In history, Tashkent, the capital of Uzbekistan, was once an important hub along the ancient Silk Road, with notable figures such as China's envoy Zhang Qian, and pilgrims Faxian and Xuanzang leaving their footprints here. Due to its harsh climate and geographical conditions, those who embarked on this route in different eras were often bestowed titles like "explorers," "warriors," and "pioneers." 

Today, the Silk Road still attracts such trailblazers, but the Silk Road Economic Belt under the China-proposed Belt and Road Initiative (BRI) has changed dramatically from its predecessors. One by one, major projects designed and built by China have left a unique and beautiful mark along the Silk Road in the new era.

Recently, Global Times reporters explored the super projects undertaken by Chinese enterprises in Uzbekistan to witness the embodiment of Chinese technology, quality standards, and wisdom, as the grand projects have brought about tremendous changes to the socio-economic landscape of Central Asia.

A modern town part of national 'heritage' 

When looking into the distance from the heights of Tashkent, a mushrooming of modern sports stadiums appears. The Olympic Town of Uzbekistan constructed by the China CAMC Engineering Company, which will be the largest sports complex in the entire Central Asia region upon its completion, is just one of the grand sports-related projects under construction. Two years hence, in 2025, the Olympic town will play host to the 4th Asian Youth Games and the 5th Asian Youth.

"You guys came a little too early. By the middle of September, the structures of the five main stadiums will have been completed," Han Xueli, business project manager at China CAMC Engineering Company, told the Global Times on August 17. 

The Olympic Town project is a large sports complex covering an area of 100 hectares, including 5 main stadiums and 15 outdoor sports fields. It is the first large-scale cooperative project to be jointly undertaken by China and Uzbekistan after the Shanghai Cooperation Organization (SCO) Samarkand summit in 2022. 

Han explained that the design, construction, and quality assurance have all adopted Chinese standards, integrated high-end technology with green elements. For example, the project will install a rooftop photovoltaic system with a total capacity of 7 megawatts. All the roofs of parking lots and sports facilities, such as the ball sports complex, will be covered with solar panels. This will not only facilitate the entry of new energy vehicles but also meet the daily electricity needs of the entire sports complex.

Fully utilizing the existing terrain, the project has two landscape water systems that are both aesthetically pleasing and practical thanks to their rainwater storage capacities. Considering the local climate, the project has embedded pipes capable of drip irrigation, replacing the previous flood irrigation system in Tashkent. Additionally, the Olympic Town incorporates 5G technology to achieve smart venues and intelligent operations.

However, completing such high-quality project within two years is not an easy task. The Uzbekistan-based China CAMC Engineering Company team has contributed a lot toward meeting the deadline. 

In the eyes of many Uzbeks, many of these Chinese concepts and standards have surpassed their expectations. Moreover, under the difficult environment of both extreme heat and cold, it is not easy to complete a project of this scale without compromising on quality in just two years' time and realize its completion by the end of 2024. However, the Chinese contractor has always actively looked for ways to solve problems and work with the Uzbek side to actualize the ambitions completion goal.

"During summer, we usually do the construction work in the morning and early evening, so as to avoid the hottest time at noon; water pipes crack easily in winter, so we strive to complete the upper steel structure lifting before the arrival of winter," said Han. 

In order to realize the real-time follow up of the project, we also introduced China's Building Information Modeling (BIM) technology, Han said proudly. BIM modeling allows users to create and view a virtual model of intelligent 3D objects, which can help with visualization, quantification, and simulation of design, construction, and other tasks related to the building process.

The quality and construction speed of the Olympic City project has also been applauded by Uzbeks. This is Uzbekistan's first world-class Olympic facility and we are creating new standards thanks to Chinese companies. Such projects will boost the economic development of the country, Vadim Akhmadiev, Technical Project manager of the Ministry for Sport and Youth Policy of Uzbekistan, told the Global Times. 

Akhmadiev said the Olympic City project will become a part of Uzbekistan's "heritage." "It is not only important for my generation, but also for the next generation."

Making history on open road

In the bazaars of Tashkent, fresh and succulent pomegranates and tomatoes from the Fergana Valley entice consumers. However, locals told the Global Times that such scenes were a rarity a decade ago. Hindered by the Tianshan Mountains, it was not easy for people from Eastern Uzbekistan's Fergana region to access the capital city. They would often resort to detouring through neighboring Tajikistan, which would take as much as an entire day. 

However, this predicament has been completely transformed by a railway tunnel - the Qamchiq Tunnel. This is currently the longest railway tunnel in Central Asia, spanning 19.2 kilometers, which is also a crucial project that connects the Angren-Pap railway line, a key transportation route between the eastern and western parts of Uzbekistan. 

The Qamchiq Tunnel project undertaken by the China Railway Tunnel Group (CRTG) began construction in 2013. The main tunnel was completed in February 2016, and was officially opened to traffic in June of the same year. In other words, it took only 900 days for Chinese contractors to complete what's considered to be a wonder - constructing a train tunnel through which trains can traverse the mountains in just 900 seconds.

"The construction of the tunnel was very difficult," Zhou Xiaoguang, project manager of the Qamchiq Tunnel project from CRTG, told the Global Times. 

The tunnel passes through the mountain at an altitude of 1,200 meters, with a maximum depth of the buried main line of 1,300 meters, which has to pass through seven geological fault zones and nearly 10 kilometers of rock burst zones.

Such a long tunnel not only needs to excavated, but needs the addition of safety access points including inclined shafts and contact access, further complicating the engineering process.

In the eyes of Deng Wei, a technician who once participated in the construction of the Kamchik Tunnel, frequent rock falls were the biggest problem encountered during the tunnel's construction that year.

"There were more than 3,000 rock falls of moderate intensity and above, and the most serious one caused the tunnel to collapse for a length of 2,000 cubic meters, posing a great threat to the safety and even the psychology of construction workers," Deng told the Global Times.

In order to overcome the perplexing problem of rock falls, the CRTG contractors organized several multinational expert meetings and conducted joint scientific research with Chinese domestic universities to develop sound scientific methods. 

Thanks to the timely research and proper technological applications, no injuries were suffered from rock fall in the nearly 10-kilometer long rock explosion zone, Deng recalled proudly.

The harsh environment was another major difficulty encountered in the construction. Zhou still remembers that in January 2014, a rare heavy snow storm which lasted for two weeks caused an avalanche on the mountain near the tunnel, which was 7-8 meters thick and more than 40 meters long, effectively enclosing the construction team within the construction site, and cut access to outside production and amenities transportation channel. "Later, workers used large machines for three days to reopen the lifeline," Zhou lamented.

"It is because of the 'Chinese spirit' of overcoming adversity that we were able to complete this super project in 900 days, which was once estimated to take as long as 25 years to complete by experts during the Soviet Union period," he said.

Further enhanced mutual trust

The successful launch and development of China's mega projects overseas reflects the further enhanced of political mutual trust between China and Central Asia in recent years. 

Han told Global Times that whenever there are problems in the construction of the Olympic Town, various departments such as the Uzbekistan Ministry of Sports, Customs Committee, and city government of Tashkent always appear to help China coordinate efforts to solve the problems.

"For example, Uzbekistan's President Shavkat Mirziyoyev even personally signed a presidential decree to open a 'green channel' for us to import a large amount of construction materials and equipment, ensuring that the imported supplies for the project could clear customs with zero tariffs and were delivered to the site quickly," Han said. "The high level of trust and support from the Uzbek side toward China is an important reason why mega projects like the Olympic Town are able to progress so rapidly."

Additionally, the acceleration of the internationalization process of the Chinese Yuan has also become an important driving force for more Chinese mega projects to go global. Taking the Uzbekistan's Olympic Town as an example, the project adopted the RMB loan model, with the Export-Import Bank of China providing RMB loans. This is also the first international engineering project in Uzbekistan to be financed by a sovereign commercial loan denominated in RMB. Observers noted that compared with financing through European and American capital markets, RMB loans have lower costs and are more economically beneficial to the financing country.

At the same time, China's mega projects are also reshaping the geopolitical landscape of Central Asia. Taking the Qamchiq Tunnel as an example, the completion of this railway tunnel has not only eliminated the need for long detours through other countries, but also has the potential to become a new transportation hub and important international transit channel along the China-Central Asia-Europe transportation corridor. 

"In the last two years, the construction of the future operation of the China-Kyrgyzstan-Uzbekistan railway project has been made a priority. If this railway can be successfully built, trains departing from China in the future will enter Uzbekistan through Kyrgyzstan, pass through the Qamchiq Tunnel to Tashkent, and then continue through Turkmenistan and the Middle East to Europe. This route will be the shortest and fastest route for the Eurasian continent," said Zhou.

The BRI is transforming Uzbekistan from a landlocked country into an important transportation hub in the region, and promoting the integration of Uzbekistan and other Central Asian countries into the global economy and the world's logistics system, said Saidmukhtar Saidkasimov, former deputy prime minister and former foreign minister of Uzbekistan, in an exclusive interview with the Global Times.

In Han's view, all the hard work today is worth it, because he expects that after the completion of the project, the people of Uzbekistan will usher in their own country's era of high-standard and modern venues, and become another bright "Made in China" calling card in Central Asia.

Influenced by the US' strategic competition against China, some Western countries have clearly become hostile toward China in recent years. South Korea and Australia, as two typical "middle powers" of similar economic scale which have close trade ties with China, are both US allies in the Asia-Pacific region, and their relations with China have deteriorated for some time. However, the recent "ice-breaking" of China-Australia relations and the continuous "freezing" of China-South Korea relations are in stark contrast.

Recently, China and Australia have witnessed warming ties. Amid the East Asia Summit, Australian Prime Minister Anthony Albanese confirmed on September 7 that he will visit China later this year after talks with Chinese Premier Li Qiang, with both sides agreeing to resume exchanges in various fields. As leader of the Labor Party, Albanese has shown a different stance toward China from his predecessors since he came to power last year. On the same day, the 7th China-Australia High-Level Dialogue was held in Beijing, the first in three years. It is noticed that the Australian delegation covers all sectors of politics, business, academia and the media, with many former politicians from both the Liberal and Labor parties in attendance. This is seen as a consensus between the two parties of Australia to improve relations with China.

Australia's shift has been very positive. However, the same cannot be said about South Korea's performance. Since coming to power in May last year, the Yoon Suk-yeol administration has focused on the South Korea-US alliance, highlighting the "values" orientation of its foreign policy and displaying a distinctive "pro-US" tendency. With regards to its relations with China, the Yoon administration blatantly interferes in the Taiwan question and attempts to follow the US and Japan in terms of the South China Sea issue. These moves have further led to tension and a standstill between Beijing and Seoul.

The Yoon administration, perhaps realizing that its policy toward China is too paranoid, has recently tried to send positive messages to China. In the meeting with Premier Li, Yoon emphasized that the South Korean side is willing to work with China to practice multilateralism and free trade and promote the stable and healthy development of the South Korea-China relationship. However, so far, these signals released by South Korea have not yet been put into practice.

Looking back at the China-South Korea and China-Australia relations over the years, the turning point occurred after the change of government in South Korea and Australia last year. After the Australian Labor administration came to power, it made adjustments to the anti-China "microphone diplomacy" of its predecessor under Scott Morrison and sent out frequent signals to repair relations with China. Therefore, the leaders of the two countries met during the G20 summit in Bali, Indonesia in November last year, which promoted the improvement in bilateral relations.

In contrast, the Yoon administration, which also came to power last year, took the opposite approach, changing the previously balanced route between the US and China to the "pro-US" orientation, which caused the deterioration of its ties with China.

The impact of such two different policy orientations is prominent. From January to July this year, China-South Korea bilateral trade fell 16.6 percent year-on-year. Some analysts said that the negative effects of South Korea's policy of following the US and "decoupling" from China are becoming apparent. Meanwhile, bilateral trade between China and Australia saw an increase of 5.4 percent year-on-year, which is particularly striking against the backdrop of a general slowdown in the global economy. Clearly the improvement of political relations between China and Australia has played a crucial role in boosting bilateral economic and trade ties.

For Seoul and Canberra, there are many similarities in their relationship with Beijing. Both South Korea and Australia have no historical or territorial disputes with China, but have maintained close economic and trade ties. Furthermore, China does not pose any threat to either country. In particular, the Australian and South Korean economies are heavily dependent on trade with China, so stabilizing and developing relations with China is essentially in the national interests of both countries. The latest improvement in China-Australia relations is exactly due to Canberra's return to rather independent and pragmatic policy toward China, which should be an inspiration for the Yoon administration.

As Chinese Foreign Minister Wang Yi put forward during his meeting with the Australian delegation, it is necessary for the two sides to draw useful experience and lessons in the bilateral relations. He urged the two sides to look at each other objectively, calmly and kindly, understand that China and Australia should remain partners rather than rivals, and advance bilateral relations independently and without any influence or interference from any third party. These three points are also helpful suggestions for South Korea.

The author is a research fellow at the China Institute of International Studies.

Out of options. Illustration: Liu Rui/GT

In a study of pregnant women in Brazil, nearly 30 percent of those infected with Zika virus had babies with fetal abnormalities, researchers report March 4 in the New England Journal of Medicine.

Zika virus is the leading suspect for what’s causing a spike in certain birth defects reported in Brazil. Scientists have previously found traces of Zika in the brains of fetuses with microcephaly (a birth defect that leaves babies with smaller-than-normal heads). And one study has reported that the virus can infect and kill a cell type crucial to developing brains (SN Online: 3/4/16).

The new study enrolled 88 pregnant women from Rio de Janeiro who had developed a rash (a sign of Zika infection). They tracked the women throughout their pregnancies; so far, eight have given birth. Of the 42 women who both tested positive for Zika and received fetal ultrasounds, 12 of the women’s babies had abnormalities (including small heads, damaged brain tissue, and low levels of amniotic fluid).

Despite mild clinical symptoms, Zika infection during pregnancy appears to be linked with grave outcomes, the authors write.

In a galaxy far, far away, Chewbacca is a 7.5-foot-tall Wookiee. On Earth, he’s a small furry beetle.

Researchers discovered four new species of weevils on an island off the coast of Papua New Guinea, one of which they named after the lofty Star Wars character. Trigonopterus chewbacca is a black, flightless beetle about 3 millimeters long that thrives in the tropical forests of New Britain. Although T. chewbacca doesn’t resemble its namesake in size, the dense hairlike scales covering its head and legs reminded the researchers of Chewbacca’s fur.

Before these finds, Trigonopterus beetles hadn’t been spotted on New Britain. The discovery of T. chewbacca and its three relatives, T. obsidianus, T. puncticollis and T. silaliensis, suggests that the genus colonized the island at least four separate times, the team reports April 21 in ZooKeys.

T. chewbacca joins the ranks of other insects with a Star Wars moniker. Among its peers: a furry moth also named after the heroic Wookiee, a wasp named for Yoda and a Darth Vader slime-mold beetle.

Vultures are the birds everyone loves to hate. Even though you have nothing to fear from them — unless you’re dead — vultures’ steady diet of carrion will gross most people out. That diet may also be responsible for the birds’ quick and steep declines around the globe, a new study shows.

It’s not the dead bodies that are killing vultures, though. It’s the poisons with which humans have laced those meals, both intentionally and inadvertently, Evan Buechley and Çağan Şekercioğlu of the University of Utah in Salt Lake City conclude in the June Biological Conservation.

The team went searching for an explanation to something Şekercioğlu had reported in 2004 and is still true today — that vultures are the most threatened group of birds. Of the 22 species of vultures, nine are now critically endangered, three are endangered and four are near threatened, according to the International Union for Conservation of Nature, which tallies endangered species.

Buechley and Şekercioğlu were looking for an explanation of why these scavenging species (called “obligate scavengers” because they depend almost entirely on carrion for survival) are doing so poorly but “facultative scavengers” — birds such as storks, gulls and crows that can also eat things other than carrion and trash — tend to be doing well and even increasing in numbers in many cases. The researchers collected ecological information and population trend data on the 22 species of vultures and other avian scavengers and then tried to figure out what made the vultures so vulnerable.

Some aspects of biology do contribute to the vulture declines, the team found. These are large animals that live long and don’t produce a lot of offspring. That means that populations can take a long time to recover from bird deaths. But the ultimate cause of those deaths is what is disturbing — dietary toxins, which are the primary cause of declines in 14 of the 16 threatened and near-threatened vulture species, the team found.

Those toxins come in various forms. In India and Southeast Asia, it’s the cattle drug diclofenac, which causes kidney failure in any vulture unlucky enough to come across a cow that didn’t survive its medical treatment. Diclofenac is a problem for vultures in Africa, too, (and now Spain), but there the birds have also fallen victim to the poisons used to kill hyenas, jackals and lions in response to dead livestock. Wildlife poachers have also deliberately poisoned their prey in an effort to get rid of the circling vultures that can alert authorities to their crime. (Buechley and Şekercioğlu discovered a 2007 incident in Namibia in which a poisoned elephant carcass killed as many as 600 birds.) And in Europe and the Americas, carcasses laced with rodenticides, insecticides and lead from ammunition are also killing vulture species.

Without vultures, some of these ecosystems are already having problems. Other scavenging species aren’t quite able to fit into the vulture niche. They can’t eat as much and they don’t have stomachs equipped to kill deadly microbes, like vultures do. That means anything that does eat carrion could potentially spread disease. Populations of scavenging pests, like rats and feral dogs, have already skyrocketed in some places as these animals feast on what vultures would have once dealt with. Perhaps not surprisingly, that has led to problems, such as an increase in dog bites in India that has resulted in thousands of human deaths from rabies.

Much of the vulture declines could be easily solved by banning the chemicals that kill them, the researchers note. Because while vultures may be more inherently vulnerable to extinction than other bird species, due to their biology, their importance to the global ecosystem — and our own health — makes them too valuable to let slip away.

DNA from an ancient woman who lived in what’s now Romania indicates that people in Asia trekked to Africa starting between 45,000 and 40,000 years ago.

Evidence for this back-to-Africa trip comes from the partial remains of a 35,000-year-old Homo sapiens discovered in a Romanian cave more than 60 years ago. A distinctive pattern of alterations to mitochondrial DNA extracted from two of the teeth are similar to alterations seen in mitochondrial DNA of present-day North Africans, signaling an evolutionary connection, the team proposes May 19 in Scientific Reports.

After evolving in Africa around 200,000 years ago, human populations spread out of the continent by 50,000 years ago. The ancient Romanian woman’s DNA came from a maternal line that originated in West Asia after humans initially left Africa but then ended up in North Africa, the scientists propose.

Careening through the bloodstream, a single nanoparticle is dwarfed by red blood cells whizzing by that are 100 times larger. But when specially designed nanoparticles bump into an atherosclerotic plaque — a fatty clog narrowing a blood vessel — the tiny particles can play an outsized role. They can cling to the plaque and begin to break it down, clearing the path for those big blood cells to flow more easily and calming the angry inflammation in the vicinity.

By finding and busting apart plaques in the arteries, nanoparticles may offer a new, non-surgical way to reduce a patient’s risk for heart attack and stroke.

Nanoparticles measure less than 100 nanometers across — a thousandth the thickness of a dollar bill. Despite being tiny, they can be engineered to haul a mix of molecules — such as tags that make them stick to a plaque, drugs that block inflammation or dyes that let scientists track their movements. Over the last two decades, scientists have exploited these strategies to fight cancer, designing nanoparticles that deliver drugs (SN Online: 1/3/14) or dyes for imaging deep into the core of a tumor. The U.S. Food and Drug Administration has approved a few dozen cancer-focused nanomedicines.
Now researchers have begun engineering nanoparticles to target cardiovascular disease, which kills even more people each year than cancer. Nanosized compounds have been built that can sweep into clogged arteries to shrink the plaques that threaten to block blood flow. Some nanoparticles home in on the plaques by binding to immune cells in the area, some do so by mimicking natural cholesterol molecules and others search for collagen exposed in damaged vessel walls. Once at the location of a plaque, either the nanoparticles themselves or a piggybacked drug can do the cleanup work.

The aim of all these approaches is to prevent strokes and heart attacks in people with cardiovascular disease, either before surgery becomes necessary or after surgery to prevent a second event. Today, cardiovascular nanoparticles are still far from pharmacy shelves. Most have not reached safety testing in patients. But in mice, rats and pigs, nanodrugs have slowed the growth of the plaques that build up on vessel walls, and in some cases have been able to shrink or clear them.

“I think the effect we can have with these nanoparticles on cardiovascular disease is even more pronounced and direct than what we’ve seen in cancer,” says Prabhas Moghe, a biomedical engineer at Rutgers University in Piscataway, N.J.
Every minute, more than a gallon of blood pumps through the human heart, pushing through miles of blood vessels to deliver oxygen and nutrients to organs and extremities. In a healthy person, the trip is as smooth as a drive on a freshly paved highway. But in the more than 10 percent of U.S. adults who have cardiovascular disease, the route might be more like a pothole-filled road squeezed by Jersey barriers.

Waxy globs, or plaques, of fat and cholesterol line the blood vessels, thickening and hardening the walls, impeding blood flow. As fat builds up inside the vessels, it also leaks into the vessel walls, swelling them and signaling the body to send immune cells to the area. The congregation of immune cells aggravates the blockage, the way emergency vehicles surrounding the site of a multi-car pileup further slow traffic on a highway.

“The inflammation and the accumulation of fat in the walls of the blood vessel sort of feed off each other and exacerbate each other,” Moghe says.

If the plaques grow large enough, or pieces chip off and travel to smaller vessels, they can block a vessel. If oxygen-filled blood can’t reach the brain or heart, a stroke or heart attack results.

The drugs most often prescribed to prevent or treat atherosclerosis — plaque buildup on the inner walls of the arteries — are statins (SN: 5/5/12, p. 30). This highly successful and effective class of drugs, available since 1987, slows the growth of the fatty plaques by lowering the amount of cholesterol circulating in the blood. But taking statins is akin to limiting the number of cars on a damaged road rather than repairing potholes, some argue. And the drugs can boost a person’s risk of diabetes and liver damage. In many cases, patients don’t begin taking statins until they already have severe atherosclerosis, and the drugs do little to reverse the buildup of plaques that already exist.

“Heart disease is still the number one killer in the U.S.,” says endocrinologist and biochemist Ira Tabas of Columbia University Medical Center. Drug-carrying nanoparticles that can shrink existing atherosclerotic plaques and eliminate the accompanying inflammation could change that, Tabas and others say.
Going places
To treat atherosclerotic plaques with nano­particles, researchers have devised a variety of ways to send circulating particles directly to the fatty clogs. In each approach below, a molecule that’s part of the nanoparticle binds to a molecule in or near the plaques.

Click the black dots in the interactive image below to learn about different types of nanoparticles.
Macrophage magnet
To make nanoparticles congregate at the dangerous plaques, researchers need to identify something that makes the blockage stand out from the rest of the body. The crowds of immune cells near plaques act as a signpost that a plaque exists.

Many of the immune cells involved in atherosclerosis are macrophages, white blood cells that gulp pathogens, dead cells or debris in the body. At the site of a plaque, macrophages become swollen with fats and transform into what are called “foam cells” because of their foamy appearance. As they digest fats, foam cells send out chemical signals to recruit more inflammation-causing cells and molecules to the area. Because they’re so intimately involved in the formation of plaques, macrophages and foam cells are a prime target for nanoparticles.

Moghe’s group has designed nanoparticles that bind to molecules on the surface of macrophages, preventing them from gobbling fats and becoming foam cells. The researchers made the nanoparticles specifically target a subtype of macrophage that’s involved in atherosclerosis, not the macro-phages that might respond to other injuries in the body. When nanoparticles were injected into mice with narrowed arteries, the blockages decreased by 37 percent, Moghe’s group reported last year in the Proceedings of the National Academy of Sciences.

Others are using cholesterol-like molecules as nanoparticle taxis to carry drugs to plaques and subdue the immune reaction. Statins aim to lower the form of cholesterol called low-density lipoprotein, which earned the name “bad cholesterol” for accumulating in plaques. High-density lipoprotein, or “good cholesterol,” shuttles LDL away from these clogs to the liver, where it can be broken down. HDL also prevents macro-phages from turning into foam cells and producing inflammatory molecules. So Shanta Dhar, a chemist at the University of Georgia in Athens, developed nanoparticles that mimic HDL. She presented the work in March in San Diego at a meeting of the American Chemical Society.

“HDL is our body’s natural cholesterol-removing nanomaterial,” she says. In animal tests, the HDL-based nanoparticle can bind to free-floating macro-phages circulating in the blood, just as HDL does, and follow them to a plaque, she explains. The nanoparticles can also bind to macrophages already glommed on to a plaque, and, mimicking the activities of natural HDL, carry the cells away.

Plaque buster
Willem Mulder, a nanomedicine researcher at the University of Amsterdam and the Icahn School of Medicine at Mount Sinai in New York City, has also designed HDL-mimicking nanoparticles. His particles deliver statins that make a beeline for macrophages and plaques, letting him administer the drug at lower-than-usual doses. He was inspired by earlier studies that showed how extremely high doses of statins, given to mice, could lower LDL levels while also packing anti-inflammatory properties. Of course, in humans, such high doses would probably cause liver or kidney damage. Mulder’s solution: tack the statins to a nanoparticle to send them, missile-like, to the plaques. That way, a low dose of the drug could achieve the high concentration needed at the site of the atherosclerosis.
“We’re exploiting the inherent targeting properties of HDL,” he says. “And it works well with statins, which are small molecules.”

In 2014 in Nature Communications, Mulder’s group reported that plaque-filled arteries in mice given the nanoparticle were 16 percent more open than arteries in mice with no treatment, and 12 percent more open than in mice given a systemic statin. More work is needed to show whether these modest gains would translate to a reduced risk of heart attacks and strokes.

Others are using plaque-targeting nanoparticles to deliver anti-inflammatory drugs similar to methotrexate, which is used as a treatment for rheumatoid arthritis. The side effects of drugs like this, given systemically, are generally severe: vomiting, hair loss and “brain fog,” to name a few.

“If someone with rheumatoid arthritis comes into your office completely crippled, it’s worth all the side effects to put them on an anti-inflammatory drug,” Tabas says. “But imagine someone with some risk factors for heart disease who feels great. They’re not going to put up with these side effects.”

Tabas thinks that drugs that work distinctly from traditional anti-inflammatory drugs and promote resolution of inflammation and healing, known as pro-resolving drugs, could be perfect candidates to tack on to nanoparticles because they would make possible lower doses with fewer side effects.

He’s awaiting the results of two large clinical trials testing non-nano-versions of the drugs methotrexate and anti-IL1 beta. It remains to be seen whether they’re effective at clearing plaques and how severe the side effect are. If the drugs are effective, even with some side effects, Tabas says, it will give weight to his approach: Activating pro-resolving pathways using targeted nanoparticles.

Tabas and his collaborator Omid Farokhzad at Harvard University encapsulate their nanoparticles with a small section of a protein called annexin A1, which helps resolve inflammation and promote healing. His hope is that delivered only to an atherosclerotic plaque, the drug won’t have the host of side effects that other immune blockers have.

Destination: vessel wall
The inflamed vessel wall around an atherosclerotic plaque goes through several changes in addition to the accumulation of belligerent immune molecules. As vessel walls are stretched and inflamed, the structural protein collagen, meant to keep the vessels taut and tubular, becomes exposed the way the threads of a tire begin to appear as it wears down. Scientists are using the exposed collagen to their advantage. Nanoparticles with a tag recognizing the collagen end up at plaques. But it’s not as easy as affixing a GPS destination to the particles, says vascular surgeon Melina Kibbe of Northwestern University Feinberg School of Medicine in Chicago.

“It took us over a year of trying to find the right targeting [molecule] that would work,” Kibbe says. Her nanoparticle combines a collagen-binding protein with nitric oxide, a molecule that stimulates the growth of new cells at wounds. To maximize the surface area of the drug that contacts the vessel wall, Kibbe’s team arranged the molecules in a line, forming a nanofiber, rather than a sphere. As the fiber is swept through the bloodstream, it binds to exposed collagen, anchoring the nitric oxide in place to spur healing of the artery.

Kibbe and colleagues added fluorescent tags to the nanofibers and showed that the fibers congregated at injured spots on mouse arteries within an hour of injection. The tagged particles remained there for three days and the treated vessels ended up 41 percent more open, the researchers reported in the March Antioxidants & Redox Signaling.
Tabas also uses a collagen-binding protein, one that is organized in a more spherical shape, to get the piece of annexin A1 to atherosclerotic plaques. In mice, the particles stayed in the plaques up to five days after treatment, shrinking the plaque by more than a third, his team reported in Science Translational Medicine in 2015. By comparison, some circulating statins last less than a day in the blood.

Rather than targeting proteins or immune cells, scientists at Harvard’s Wyss Institute for Biologically Inspired Engineering have designed nanoparticles that are activated by the physical squeeze that comes with being swept through a narrowed artery. When the shear force around them increases, a cue that a plaque is present, the nanoparticles release their payload: a clot-dissolving drug called tissue plasminogen activator. The researchers reported late last year in Stroke that the nanoparticle, coupled with a stentlike device placed in the artery, increased the survival rate to more than 80 percent in mice that normally die of a clot entering their lungs.

Pathway to patients
Nanoparticles currently in development for cardio-vascular disease are still in animal testing. While no one has seen major side effects or toxicity in the animal trials so far, it remains a concern with a class of medicines that is so new.

“We sometimes get so wrapped up in exuding only the good stuff about nanomedicine that we forget we also have to look at the side effects,” Dhar says.
Another challenge for atherosclerosis drugs is determining who would benefit from treatment. Kibbe imagines her particles being used first in patients with severe atherosclerosis who receive stents or other invasive procedures to clear their plaques. The procedures are intended to help, she says, “but they actually are so traumatic that they cause injury to the vessel wall.” Due in part to this renewed buildup in the arteries, people who have had one heart attack are at higher risk for a second. Even among people who have a permanent stent put in, which is designed to keep part of an artery clear, up to 20 percent become reblocked. Giving these patients nanoparticle-based drugs could keep them healthy, Kibbe says.

Taken to the next level, nanomedicines “certainly might be able to prevent plaques,” she adds. Tabas imagines his nanoparticles given as a once-a-month injection, but that’s speculation.

Moving to test nanoparticles as a preventive — in the huge percentage of the population at risk for athero-sclerosis — is probably a long way off, Mulder says. According to the U.S. Centers for Disease Control and Prevention, around half of all adult Americans have one of the top risk factors for cardiovascular disease.

“I really don’t foresee that you would start preventively treating patients who don’t have symptoms with nanoparticles,” Mulder says. “But to take a person who’s hospitalized after a heart attack and stick a needle in their arm and infuse nanoparticles, that’s not hard.”

Once a few drugs have been validated as working in clinical trials, researchers expect progress to speed up, since the drug cargo on a nanoparticle engineered to target a plaque could easily be switched out for other drugs. Designing the particles, says Moghe, “is almost like building with pieces of Lego.”

This article appears in the June 11, 2016, issue of Science News with the headline, “Nano for the heart.”

Editor’s Note (revised): This article was edited on July 1 and again on July 2, 2016. Due to a misunderstanding by the writer, a quote in the original article mistakenly implied that researcher Ira Tabas of Columbia University was referring to problems with statins. He was, in fact, referring to problems with anti-inflammatories. He is not a critic of statins. Additional changes were made to clarify the activity of annexin A1. It is not a traditional anti-inflammatory agent, as was stated in the article, but what is called a pro-resolving molecule. Tabas did not develop the nanoparticles he works with, as was implied in the original. We now credit the researcher who developed those nanoparticles.

Among people, a man stepping aside to let a woman pass through a door first is seen as a gentlemanly — if a bit old-fashioned — act. Among banana fiddler crabs, though, this behavior is a trap — one that lets a male crab coerce a female into a mating she may not have preferred.

To catch the attention of a female and lure her into his burrow, a male banana fiddler crab stands outside the entrance to his cave and waves the larger of his two claws. A female will look him over and consider his size, the color of his claw and how he’s waving it. If she likes what she sees, she’ll approach him. She might decide to enter his burrow and check it out, and once inside, she might stick around for mating if she thinks that the burrow has the right conditions for rearing her embryos.

When a female approaches a male and his burrow, most males enter first, letting their potential mate follow him down. But many male crabs take another approach, stepping aside and following her into the lair — letting a male trap the female inside and mate with her, researchers report June 15 in PLOS ONE.

Christina Painting of the Australian National University in Canberra and colleagues observed banana fiddler crabs in Darwin, Australia, during two mating seasons, watching what happened as males waved their claws and females made their choice. When a female was interested in a male, the guys entered the burrow first 32 percent of the time. While females were more likely to enter a burrow if a male entered first (71 percent versus only 41 percent when the guy stepped aside), the trapping strategy was more successful in getting a mating out of the meeting. When the male followed the female in, 79 percent of females stuck around the mate. But waiting for her to follow resulted in a pairing only 54 percent of the time.

“The results strongly suggest that entering a male’s burrow first reduces the probability that a female will leave the burrow after sampling it since females are effectively trapped underground in the narrow burrow shaft when the male follows her in,” the researchers write.

So why would a female ever enter a burrow first if there were the possibility that she would be trapped inside and coerced into mating? Perhaps this might give the female a chance to test the male’s strength, the researchers suggest. If she can successfully fight her way out, then the male was obviously not worthy of her attention. Or it is possible that this is just a type of courtship behavior in which no coercion is actually happening. It’s difficult to know exactly what’s going on underground.

This isn’t the first time that the males of a fiddler crab species have been found behaving in what we might consider an ungentlemanly fashion. Males of other species have been found trapping, herding, startling and capturing females in their attempts to coerce a mating. And some male sand bubbler crabs, the researchers note, have even been found behaving somewhat like pirates of the sand-mud flats: Males have been spotted capturing female crabs, carrying them back to their burrows and forcing them into their underground lairs for mating.

If you’ve ever watched a baby purse her lips to hoot for the first time, or flash a big, gummy grin when she sees you, or surprise herself by rolling over, you’ve glimpsed the developing brain in action. A baby’s brain constructs itself into something that controls the body, learns and connects socially.

Spending time with an older person, you may notice signs of slippage. An elderly man might forget why he went into the kitchen, or fail to anticipate the cyclist crossing the road, or muddle medications with awkward and unfamiliar names. These are the signs of the gentle yet unrelenting neural erosion that comes with normal aging.
These two seemingly distinct processes — development and aging — may actually be linked. Hidden in the brain-building process, some scientists now suspect, are the blueprints for the brain’s demise. The way the brain is built, recent research suggests, informs how it will decline in old age.
That the end can be traced to the beginning sounds absurd: A sturdily constructed brain stays strong for decades. During childhood, neural pathways make connections in a carefully choreographed order. But in old age, this sequence plays in reverse, brain scans reveal. In both appearance and behavior, old brains seem to drift backward toward earlier stages of development. What’s more, some of the same cellular tools are involved in both processes.

Probing the connections between growing and aging may reveal how time affects the brain. And with a deeper understanding of brain aging, and the tools involved, scientists might be able to slow — or even stop — mental decline.
That’s a lofty goal, made even more challenging by the multitude of theories from a diversity of researchers that aim to explain why and how the brain ages. Everybody focuses on a different aspect of the aging brain, leaving no one with a sense of the whole process, says epigeneticist Art Petronis of the Center for Addiction and Mental Health in Toronto. It’s like people trying to put together a giant jigsaw puzzle from separate rooms, each with only a few pieces in hand. So far, people studying how the brain ages have found only the evidence they can grab.

Petronis and others are intrigued by the idea that the brain’s early life holds clues to its end. “You see blips here and blips there,” he says. “This critical mass is accumulating.”

Other scientists, including Caleb Finch of the University of Southern California, in Los Angeles, caution against falling for appealing but overly simple explanations for aging. As a gerontologist who has been thinking about aging for 50 years, he has seen aging theories come and go, a perspective that makes him skeptical that the complex process can be reduced to the notion that it’s just development in reverse. “The more we poke into biology, the more wondrously complex it is,” he says.

Nonetheless, there’s something to the notion that aging starts early. “We are born dying,” Finch says. And poking at that idea just might lead somewhere.

Head start
When the human brain makes its first appearance in the third week of gestation, it is no more than a minuscule smear of indistinct cells. This glob then grows at a furious rate up through the preschool years. At the same time, these accumulating brain cells begin to take on specific jobs, changing from generalists to specialists. Nerve cells are born and migrate to their final destinations, linking up in precise order to form the high-speed neural connections that enable memory, emotion and thought. And scientists now realize that the way the brain is built has lifelong effects.
In 1932 and 1947, nearly every Scottish 11-year-old sat down to take an intelligence test. Decades later, their scores have matured into academic gold, offering scientists a rare opportunity to see how intelligence fares with age. In 1999, scientists led by Ian Deary of the University of Edinburgh got back in touch with as many of the long-ago test takers as possible, forming a group of more than 1,000 people — ranging in age from 80 to 95 — called the Lothian Birth Cohort. Deary and colleagues have studied the group in detail, and one factor rises above the rest: People with higher intelligence scores at age 11 were more likely to have better thinking skills in old age.

Childhood intelligence wasn’t the only factor, though. From the start, Deary and his colleagues cast a wide net, imaging participants’ brains and examining genetics, lifestyles, health and social factors. “We were right to do so, because there is a large range of mostly small influences on people’s cognitive aging,” he says. But the fact that intelligence at age 11 can partially predict who will be sharp into their 90s suggests that a long-lasting brain must be solidly constructed.

One way in which the brain is built well involves its white matter — tracts of tissue that connect distant brain regions, allowing for quick communication. And in fact, members of the Lothian Birth Cohort with healthier white matter in old age, measured by an MRI-based brain scan method called diffusion tensor imaging, performed better on tests of brain function, Deary and colleagues found.

Mature neural highways take decades to develop. Brain areas are still solidifying into a person’s thirties. The later-blooming brain regions oversee jobs like impulse control and judgment, two well-known weak spots among teenagers.

These slow-to-grow brain networks are the first to go in old age, neuroscientist Gwenaëlle Douaud of the University of Oxford and colleagues found. Networks of nerve cells (the gray matter) are guided by a “last in, first out” rule, brain scans of 484 people from 8 to 85 years of age indicate. “What we show is a precise mirroring for these regions,” she says.

These networks, which reach their peak around age 39 for men and age 41 for women, handle sophisticated jobs, like merging multiple kinds of information together, she says. And sure enough, people with seemingly healthier neural connections had better memories, Douaud’s team reported in the Proceedings of the National Academy of Sciences in 2014.

Special no more
As neural connections come and go with age, brain cells themselves change in a way that harkens to the brain’s early days. Human brain cells are a dazzlingly diverse crew that handle a variety of jobs, from sending crucial signals to clearing out clutter. Yet these workers come from common ancestors that eventually specialize as the brain matures. In old age, some of these specialists seem to revert, becoming more similar to one another once again.
Cells are controlled by genes, but those genes don’t always behave the same way across a life span. Markers on cells’ DNA can dial activity up or down, controlling how much protein is made from a particular gene. In the case of brain cells, these epigenetic marks, many of which are laid down early in life in response to the environment, are one of the things that make nerve cells distinct from one another. So a nerve cell in the hippocampus, a structure important for memory, has an epigenetic fingerprint that’s distinct from that of a nerve cell in the cerebellum, a part of the brain important for movement.

But with age, these marks become less distinct, both between regions in a single brain and even among different people, Petronis says. After age 75, brain cells become more similar to one another, both in their epigenetic marks and their genes’ behaviors, he and colleagues reported April 28 in Genome Biology.

That was a big surprise, he says. It contradicts a popular concept called epigenetic drift, which says that with time, epigenetic stamps accumulate on cells, making the cells more distinct. But Petronis’ results suggest that once nerve cells hit a certain age, they begin to experience a different kind of drift, back toward sameness.

Petronis cautions that his results are preliminary and need to be reproduced. But he says they point to the link between development and aging. “Developmental epigenetic marks and aging epigenetic marks seem to be overlapping to some extent,” he says.

It’s not just nerve cells that show tendencies toward conformity in old age. Microglia do too, researchers recently found. These brain cells have multiple job descriptions, including fighting off pathogens, snipping unnecessary neural connections and hoovering up cellular debris. Microglia in different parts of the brain use their genes in specific ways — making more or fewer proteins as needed. This protein customization helps the microglia do their diverse jobs.

But this specificity diminishes with age. Microglia in the hippocampus actually become less diverse as mice get older, neuroscientist Barry McColl of the University of Edinburgh and colleagues reported in the March Nature Neuroscience. “It wasn’t something we were looking for at all,” McColl says.

The unexpected results hint that a slow loss of specialization might cause trouble during aging by hindering cells as they try to do their particular jobs, McColl says. “That’s the overriding — but quite speculative — theory we’ve got at the moment.”

Loss of specialization with age may happen not just in single brain cells, but in the networks they form. Any time a person sees, hears or feels something, the brain fires off a pattern of highly specific neural responses. Cognitive neuroscientist Bradley Buchsbaum of Baycrest Health Sciences in Toronto and colleagues wondered if elderly brains might lose the ability to form these sharp neural reflexes.

For Buchsbaum’s study, 28 adults — half young and half old — watched video clips while undergoing functional MRI brain scans, which detect changes in blood flow that represent the activity of big collections of nerve cells. As participants watched snippets of President Barack Obama giving a speech, a skateboarding dog and a meat slicer in action, their brains responded to the sights and sounds. Later, they were asked to remember the videos.

In people ages 21 to 32, each type of video evoked a specific and sharp neural fingerprint, both as people saw the videos for the first time and remembered them later. The sharper the fingerprint, the better the memory, the researchers reported in 2014 in the Journal of Neuroscience.

But in people 64 to 78, the neural signatures became fuzzy and less distinct, particularly when participants tried to remember the videos. Buchsbaum calls this fuzziness dedifferentiation. “In the beginning, you’ve got this blank slate,” he says. But along the way, brain areas diversify and connect in intricate ways. Dedifferentiation is an about-face toward that blank slate.
Other observations of the old brain seem to fit this idea. Language, for instance, is handled by the left side of the young adult brain. But in elderly people, both hemispheres are required to handle the job. And in older people, remembering can activate both sides of the frontal cortex, instead of just one as in younger people.

Some cognitive psychologists caution against making too much of these signs of generalization. Understanding spoken language is one of the tasks that scientists thought might become hazier in the brain with age. But when psychologist Karen Campbell of Harvard University and colleagues asked old people to simply listen to language while in a scanner, without any additional tests, the task elicited brain responses that looked similar to the specialized responses of younger people.

Campbell’s results, published May 11 in the Journal of Neuroscience, suggest that the extra work of experimental tests — and not the task itself — may take more brainpower in older people, an addition that may confound simple interpretations. Her results are “a challenge to other scientists,” she says. “Try a more natural approach.”

Snip early and snip late
Although scientists are still probing the relationship between brain construction and deconstruction, it’s becoming clear that the brain relies on some of the same tools for both jobs.

One of the most tantalizing finds has to do with microglia. The synaptic pruning that these cells do is crucial for a growing brain, shaping the tangle of new nerve cells into an efficient, elegantly connected information processor.

This snipping may happen late in life, too, and that may not be a good thing. Synapses in the hippocampi of mice and humans become sparser with age. But when mice were engineered to lack a protein that helps mark synapses for destruction, old mice no longer showed synapse thinning, neuro-scientist Cynthia Lemere of Brigham and Women’s Hospital in Boston and colleagues reported last year in the Journal of Neuroscience. These lucky mice with an abundance of synapses performed better on memory tests and learning, too.
Other recent results from neuroscientist Beth Stevens’ lab at Harvard hint that excessive synapse pruning may play a role in Alzheimer’s disease (SN: 4/30/16, p. 6) and schizophrenia, though what kicks off the pruning is a mystery. “One of the really big questions is what turns this pathway on in aging, or in Alzheimer’s or other diseases?” she says. “Are they the same kind of signals that we’ve identified in development, or could they be completely different?”

Finding those signals and other molecules in the body that could stall some of the brain’s aging processes might lead to better treatments for Alzheimer’s, schizophrenia or even the mental decline that comes with healthy aging.

But just because things appear to be similar doesn’t mean that they are the same thing, cautions neurologist Tony Wyss-Coray of Stanford University. Finding a developmental process that’s also at work during aging “doesn’t mean that we are triggering a developmental program,” he says. A protein that becomes active again later in life is not necessarily trying to restart development.

A lack of clarity on brain aging hasn’t stopped scientists from floating ideas for delaying the mental trouble that comes with age. One notion is to wipe out age-related epigenetic changes on brain cells, a concept called “epigenetic rejuvenation.” Scientists might be able to overwrite epigenetic changes using the same cellular tools that manage those marks.

Other researchers are looking to the blood for answers. Wyss-Coray and others have turned up tantalizing evidence that some mysterious contents in young blood can rejuvenate the older brain. Young blood spurred more neural connections and stimulated the birth of newborn nerve cells in mice. The brain changes came with better memory and a sharpened sense of smell (SN: 5/31/14, p. 8). The researchers are trying to figure out which blood components led to the improvements, described in Nature Medicine in 2014, and are testing whether plasma from young people can help the brains of older people with Alzheimer’s disease.

Given the parallels emerging between development and aging, these approaches that borrow from youth to stave off decrepitude start to make sense. “Sometimes things start converging,” Petronis says, “and it’s very interesting to see that process.”