Research illuminates the pathway that gets fuel to muscles depending on their activity level — ScienceDaily

Muscles require energy to perform all of the movements that we do in a day, and now, for the first time, researchers at the Texas A&M College of Medicine have shown how muscles “request” more energy from fat storage tissues in fruit fly models. They also discovered that this circuit is dependent on circadian rhythms, which could have implications for obesity in humans. Their findings published today in the journal Current Biology.

“This is required for diurnal regulation of blood lipid levels,” said Jason Karpac, PhD, assistant professor at the College of Medicine and principal investigator on the project. “In other words, during the day when our muscles are moving and requiring energy, this communication is important to make sure lipids are maintained for higher energy demand, and at night, when we’re less active, it shuts down to avoid excess fat accumulation, which could lead to obesity.”

This balance — called metabolic homeostasis — can be manipulated by changing an organism’s genetics to alter the amount of lipid stored. One gene is involved in the muscle, and another gene is involved in the fat tissue to make this signaling pathway work. The relatively simple genetics of the fruit fly model allow Karpac and his team to make very specific changes. At the same time, though, lipid metabolism — or the ability to take in energy, store it as fats, and then release the energy — is very similar in fruit flies and in humans. “The fruit fly, just like us, has very hard working muscles,” Karpac said. “They also store large amounts of lipids for energy in tissues that are analogous to ours.”

The pathway is coordinated with the body’s own internal clock to regulate fat storage and release. When muscles need energy, they inhibit the secretion of leptin (or the leptin homolog in the fruit fly) from the muscle itself, which in turn controls glucagon levels. Decreases in glucagon signals lipids to be made, and subsequently released, from tissues that are storing them. “This is the first time in the fruit fly model that someone has really been able to connect the dots in terms of how these tissues are coordinated,” Karpac said. “Here we’re able to actually say that a certain gene is absolutely crucial for controlling how much lipids you have in circulation at a given time.” These genes also help regulate insulin levels, which tell the body whether to store energy as fats or to release it.

“Now that we know how this signaling pathway normally functions, we can begin to ask all kinds of interesting questions about what happens when you change sleeping or eating behaviors,” Karpac said. “We can also take away this signaling pathway genetically and see if it is indeed this pathway that is responsible for metabolic variations associated with these behavioral changes.”

If breaking the pathway leads to obesity, there could be large implications for human health.

“Based on this research, it is very likely that our muscles also talk to fat storage tissues and coordinates its own energy usage,” Karpac said. “It also underscores that it probably does matter when you eat, because there are signaling pathways that are affected by circadian rhythms based on muscle energy needs.”

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Diet study finds link between brain inflammation and obesity in mice — ScienceDaily

Immune cells in the brain trigger overeating and weight gain in response to diets rich in fat, according to a new study in mice led by researchers from UC San Francisco and the University of Washington Medical Center, and published online on July 5 in Cell Metabolism.

Neurons within a region at the base of the brain known as the hypothalamus, which plays a crucial role in eating, have long been a target for the development of drugs to treat obesity. But the new study suggests that brain-resident immune cells called microglia could also be targets for obesity treatments that might avoid many side effects of the obesity drugs currently in clinical use.

“Microglia are not neurons, but they account for 10 to 15 percent of the cells in the brain,” said Suneil Koliwad, MD, PhD, assistant professor of medicine at the UCSF Diabetes Center, and a co-senior author of the new study. “They represent an untapped and completely novel way to target the brain in order to potentially mitigate obesity and its health consequences.”

Microglia in the Hypothalamus are Responsible for Diet-Driven Weight Gain

A brain region called the mediobasal hypothalamus (MBH) contains key groups of neurons that regulate food intake and energy expenditure. Normally this region attempts to match the number of calories ingested in food with our need for energy to maintain a healthy weight, but previous research has shown that dietary fats can drastically throw off this balancing act.

In the new study, the researchers fed mice a fast food-like diet rich in fat for four weeks, which is known to cause microglia to expand in number and to trigger local inflammation within the MBH. Mice fed such a diet also eat more food, burn fewer calories, and gain more weight compared to mice eating a more healthy, low-fat diet.

To learn whether the multiplying microglia are a cause of overeating and obesity in these mice, rather than a result of their weight gain, Koliwad’s team at UCSF depleted the number of microglia in the MBH of mice on the fatty diet by giving them an experimental drug, called PLX5622, which is made by Plexxikon Inc., a Berkeley, California-based biotech company. The researchers found that mice treated with the drug ate 15 percent less and gained 20 percent less weight than untreated mice on the same diet.*

The University of Washington team, led by Joshua Thaler, MD, PhD, associate professor of medicine with the UW Medicine Diabetes Institute, genetically engineered mice to prevent microglia from activating inflammatory responses, and found that these mice ate 15 percent less and gained 40 percent less weight on a high fat diet, suggesting that the inflammatory capacity of microglia itself is responsible for the animals’ overeating and weight gain.

To confirm this finding, the UCSF researchers developed a strain of genetically engineered mice in which they could use a drug to activate the inflammatory response of microglia at will. They found that even in mice fed a healthy, low-fat diet, forcing microglia-induced inflammation in the hypothalamus caused mice to eat 33 percent more food and expend 12 percent less energy, leading to a four-fold (400 percent) increase in weight gain compared to untreated mice on the same healthy diet.

“From these experiments we can confidently say that the inflammatory activation of microglia is not only necessary for high-fat diets to induce obesity, but also sufficient on its own to drive the hypothalamus to alter its regulation of energy balance, leading to excess weight gain,” said Thaler, who was a co-senior author on the new paper.

Drugs Targeting Brain Inflammation Could Help Treat Obesity

It may soon be possible to learn whether eliminating microglia can thwart weight gain in humans as well. For example, another drug made by Plexxikon, called PLX3977, which is currently in clinical trials for hard-to-treat leukemias, solid tumors, and rare forms of arthritis, acts by the same biological mechanism as PLX522, the experimental drug the UCSF team used to reduce microglia numbers in the new study. It may thus be possible to see whether cancer patients in the PLX3977 trials experience beneficial effects on body weight, Koliwad said.

In their new paper, the researchers also report that high-fat diets trigger microglia to actively recruit additional immune-system cells from the bloodstream to infiltrate the MBH. Once there, the new recruits shape-shift to take on features similar to those of the brain’s own microglia, augmenting the inflammatory response and its impact on energy balance. Therefore, the authors said, it may be possible to control overeating and weight gain through multiple immunologic approaches — targeting bona fide microglia as well as targeting cells in the blood with the capacity to enter the hypothalamus and take on microglia-like functions.

The researchers next plan to further investigate how, exactly, consumption of high-fat foods leads to the activation of microglia, and whether there are ways to intervene to block these signals.

Did Microglia Evolve Ability to Help Animals Take Advantage of Rare Feasts?

Human brain imaging studies in recent years have found that, compared to lean individuals, those who are obese are more likely to have expanded populations of glial cells — the broader class of brain cells to which microglia belong — in the hypothalamus. This same sort of phenomenon, called gliosis, is commonly seen in neurodegenerative diseases, brain trauma, bleeding, infection and brain cancer, Koliwad said, leading researchers to initially conclude that dietary excess might essentially cause a form of brain injury.

But Koliwad believes that there could be a more positive explanation for the fact that microglia have evolved the ability to rapidly trigger increased appetite and weight gain in response to a high-fat diet: rich food was only rarely available during mammalian evolutionary history, and when it was available, it would be advantageous for animals to stop hunting or foraging and focus on chowing down.

“Microglial responsiveness to dietary fats makes some sense from this evolutionary perspective,” Koliwad said. “Fats are the densest form of calories that ancient humans might ever had the opportunity to consume. So, when primitive humans finally obtained a meal after a long period of fasting, microglia may have been essential in relaying the presence of this meal to those neurons that would stimulate maximal appetite.”

But in modern environments, in which high-fat food is continually available, this same adaptation can be damaging, Koliwad said. “In our modern world, when people constantly overeat rich, high-fat foods, chronic microglial activation could produce a more permanent stimulation of neural circuits that further increase high-fat food intake, leading to the development of a vicious cycle.”

Mice that lost sense of smell stayed slim on high fat diet, while littermates ballooned in weight — ScienceDaily

Our sense of smell is key to the enjoyment of food, so it may be no surprise that in experiments at the University of California, Berkeley, obese mice who lost their sense of smell also lost weight.

What’s weird, however, is that these slimmed-down but smell-deficient mice ate the same amount of fatty food as mice that retained their sense of smell and ballooned to twice their normal weight.

In addition, mice with a boosted sense of smell — super-smellers — got even fatter on a high-fat diet than did mice with normal smell.

The findings suggest that the odor of what we eat may play an important role in how the body deals with calories. If you can’t smell your food, you may burn it rather than store it.

These results point to a key connection between the olfactory or smell system and regions of the brain that regulate metabolism, in particular the hypothalamus, though the neural circuits are still unknown.

“This paper is one of the first studies that really shows if we manipulate olfactory inputs we can actually alter how the brain perceives energy balance, and how the brain regulates energy balance,” said Céline Riera, a former UC Berkeley postdoctoral fellow now at Cedars-Sinai Medical Center in Los Angeles.

Humans who lose their sense of smell because of age, injury or diseases such as Parkinson’s often become anorexic, but the cause has been unclear because loss of pleasure in eating also leads to depression, which itself can cause loss of appetite.

The new study, published this week in the journal Cell Metabolism, implies that the loss of smell itself plays a role, and suggests possible interventions for those who have lost their smell as well as those having trouble losing weight.

“Sensory systems play a role in metabolism. Weight gain isn’t purely a measure of the calories taken in; it’s also related to how those calories are perceived,” said senior author Andrew Dillin, the Thomas and Stacey Siebel Distinguished Chair in Stem Cell Research, professor of molecular and cell biology and Howard Hughes Medical Institute Investigator. “If we can validate this in humans, perhaps we can actually make a drug that doesn’t interfere with smell but still blocks that metabolic circuitry. That would be amazing.”

Riera noted that mice as well as humans are more sensitive to smells when they are hungry than after they’ve eaten, so perhaps the lack of smell tricks the body into thinking it has already eaten. While searching for food, the body stores calories in case it’s unsuccessful. Once food is secured, the body feels free to burn it.

Zapping olfactory neurons

The researchers used gene therapy to destroy olfactory neurons in the noses of adult mice but spare stem cells, so that the animals lost their sense of smell only temporarily — for about three weeks — before the olfactory neurons regrew.

The smell-deficient mice rapidly burned calories by up-regulating their sympathetic nervous system, which is known to increase fat burning. The mice turned their beige fat cells — the subcutaneous fat storage cells that accumulate around our thighs and midriffs — into brown fat cells, which burn fatty acids to produce heat. Some turned almost all of their beige fat into brown fat, becoming lean, mean burning machines.

In these mice, white fat cells — the storage cells that cluster around our internal organs and are associated with poor health outcomes — also shrank in size.

The obese mice, which had also developed glucose intolerance — a condition that leads to diabetes — not only lost weight on a high-fat diet, but regained normal glucose tolerance.

On the negative side, the loss of smell was accompanied by a large increase in levels of the hormone noradrenaline, which is a stress response tied to the sympathetic nervous system. In humans, such a sustained rise in this hormone could lead to a heart attack.

Though it would be a drastic step to eliminate smell in humans wanting to lose weight, Dillin noted, it might be a viable alternative for the morbidly obese contemplating stomach stapling or bariatric surgery, even with the increased noradrenaline.

“For that small group of people, you could wipe out their smell for maybe six months and then let the olfactory neurons grow back, after they’ve got their metabolic program rewired,” Dillin said.

Dillin and Riera developed two different techniques to temporarily block the sense of smell in adult mice. In one, they genetically engineered mice to express a diphtheria receptor in their olfactory neurons, which reach from the nose’s odor receptors to the olfactory center in the brain. When diphtheria toxin was sprayed into their nose, the neurons died, rendering the mice smell-deficient until the stem cells regenerated them.

Separately, they also engineered a benign virus to carry the receptor into olfactory cells only via inhalation. Diphtheria toxin again knocked out their sense of smell for about three weeks.

In both cases, the smell-deficient mice ate as much of the high-fat food as did the mice that could still smell. But while the smell-deficient mice gained at most 10 percent more weight, going from 25-30 grams to 33 grams, the normal mice gained about 100 percent of their normal weight, ballooning up to 60 grams. For the former, insulin sensitivity and response to glucose — both of which are disrupted in metabolic disorders like obesity — remained normal.

Mice that were already obese lost weight after their smell was knocked out, slimming down to the size of normal mice while still eating a high-fat diet. These mice lost only fat weight, with no effect on muscle, organ or bone mass.

The UC Berkeley researchers then teamed up with colleagues in Germany who have a strain of mice that are supersmellers, with more acute olfactory nerves, and discovered that they gained more weight on a standard diet than did normal mice.

“People with eating disorders sometimes have a hard time controlling how much food they are eating and they have a lot of cravings,” Riera said. “We think olfactory neurons are very important for controlling pleasure of food and if we have a way to modulate this pathway, we might be able to block cravings in these people and help them with managing their food intake.”

Higher BMI linked with increased risk of high blood pressure, heart disease, type 2 diabetes — ScienceDaily

Results of a new study add to the evidence of an association between higher body mass index (BMI) and increased risk of cardiometabolic diseases such as hypertension, coronary heart disease, type 2 diabetes, according to a study published by JAMA Cardiology.

A connection between higher BMI and cardiometabolic disease risk usually arise from observational studies that are unable to fully account for confounding by shared risk factors. Mendelian randomization (a method of analysis using genetic information) is an approach that partially overcomes these limitations. Using mendelian randomization, Donald M. Lyall, Ph.D., of the University of Glasgow, Scotland, and colleagues conducted a study that included 119,859 participants in the UK Biobank (with medical, sociodemographic and genetic data) to examine the association between BMI and cardiometabolic diseases and traits.

Of the individuals in the study, 47 percent were men; average age was 57 years. The researchers found that higher BMI was associated with an increased risk of coronary heart disease, hypertension, and type 2 diabetes, as well as increased systolic and diastolic blood pressure.

These associations were independent of age, sex, alcohol intake, and smoking history.

The authors write that the results of this study has relevance for public health policies in many countries with increasing obesity levels. “Body mass index represents an important modifiable risk factor for ameliorating the risk of cardiometabolic disease in the general population.”

A limitation of the study was that the sample lacked data on a complete range of potential mediators, such as lipid traits and glucose levels.

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Prompt removal of ticks can help prevent transmission of Borrelia mayonii — ScienceDaily

A new species of bacteria that causes Lyme disease needs the same amount of time for transmission after a tick bite compared to previously implicated bacteria, according to new research by the Centers for Disease Control and Prevention (CDC). Existing guidelines for frequent tick checks and prompt removal of attached ticks remain the same.

The duration of attachment of a single nymphal blacklegged tick (Ixodes scapularis) needed for the tick to be likely to transmit the bacterial species Borrelia mayonii, identified in 2016, is 48 hours or more, according to the study. By 72 hours, however, likelihood of transmission has risen significantly. This timeframe aligns with existing research on Borrelia burgdorferi, previously the sole bacteria species known to cause Lyme disease in the United States. The research is published in the Entomological Society of America’s Journal of Medical Entomology.

“Our findings show that recommendations for regular tick checks and prompt tick removal as a way to prevent transmission of Lyme disease spirochetes to humans via the bites of infected ticks applies to the newly recognized B. mayonii as well as B. burgdorferi, for which these recommendations originally were developed,” says Lars Eisen, Ph.D., CDC research entomologist and senior author of the study.

The study authors tested transmission rates of B. mayonii from ticks to mice at four time intervals: 24, 48, and 72 hours after attachment and after the tick’s full feed. Their experiment focused on nymphal-stage ticks (the more common source of pathogen transmission, compared to larval or adult ticks) and exposed the mice to a single infected tick each. They found no evidence of transmission by single nymphs infected with B. mayonii in the first 24 or 48 hours, but 31 percent of mice examined after 72 hours were found to be infected. In mice examined after a tick’s complete feed (4-5 days), the infection rate was 57 percent.

“Our findings underscore the importance of finding and removing ticks as soon as possible after they bite,” says Eisen.

Lyme disease is the most commonly reported vector-borne illness in the United States, with around 300,000 people estimated to be diagnosed each year, mostly in the Northeast and upper Midwest regions. The blacklegged tick is the primary vector of Lyme disease as well as at least a dozen other illnesses.

To reduce the risk of tick bites and tickborne diseases, CDC recommendations include:

  • Avoid wooded and brushy areas with high grass and leaf litter.
  • Use insect repellent when outdoors.
  • Use products that contain permethrin on clothing.
  • Bathe or shower as soon as possible after coming indoors to wash off and more easily find ticks.
  • Conduct a full-body tick check after spending time outdoors.
  • Examine gear and pets, as ticks can come into the home on these and later attach to people.

The bacterial species B. mayonii was discovered when six patients exhibiting symptoms of Lyme disease at the Mayo Clinic in Rochester, Minnesota, in 2013 showed unusual blood-test results. The discovery of the new species was confirmed in 2016.

“There is much still to discover about B. mayonii, including to clarify the geographic range of this emerging human pathogen in the U.S., to determine how commonly different life stages of the blacklegged tick are infected with B. mayonii, and to find out whether the same vertebrate animals that serve as natural reservoirs for B. burgdorferi play the same role also for B. mayonii,” says Eisen.

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Engineering digestive system tissues: Significant progress — ScienceDaily

Researchers at Wake Forest Institute for Regenerative Medicine have reached important milestones in their quest to engineer replacement tissue in the lab to treat digestive system conditions — from infants born with too-short bowels to adults with inflammatory bowel disease, colon cancer, or fecal incontinence.

Reporting today in Stem Cells Translational Medicine, the research team verified the effectiveness of lab-grown anal sphincters to treat a large animal model for fecal incontinence, an important step before advancing to studies in humans. And last month in Tissue Engineering, the team reported success implanting human-engineered intestines in rodents.

“Results from both projects are promising and exciting,” said Khalil N. Bitar, Ph.D., AGAF, senior researcher on the projects, and professor of regenerative medicine at the institute. “Our goal is to use a patient’s own cells to engineer replacement tissue in the lab for devastating conditions that affect the digestive system.”

Sphincter Project: The lab-engineered sphincters are designed to treat passive incontinence, the involuntary discharge of stool due to a weakened ring-like muscle known as the internal anal sphincter. The muscle can lose function due to age or can be damaged during child birth and certain types of surgery, such as cancer.

Current options to repair the internal anal sphincter include grafts of skeletal muscle, injectable silicone material or implantation of mechanical devices, all of which have high complication rates and limited success.

“The regenerative medicine approach has a promising potential for people affected by passive fecal incontinence,” said Bitar. “These patients face embarrassment, limited social activities leading to depression and, because they are reluctant to report their condition, they often suffer without help.”

Bitar’s team has been working to engineer replacement sphincters for more than 10 years. In 2011, the team was the first to report functional, lab-grown anal sphincters bioengineered from human cells that were implanted in immune-suppressed rodents. The current study involved 20 rabbits with fecal incontinence. Eight animals were treated with sphincters engineered from their own muscle and nerve cells, eight animals were not treated and four received a “sham” surgery.

The sphincters were engineered using small biopsies from the animals’ sphincter and intestinal tissue. From this tissue, smooth muscle and nerve cells were isolated and then multiplied in the lab. In a ring-shaped mold, the two types of cells were layered to build the sphincter. The entire process took about four to six weeks.

In the animals receiving the sphincters, fecal continence was restored throughout a three month follow-up period, compared to the other groups, which did not improve. Measurements of sphincter pressure and tone showed that the sphincters were viable and functional and maintained both the muscle and nerve components. Currently, longer follow up of the implanted sphincters is close to completion with good results..

Intestine Project: The intestine project is aimed at helping patients with intestinal failure, which is when the small intestine malfunctions or is too short to digest food and absorb nutrients essential to health. Patients must get nutrition through a catheter or needle. The condition has a variety of causes. Infants can be born with missing or dysfunctional small intestines. In adults, surgery to remove sections of intestine due to cancer or other disease can result in a too-short bowel. Intestinal transplant is an option, but donor tissue is in short supply and the procedure has high mortality rates.

“A major challenge in building replacement intestine tissue in the lab is that it is the combination of smooth muscle and nerve cells in gut tissue that moves digested food material through the gastrointestinal tract,” said Bitar.

Through much trial and effort, his team has learned to use the two cell types to create “sheets” of muscle pre-wired with nerves. The sheets are then wrapped around tubular molds made of chitosan, a natural material derived from shrimp shells. The material is already approved by the U.S. Food and Drug Administration for certain applications.

In the current study, the tubular structures were implanted in rats in two phases. In phase one, the tubes were implanted in the omentum, which is fatty tissue in the lower abdomen, for four weeks. Rich in oxygen, this tissue promoted the formation of blood vessels to the tubes. During this phase, the muscle cells began releasing materials that would eventually replace the scaffold as it degraded.

For phase two, the bioengineered tubular intestines were connected to the animals’ intestines, similar to an intestine transplant. During this six-week phase, the tubes developed a cellular lining as the body’s epithelial cells migrated to the area. The rats gained weight and studies showed that the replacement intestine was healthy in color and contained digested food.

The researchers are excited by the results and their next step is to test the structures in larger animals.

“Our results suggest that engineered human intestine could provide a viable treatment to lengthen the gut for patients with gastrointestinal disorders, or patients who lose parts of their intestines due to cancer,” said Bitar.

Combining antibiotics proves more effective against common infection — ScienceDaily

The common and highly resistant Pseudomonas aeruginosa bacterium is a fatal threat to weakened and ill patients. A new study from Lund University in Sweden now shows that a combination treatment using two different types of antibiotics can reduce mortality up to five times.

The findings are part of a new doctoral thesis, which also describes some of the bacterium’s ingenious survival strategies in the human body.

“The combination treatment against Pseudomonas aeruginosa was effective in all age groups and for various types of infections, including pneumonia and urinary tract infections. The results are ready to be put into practice at Swedish hospitals immediately,” says Magnus Paulsson, a doctor of medical science at Lund University and physician at Skåne University Hospital.

Pseudomonas aeruginosa is a very common bacterium, found in most environments. It is practically resistant to our most common antibiotics, and nowadays certain bacterial strains have become completely resistant to all antibiotics.

However, Pseudomonas aeruginosa mainly poses a serious threat to weakened and ill patients, usually already undergoing care. For example, people with cystic fibrosis, COPD (chronic obstructive pulmonary disease) or urinary catheters have a high risk of developing an infection caused by this bacterium. Some of these patients subsequently develop sepsis (blood poisoning) which can be fatal.

“We live longer, which also means that there are more people who live with various diseases. Therefore, infections caused by Pseudomonas aeruginosa and other bacteria that affect people with impaired immune systems have become more common,” explains Magnus Paulsson.

In his thesis, he offers new explanations as to why Pseudomonas aeruginosa survives in the human body — despite antibiotic medication. The focus of the research is on the bacterial vesicles — a type of excreted nanoparticles, which are dislodged from the bacterial surface. These carry and spread many of the bacterial properties.

Pseudomonas aeruginosa, like the related Moraxella catarrhalis bacterium, produces beta-lactamase which breaks down antibiotics. The bacteria can then use the vesicles to spread the substance.

Paulsson’s thesis shows that the vesicles help enable these and other bacteria to effectively colonise the body: when the vesicles spread, the body responds by engaging its immune system. But the vesicles do not let themselves be defeated; instead, protect their interior cargo and inhibit the immune system’s ability to neutralise the beta-lactamase, promoting bacterial invasion in the body.

Another trick in which Pseudomonas aeruginosa uses its vesicles was studied with particular focus on infection in the lungs. In this case, the vesicles trigger an increased production of vitronectin — a protective protein that controls the body’s immune system. The Pseudomonas bacteria binds vitronectin to its surface and the immune response is subsequently stopped.

“The process was previously known, but our study is the first to show that this can happen in our lungs,” says Magnus Paulsson.

The thesis is based on both patient and laboratory studies. Now, the research continues on how to stop the bacterial progression using a vaccine or various bodily defence mechanisms.

Magnus Paulsson defended his thesis “Host-pathogen interactions in Pseudomonas aeruginosa invasive and respiratory tract infection” at Lund University on 24 May 2017. Find more information at: http://portal.research.lu.se/portal/en/publications/hostpathogen-interactions-in-pseudomonas-aeruginosa-invasive-and-respiratory-tract-infection(076b2f13-acff-4bc5-9f27-f63e686345b4).html

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