Publisher Health

A single hormone appears to coordinate the lifespan extension produced by a low-protein diet.
A new study from Pennington Biomedical Research Center, published in the journal Nature Communications, found that reducing the amount of protein in the diet produced an array of favorable health outcomes, including an extension of lifespan, and that these effects depend on a liver-derived metabolic hormone called Fibroblast Growth Factor 21 (FGF21).
It has long been known that reducing the amount you eat improves health and extends lifespan, and there has been increasing interest in the possibility that reducing protein or amino acid intake contributes to this beneficial effect. Several recent studies suggest that diets that are low in protein, but not so low that they produce malnutrition, can improve health. Conversely, overconsumption of high-protein diets has been linked to increased mortality in certain age groups.
A few years ago, Pennington Biomedical’s Neurosignaling Laboratory discovered that the metabolic hormone FGF21 was a key signal linking the body to the brain during protein restriction. Without this signal, young mice failed to change their feeding behavior or metabolism when placed on a low-protein diet.
“Our data suggest that FGF21 talks to the brain, and that without this signal the mouse doesn’t ‘know’ that it is eating a low-protein diet. As a result, the mouse fails to adaptively change its metabolism or feeding behavior,” said Christopher Morrison, Ph.D., Professor and Director of the Neurosignaling Lab.
The group’s newest work, led by postdoctoral researcher Cristal M. Hill, Ph.D., demonstrates that low-protein diets produce beneficial metabolic effects in aged mice, improving metabolic health, reducing frailty, and extending lifespan. These beneficial effects were also apparent when protein intake was reduced in middle-aged mice, even protecting against the detriments of obesity. Importantly, these beneficial effects were lost in mice that lacked FGF21, suggesting that its action in the brain is critical for the increase in health and lifespan.
“We previously showed that FGF21 acts in the brain to improve metabolic health in young mice fed a low-protein diet. These new data extend this work by demonstrating that FGF21 also improves metabolic health and extends lifespan. Collectively, these data provide clear evidence that FGF21 is the first known hormone that coordinates feeding behavior and metabolic health to improve lifespan during protein restriction,” Dr. Hill said.
However, Dr. Hill said several questions remain. It’s unclear exactly how these observations will translate to aging humans, but the hope is that this work will uncover novel molecular and neural pathways that can be leveraged to improve health in people.
“This groundbreaking research has important implications for extending the health and lifespan of people. If scientists can better understand how diets and nutritional hormones like FGF21 act to extend lifespan, these discoveries could offset many of the health issues that occur in middle age and later,” said Pennington Biomedical Executive Director John Kirwan, Ph.D.
This work was supported by the National Institutes of Health grants R01DK105032, R01DK121370, R01DK123083, and F32DK115137. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Switching to low carbon fuels for transportation, cooking, heating, power generation and other needs would help fight climate change and also reduce racial and ethnic disparities in exposure to air pollution, according to researchers at the University of California, Davis.
Research published in the journal Science of the Total Environment found that differences in exposure to fine and ultrafine particle pollution could be reduced between 20 and 40% in 2050 if solar, wind and electric sources were used rather than fossil fuels.
The findings factor in California’s ban on the sale of new gas-powered passenger vehicles beginning in 2035 and illustrate the need to focus beyond transportation pollution, which has been a significant source of climate-damaging emissions.
“Even though transportation pollution has been largely decreased by 2050, the other sectors will still be important,” said Yiting Li, a Ph.D. candidate in atmospheric sciences who is the first author on the journal article.
Energy, climate and emissions
The UC Davis researchers analyzed future energy use and emissions scenarios in four regions — the San Francisco Bay area including Sacramento, San Joaquin Valley, Los Angeles and San Diego. The energy scenarios ranged from business as usual to strict reductions in greenhouse gas emissions.

The lone star tick can trigger an allergic reaction to red meat in those bitten. Now this arachnid’s territory is expanding.One night in 2008, Deborah Fleshman awoke in her bed to find that her legs had turned beetroot red. Welts, some a foot wide, had appeared along her torso.Ms. Fleshman, a nurse at the time, had earlier that evening hosted a cookout at her home in Greenwood, Del., a town of about 1,000 people 25 miles south of Dover. She drank a couple of beers. She ate a cheeseburger.Hours later, she told her worried father, “I feel like I’m dying.”Ms. Fleshman, now 60, is among the thousands of Americans diagnosed with alpha-gal syndrome, an allergic reaction to mammal meats like pork, beef and lamb, which growing evidence shows can be triggered by a tick bite.“It feels like you’re on fire, and then it feels like you slept with a cactus,” she said. “The itching is unbearable.”Researchers have traced the syndrome to the lone star tick, named for the signature white splotch, or “lone star,” on females’ backs. They’re historically found in the southern United States, but increasingly, these arachnids are being spotted in parts of the Midwest and the Northeast.The tick’s territory is expanding, thanks in part to global warming, say scientists. With more hot days each year, the ticks, which thrive in warm and humid conditions, have more time to feed on their hosts and reproduce. At the same time, alpha-gal diagnoses appear to be rising.“What we’re now seeing is a wide open door for ticks to continue expanding their range further northward; bringing more people into the fold of the arthropod-borne diseases,” said Michael Raupp, a professor emeritus in entomology at the University of Maryland.The Centers for Disease Control and Prevention estimates that between 2004 and 2019, the total number of tick-borne diseases in the United States more than doubled. In the meantime, other devastating pests that were previously constrained by cooler temperatures — like the dengue virus-carrying tiger mosquito, or the cabbage-munching harlequin bug — have also marched forth beyond their historic ranges.“We’re venturing into uncharted waters in so many dimensions with climate change,” Dr. Raupp said.By nature, ticks are travelers; they attach themselves to hosts in order to suck their blood, hitching a ride in the process. Scientists say an explosion in the population of the white-tailed deer, their primary host, has also helped them to spread.According to some maps, the lone star tick has advanced as far west as parts of Nebraska, and as far northeast as Maine. Climatic conditions are also suitable for the ticks to establish populations along the coast of Washington, Oregon and California, other models indicate.Scientists first began noticing an allergic reaction to alpha-gal in 2006, but it was not until several years later that they understood it was likely caused by the bite of the lone star tick. By 2012, it had already been found in 39 states, according to one study.“The spatial distribution of the species has definitely increased by at least 30 to 50 percent in the last half a century,” said Ram Raghavan, an assistant professor in epidemiology and disease ecology at the University of Missouri, who has mapped the lone star tick’s spread. According to his research, the ticks are expected to continue to shift and expand their range; both to the north and west.Goudarz Molaei, the director of a state-run tick and pathogen surveillance program in Connecticut, said that the lone star tick has firmly established itself in at least two counties in the state. “Because of climate change, what lands in our region, stays,” he said.The lone star tick bite can result in several other illnesses, including the recently identified Heartland virus disease and Bourbon virus disease, both of which can lead to fever, fatigue and in some cases hospitalization, and even death. Unlike the blacklegged tick, it cannot transmit Lyme disease, though one study indicates that the blacklegged tick may also be implicated in spreading alpha-gal.Alpha-gal syndrome is triggered by a complex sugar called galactose-alpha-1, 3-galactose, or alpha-gal, for short. The sugar is found in most mammals, but not in fish, reptiles, birds or humans. When the lone star tick feeds, alpha-gal is spread through its saliva, exposing the host’s immune system to the sugar. For some people, this triggers an overactive immune response the next time they encounter it.More than 34,000 people in the United States have tested positive for alpha-gal syndrome, according to a 2021 paper. A map publicly generated by individuals who say they suffer from the condition indicates that the syndrome may have spread as far as Washington and Hawaii, though this does not mean the sufferers were bitten by ticks in those states.Though the conditions present mildly for some, others suffer hives, swelling, wheezing, diarrhea or even anaphylaxis, which can be fatal. Unlike many other allergic conditions, the symptoms may take several hours to appear after consuming meat products, making the syndrome difficult to diagnose.“It’s never predictable,” said Jennifer Platt, an adjunct professor in public health at the University of North Carolina at Chapel Hill and a co-founder of the nonprofit Tick-Borne Conditions United. “I know people that spend the night in the emergency room parking lot, waiting for a reaction,” she said, adding, “I think of alpha-gal syndrome as Lyme 2.0.”“There are so many parallels in terms of patients being told by their providers that it’s all in their head,” Dr. Platt said.Even after treatment, some symptoms of Lyme disease, including pain and fatigue, can linger for months, according to the C.D.C. But some medical experts remain skeptical of this chronic version of the disease, disagreeing about its presentation, diagnosis and treatment.Some sufferers of alpha-gal — especially in states where the ticks have been thought to be less common — described the frustration of seeking a diagnosis and encountering disbelief from medical professionals.In Ms. Fleshman’s case, it took more than seven years and about a dozen trips to the emergency room before she finally found out what was wrong. At one point, an infectious disease doctor told her she could not have alpha-gal syndrome, because there were no lone star ticks in the state of Delaware.“I was livid,” Ms. Fleshman said. “Do you really think they read a sign that says, ‘Do Not Enter,’ and they listen?”

After scandals in which doctors let unsupervised assistants operate on patients, the country is becoming one of the first to require cameras in operating rooms.

SharecloseShare pageCopy linkAbout sharingImage source, Getty ImagesNorth Korea has confirmed its first death from Covid-19, with state media adding that tens of thousands more are experiencing fever symptoms.Six people died after suffering a fever with one testing positive for Omicron, state media reported on Friday.It said 187,000 people with a fever were being “isolated and treated”.While experts believe the virus has been present in the country for some time, the authorities only announced the first cases on Thursday.They said there had been an outbreak of the Omicron variant in the capital, Pyongyang, and announced lockdown measures. They did not give precise case numbers.But in an update on Friday, the official KCNA news agency reported that the outbreak extended beyond the capital. “A fever whose cause couldn’t be identified spread explosively nationwide from late April,” it said.Around 350,000 people had shown signs of that fever, it added, without specifying how many had tested positive for Covid. Image source, EPAAnalysts suggest the latest figures from state media, including the acknowledgement that the unspecified fever had spread nationwide, may indicate the country is experiencing an outbreak unlike any it has seen so far.Its population of 25 million is vulnerable due to the lack of a vaccination programme and poor healthcare, experts say. Why doesn’t North Korea have enough food?How dangerous is the situation in North Korea?North Korea rejected offers from the international community to supply millions of AstraZeneca and Chinese-made jabs last year. Instead, it claimed it had controlled Covid by sealing its borders early in January 2020.The country shares land borders with South Korea and China, which have both battled outbreaks. China is now struggling to contain an Omicron wave with lockdowns in its biggest cities.On Friday, KCNA reported that the North Korean leader Kim Jong-un had visited a healthcare centre and “learned about the nationwide spread of Covid-19”. It described the situation as an “immediate public health crisis”. These numbers give us the first indication that the virus has spread rapidly around the country, far beyond the capital Pyongyang.This puts the entire population of 25 million at risk. No-one is vaccinated, many are malnourished, and the health care system is poor.But the virus itself may not present the biggest danger. The lockdown could have devastating consequences for people.Food and medicine are already in short supply, thanks to efforts by authorities to keep the virus out – they’ve sealed the country’s borders for more than two years, cutting off virtually all trade.We don’t know yet how aggressive these lockdowns will be, and whether people will be confined to their homes.Kim Jong-un wants some work to continue. But it is very possible that the markets, where many earn a living, will be closed. It will also be more difficult for people to move around the country. This in turn will make it even harder for them to get hold of the food and supplies they need to survive. By publishing these figures today, some say North Korea is showing it might finally be willing to accept outside help.At a meeting outlining new Covid rules on Thursday, Mr Kim was seen wearing a face mask on television for what was believed to be the first time.He ordered “maximum emergency” virus controls, which appeared to include orders for local lockdowns and gathering restrictions in workplaces.There are fears a major outbreak could make it even more difficult for essential supplies to enter the country, worsening food shortages and a faltering economy.South Korea has said it offered humanitarian aid after Thursday’s announcement, but Pyongyang is yet to respond.Despite North Korea’s earlier claims that it had “shining success” in keeping out Covid, there have been signs throughout the pandemic of its possible presence in the country, including unconfirmed reports of cases and workers wearing hazmat suits.More on this storyN Korea in lockdown over ‘first ever’ Covid casesKim claims ‘shining success’ against virusNorth Koreans put hazmat suits on for paradeKim Jong-un admits North Korea food concerns

Six predictors could help determine the amount of lithium needed to treat patients with bipolar disorder, according to a large study led by researchers at Karolinska Institutet in Sweden. The study, published in the journal The Lancet Psychiatry, also pinpoints genetic markers that seem to influence how quickly the body eliminates lithium from its system.
“Our model could already now be used to predict how much lithium a patient with bipolar disorder will need. This could cut valuable time spent on finding the right dose for each patient, potentially with life-saving impact,” says Martin Schalling, professor at the Department of Molecular Medicine and Surgery, Karolinska Institutet and the study’s senior author.
Lithium is one of the most important treatments for patients with bipolar disorder, a condition that has been linked to an increased risk of suicide. The chemical substance works as a mood stabilizer and reduces episodes of depression and mania. How much is needed vary greatly between individuals and finding the right dose for each patient is key as too much can be toxic while too little is ineffective. To minimize the risk of side-effects, clinicians tend to initiate treatment at low doses that increase over time, meaning it could take months before the treatment has an effect.
To overcome this, researchers have long sought to find a model that could predict dose response in individual patients. Previous studies have identified markers such as age, sex and kidney function as possible predictors of how quickly the body eliminates lithium from its system (lithium clearance), which can be used to determine the amount needed on a daily basis. However, most studies have been limited by small sample sizes.
In the current study, the researchers examined electronic health records and registry data from a total of 2,357 patients with bipolar disorder, which may represent the largest sample size for this kind of study to date. Both men and women in ages ranging from 17 to 89 were included, mainly of European ancestry.
The study found associations between the speed of lithium clearance and age, sex, kidney function (measured as eGFR), serum lithium concentrations and medication with diuretics and substances targeting the renin-angiotensin-aldosterone system (RAAS), which could be used to treat hypertension and other conditions.
“Our findings suggest that older patients, women, patients with reduced kidney function, and those taking certain medications require lower doses of lithium. Interestingly, we also discovered that the amount of lithium taken and lithium concentrations in the blood do not seem to be completely proportional, which goes somewhat against current thinking. Our model based on these predictors explained around 50-60 percent of the variance in lithium clearance, which is better than previous models and could be used to inform treatment decision,” says first author Vincent Millischer, a postdoctoral researcher at the Department of Molecular Medicine and Surgery, Karolinska Institutet, and resident in psychiatry at the Medical University of Vienna.
The study also found associations between a lower lithium clearance and one genetic locus on chromosome 11 and could also show that genetic variants affecting BMI and kidney function were associated with lithium clearance.  Even though adding the genetic markers only marginally improved the model’s predictive capability, the researchers say it opens the opportunity of personalized medicine in lithium treatment in the future.
“Next we will test our model in a clinical trial to see if it can reduce the time it takes to find the right amount of lithium for each patient,” Martin Schalling says. “If the outcome is positive, we will develop a digital app that could be used by psychiatrists in the future to help assess lithium dosage for patients with bipolar disorder.”
The study was funded by the Stanley Medical Research Institute, the Swedish Research Council, the Swedish Foundation for Strategic Research, the Swedish Brain Foundation, the Söderström Königska Foundation, the Bror Gadelius Minnesfond, the Swedish Mental Health Fund, Karolinska Institutet and Karolinska University Hospital. Some of the authors have declared receiving consulting and lecture fees from various pharmaceutical companies while others have declared no competing interests.
 
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An unexpected trick in cancer’s playbook may fool an important component of our immune systems into knocking down our natural defenses against solid tumors.
Scientists at Fred Hutchinson Cancer Center say this newfound vulnerability involves a misuse of a type of T cell, part of a large family of blood cells that are essential to a functioning immune system.
A team led by Hutch immunologist Dr. Martin Prlic, staff scientist Dr. Florian Mair and postdoctoral fellow Dr. Jami Erickson published the findings in Nature. They identified a subset of T cells that show up in great numbers in head and neck tumors, but not in similar tissues of the mouth inflamed by common ailments such as gum disease.
It seems that this odd group of T cells have mixed up their highly specialized assignments within our immune systems and are now working to protect tumor cells.
The evidence Prlic, Mair, and Erickson uncovered might help explain why cutting-edge immunotherapies that work against blood cancers are less effective against solid tumors (such as breast, prostate, kidney and colorectal cancers), which are responsible for most cancer deaths. Researchers say it points the way for future drugs that might strip away that protection, making current therapies work better for more people.
“Ironically, this is not what we tried to do,” Prlic said. “We were just interested in general about what makes the tumor environment different from ordinary inflammation. It was as if you were not looking for treasure, but then you stumble upon something many others have been looking for.”
New methods reveal unnoticed T cell trait

Following a heart attack, the human body is incapable of repairing lost tissue due to the heart’s inability to generate new muscle. However, treatment with heart progenitor cells could result in the formation of functional heart cells at injured sites. This new therapeutic approach is introduced by an international team in Nature Cell Biology. The aim is to start clinical studies within the next two years.
How can the heart function be restored after a heart attack? With an estimated 18 million deaths each year globally from cardiovascular diseases according to the World Health Organization (WHO), this is the subject of research worldwide. A possible answer could be the treatment with an enriched pool of human pluripotent stem cell derived ventricular progenitors, or HVPs for short. An international team consisting of the Technical University of Munich (TUM) and its university hospital Klinikum rechts der Isar, the Swedish Karolinska Institutet, Swedish biotech startup Procella Therapeutics and the biopharmaceutical company AstraZeneca has investigated this approach in a study published in the journal Nature Cell Biology.
Many heart disease conditions result in the death of heart muscle cells and blood vessels. They are replaced by fibrotic scar tissue, which causes further deterioration of heart function. Some animals, in particular amphibians and fish, can repair such damage — a capability almost entirely absent in the heart of an adult human. One experimental approach for restoring lost heart tissue is with stem cell therapy. Previous studies have included the use of heart cells grown from stem cells, specifically: cardiomyocytes. However, frequent side effects such as irregular heartbeats and fatal arrhythmia occurred.
Cardiac progenitor cells instead of differentiated heart cells
In contrast, the team working with Karl-Ludwig Laugwitz, Professor of Cardiology at TUM, is investigating human ventricular progenitor cells. These cells play a crucial role in the formation of the heart during development. Over time, they differentiate into the various cell types in the heart, including cardiomyocytes. The team has succeeded in producing large numbers of such HVPs from human embryonic pluripotent stem cells. “This represents the culmination of two decades of our work trying to find the ideal cell to rebuild the heart,” says Kenneth R. Chien, Professor of Cardiovascular Research at Karolinska Institutet.
Complex molecular mechanisms
With these cells, the scientists studied the complex molecular processes involved in the repair of damaged areas of the heart muscle. “In laboratory investigations, we were able to show how HVPs can, in a sense, track down damaged regions in the heart, migrate to injury sites and mature into working heart cells. They also actively prevent the formation of scar tissue by cross-talking with fibroblasts, as we call the cells that form the structural framework for the non-functional connective tissue,” says Prof. Laugwitz, who heads the First Medical Department of TUM’s Klinikum rechts der Isar.
Successful treatment of pig hearts
As the next step, the interdisciplinary team used pigs to study the effectiveness of treating a damaged heart with HVPs. Physiologically, pig hearts are quite similar to those of humans. As a result, experiments with pigs are often conducted shortly before the start of studies in human patients. The results show that damage to the heart can be reliably repaired even in large animals with no serious side effects observed. “The treatment successfully demonstrated the formation of new cardiac tissue and importantly, improved cardiac function and reduced scar tissue,” says Dr. Regina Fritsche-Danielson, Head of Research and Early Development at AstraZeneca.
Researchers aim at starting clinical studies within the next two years
In the coming months and years, the scientists plan to translate their current research findings to develop a treatment for heart patients. An important intermediate step is the development of hypoimmunogenic lines of HVPs. Currently, it is necessary to inactivate the recipient’s immune system to prevent it from destroying the cell treatment. Hypoimmunogenic cells would eliminate the need for this step, because they would not be identified as foreign bodies to the recipient. Further research will be conducted on hypoimmunogenic cells and possible side effects. The aim is to start clinical studies on the therapeutic use of HVPs within the next two years.
“The new insights on the therapeutic use of HVPs represent a milestone in the treatment of diverse patients with serious heart failure,” says Prof. Karl-Ludwig Laugwitz. “Especially older patients with coexisting conditions, for whom major heart surgery would represent an excessive strain, would benefit from treatment with HVPs.”

The country’s leader, Kim Jong-un, said 187,800 people were in quarantine, and state TV showed him wearing a mask for the first time.​SEOUL — The coronavirus has been spreading across North Korea “at an explosive rate” since late last month, killing six people and leaving 187,800 people in quarantine, the country’s state media reported on Friday.The country’s health officials made the rare admission of an emerging public health crisis while its leader, Kim Jong-un, was visiting the national disease-control headquarters on Thursday, the North’s official Korean Central News Agency said.In a sign of growing urgency, the state-run Central Television for the first time showed Mr. Kim wearing a mask during a Workers’ Party meeting.The fact that the virus was spreading across the country meant that North Korea had “loopholes in its epidemiological system,” Mr. Kim was quoted as saying.North Korea said it had learned of its first outbreak after health officials on Sunday tested people in an unidentified organization in Pyongyang, the capital, who showed symptoms such as fever. They were confirmed to be infected with the BA.2 subvariant of the virus, it said.The country declared a “maximum emergency” and ordered all cities and counties in the nation of 25 million to lock down to fight the spread.North Korea’s admission of an outbreak was an abrupt change for the secretive country, which had long insisted it had no cases of the virus that first emerged in neighboring China more than two years ago. Outside experts had been skeptical, however, citing a lack of extensive Covid testing and the North’s threadbare public health system.Mr. Kim said 350,000 people had been found to have a fever since late April, including 18,000 on Thursday. He added that 162,200 people had been successfully treated. The reports on the outbreak have so far been vague​, without clarifying, for example, how many of the 350,000 people found with fever have tested positive for the virus.“Like any other data from North Korea, the figures are up to debate, and we cannot fully trust them,” said Ahn Kyung-su, who operates the Seoul-based DPRKHealth.org, a website and network of public health experts who study North Korea. “But what’s clear is that North Korea has the Covid phenomenon, and by publicizing those figures, North Korea appears to be sending out signals that it is finally ready to accept Covid-related aid from the outside.”So far, North Korea has not accepted any pandemic-related humanitarian aid, including vaccine donations from world health organizations. South Korean officials hope that humanitarian shipments, including Covid-19 vaccines, could help restart diplomatic dialogue between North Korea and the United States and allies.The danger posed by the Covid outbreak is greater in North Korea than in most other nations because most of its people are unvaccinated. Outside health experts have long questioned the North’s ability to fight a large-scale outbreak, although its regime is capable of imposing severe controls on residents’ movement.The outbreak, if not controlled quickly, could increase the strain on the country’s economy, which already has been hit hard by years of United Nations sanctions and its decision two years ago to close its border with China, its only major trading partner, to prevent the spread of the virus.Hours after admitting to the outbreak on Thursday, North Korea launched three ballistic missiles from near Pyongyang toward the sea off its east coast, the South Korean military said. It was the North’s 16th missile test this year and an indication that it was pressing ahead with weapons tests despite the threat of the virus.

WASHINGTON — President Biden and other leaders issued an urgent call on Thursday for the world to step up its fight against Covid-19, and countries including Germany, Canada and Japan pledged large sums to finance tests, therapeutics and vaccines — a commitment Mr. Biden could not make because Congress has refused to authorize new pandemic aid.As the United States approached a harrowing milestone — one million American lives lost to the virus — fear of another deadly variant loomed large over the president’s second global Covid-19 summit, a virtual gathering co-hosted by Belize, Germany, Indonesia and Senegal. But some countries were notably absent. China, in the thick of its own Covid crisis, did not attend. Russia, waging war against Ukraine, was not invited.Senior Biden administration officials said the summit produced more than $3 billion in commitments toward the global response and toward efforts to prevent future pandemics. That is far short of the $15 billion that the World Health Organization says is needed. But the summit did lay the groundwork for a new global preparedness fund.The gathering on Thursday unfolded in a very different climate compared with that of the first Covid summit in September. The war in Ukraine is sapping energy and money from donor nations. The global vaccination campaign has stalled. Testing has plummeted around the globe. Covid antiviral pills, available in the United States, are scarce in many low- and middle-income nations. Many attendees said Covid fatigue had become as big a danger as Covid itself.“There’s still so much left to do; this pandemic isn’t over,” Mr. Biden said in his opening remarks, adding, “We have to prevent complacency.”Global coronavirus cases by regionThis chart shows how reported cases per capita have changed in different parts of the world.