10 Habits to Transform Your Mindset During Lockdown - Thrive Global

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Eyes For You and Peerless impress – The Hindu

Eyes For You and Peerless impressed when the horses were exercised here on Monday (Jan.6) morning.

Inner sand.

800m: Sultan Suleiman (David Egan) 51, 600/36. Responded well. Arabian Storm (Kaviraj) 54, 600/40. Moved freely. Market King (Nicky Mackay), Marrakesh (V.Jodha) 53.5, 600/40. They ended level. Mystic Bay (Kamble), Astounding Bay (Peter) 50, 600/37. Former finished a distance ahead. Dandi March (Nicky Mackay), Wind Whistler (V.Jodha) 51, 600/38. They moved level freely. Bodyline (Bhawani) 54, 600/40. Pressed.

1000m: Alpine Dancer (Merchant), Noble Pride (rb) 1-9, 800/54, 600/40. Former finished a distance ahead. Magistero (Rupesh) 1-9.5, 600/41. Urged. Intense Stylist (Nicky Mackay), Between The Waters (V.Jodha) 1-7.5, 800/52.5, 600/39. They moved level freely. Trouvaille (Nicky Mackay), Gold Medalist (V.Jodha) 1-6, 800/52, 600/39.5. Former moved well and they finished level. Nusrat (Merchant) 1-9, 600/40.5. Slightly urged. Grand Accord (Rupesh) 1-7, 800/52.5, 600/39.5. Moved freely.

1200m: Glacier Express (David Egan), Romanesque (Hamir) 1-23, 1000/1-8, 800/54, 600/40. Former strode out well and finished well clear.

Race track.

600m: Arazan/Equine Love (Kadam), Speaking Of Which/Highraz (rb) 37. Both moved freely. Flaming Lamborghini (Nathan Evans), Melania (David Egan) 34. Former was five lengths superior. Spring Grove (rb), Tambourine Man (D.A.Naik) 38.5. They finished level freely. Circle Of Life (Nathan Evans), Miss Muffer (Zervan) 34. Both moved neck and neck freely. Solar System (David Egan) 35. Good. Justified (David Egan) 34. Moved well.

1000m: Tacksta (Late Track Star) (A.Gaikwad) 1-3, 600/35. Moved well. Master Of Studies (Rathod) 1-3, 600/38. Slightly urged. Irish Eyes (Nazil), Wizard Of Stocks (Mansoor) 1-4, 800/49, 600/35. Former finished four lengths ahead. Conscience (Kamble), Kunwari (Peter) 49, 600/35. Pair urged and ended level. About The Cloud (Malam), Smoky Haze (Daman) and Gracida (Baria) 1-4, 800/49, 600/35. First named was the pick. Van Dyke (Kadam) 1-2, 800/47.5, 600/34. Moved impressively. Treason (Akshay) 1-5.5, 800/51, 600/36.5. Moved freely.

1200m: Eyes For You (Kadam) 1-13.5, 1000/1-1, 800/49, 600/35. Moved attractively. Peerless (Pranil) 1-15, 1000/1-1, 800/48, 600/34. Pleased. Texas Gold (Nazil) 1-17, 1000/1-3, 800/50, 600/36. Moved freely. Immortality (Zervan), Egalite (rb) and Maxine (Parmar) 1-17, 1000/1-3, 800/49, 600/35. Immortality was the pick.

Gate practice noted on the inner sand.

1000m: Touch Of Faith (Nicky Mackay), Tomorrows Dreams (V.Jodha) 1-7, 800/53, 600/40. They jumped out well and finished level freely. Noble King (Peter), Explorer (Kamble) 1-8.5, 600/41.5. Pair moved level freely. Powerful Lady (Kuldeep), Opening Verse (Aniket) 1-12, 800/56, 600/42. Pair level.

Mock race noted on January 5.

Race track.

1200m: Auburn (Zervan), Flameoftheforest (Yash), Gods Plan (Akshay), Super Girl (Parmar), Giant Star (Kamble) and Daggers Strike (Ayyar) 1-12, 600/35. Won by: Sh, 4, 1/2. Flameoftheforest who led the field throughout the race tried hard to win, but was beaten by Auburn on the post.

Second mock race.

1200m: Medici (C.S.Jodha), Her Eminence (Bhawani) and Minstrel Heights (A.Prakash) 1-11, 600/35. Won by: Dist, 6. Medici won well.

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