‘Every minute counts.’ This immunologist rapidly reshaped her lab to tackle COVID-19

“Having to adapt to different situations throughout my life prepared me [for] a different virus,” says Akiko Iwasaki of Yale University.

KATTY HUERTAS

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

Until this year, Akiko Iwasaki had never had tubes of human blood delivered to her lab. “We were mostly working with mouse models,” says the Yale University immunologist, who speaks precisely and thoughtfully. “We used to look at the data and contemplate it.” Then COVID-19 struck, and such unhurried musings flew out the window. In a matter of weeks, Iwasaki overhauled her research to launch a slew of studies on how the new virus, SARS-CoV-2, takes its toll on patients. She and her nearly two dozen lab members know their discoveries could impact people falling sick right now. “Every minute counts.”

In the months since, she has produced a string of high-profile papers in which she has redirected her expertise in the immune system, honed in mice, to questions such as why men are more likely than women to fare poorly if infected and how immune responses in hospitalized patients can help predict their prognosis. Now, she is turning her attention to long-haulers, people who suffer a bout with the virus and don’t fully recover.

Iwasaki has had decades of practice adapting to new circumstances. As a child growing up in rural Japan, she dreamed of becoming a poet, turned off science by her physicist father’s immersion in his profession. “We’d go on vacation and he’d bring papers with him,” she says, laughing. “I thought, ‘What kind of life is this?’” But when a high school teacher hooked her on math, she began to reconsider. Soon after, 9 months as an exchange student in Canada left her itching to escape the expectations for a woman in Japanese society—marry a nice man and have a family. Her mother, who worked at a local radio station, had endured jeers from co-workers for sticking with the job while raising three children. “Knowing how much she stood up for always has stayed with me,” Iwasaki says.

So she reimagined her future, embracing science and leaving Japan. She enrolled as an undergraduate at the University of Toronto—falling hard for immunology her senior year there—and stayed on for graduate school. Twenty years ago she founded her lab at Yale, where she studies how the body responds to and combats viruses. “Having to adapt to different situations throughout my life,” she says, “prepared me [for] a different virus.”

The shift called for new science, new collaborations, and new skills. In February, Iwasaki’s lab joined a universitywide testing effort for SARS-CoV-2 led by Albert Ko, Nathan Grubaugh, and Anne Wyllie at Yale’s School of Public Health. Alice Lu-Culligan, a graduate student of Iwasaki’s who had been studying the immune system during pregnancy in mice, recalls the scramble. Lab members scouted for supplies such as swabs and equipment. “We were going around our floor, to the neighboring labs, seeing how many PCR [polymerase chain reaction] machines they had,” Lu-Culligan says. It was “full-on sprint mode, collaboration and chaos.”

As Iwasaki’s lab was helping Grubaugh’s group sequence viral genomes from early patients in Connecticut to map the spread there and across the United States, she launched a separate study to examine patients’ immune responses. She recruited 113 people with COVID-19 at Yale New Haven Hospital and redeployed expertise in her lab to make the project happen. Postdoctoral fellow Carolina Lucas had been studying the mosquito-borne chikungunya virus, and her project was housed in a biosafety level 3 lab at the university, the kind used for hazardous pathogens. “Akiko asked me to coordinate this,” says Lucas, who quickly agreed.

Every few days, the team collected samples from the nose, throat, and blood of patients. There were “all these weird immune responses being engaged,” Iwasaki says. In severe cases, the immune system churned out a flood of cytokine proteins. Lucas, Iwasaki, and others found four immune signatures that appeared to correlate with later outcomes. That paper appeared in Nature in July.

Swiftly, the scientific questions mushroomed. In mid-March, the Yale hospital treated a woman with COVID-19 who was in her second trimester of pregnancy. The woman lost her fetus—and a private tragedy became interwoven with urgent questions about whether the virus could infect the placenta and pose a danger to the pregnancy. A collaborator of Iwasaki’s secured permission to collect the placenta, and late one night, Lu-Culligan retrieved it. Until that moment, the only placentas Lu-Culligan had seen belonged to mice. “This is big and bloody,” she says, and as she stared at it under a biosafety hood, “I’m thinking, ‘I don’t know what I’m doing here.’”

In that case, the virus had indeed infected the placenta, and Lu-Culligan began to collaborate with Yale obstetricians to recruit women delivering at the hospital who were positive for the virus to study their placentas, too. That paper is nearing completion.

Meanwhile, Iwasaki began to investigate sex differences and found the male immune system is more likely to spark a harmful inflammatory response to the virus, whereas in women, T cells that fight it off are activated more robustly. These distinctions, she reported in an August paper in Nature, might help explain why men who are infected tend to fare worse than women.

Iwasaki’s juggling act impresses her colleagues. “She’s made it seem so effortless, even though I know it’s probably not effortless at all,” says Angela Rasmussen, a virologist at Columbia University’s Mailman School of Public Health. Iwasaki’s husband, Ruslan Medzhitov, is also a well-known Yale immunologist (they discuss COVID-19 while walking their dog), and the pair has two daughters, ages 11 and 13. Iwasaki fears the pandemic is widening the gender gap in science as women face disproportionate pressure to support their children when schools are closed. Her husband drives their daughters to in-person school each morning, but with COVID-19 cases climbing, she wonders how much longer schools will be open.

Solutions to a COVID-19–fueled gender gap in science are elusive, she says, “other than to really have a different mindset about evaluating progress in science during this time.” Iwasaki has long advocated for female and minority scientists on Twitter, where she has 80,000 followers. In one post, she minced no words in advising female scientists who worry about pregnancy torpedoing a job interview: “If they don’t welcome you with open arms and offer child care options, they don’t deserve you.”

Her advocacy goes beyond rhetoric. Lu-Culligan met Iwasaki at a luncheon for women in science at Yale, while struggling with bullying and harassment in another lab. Iwasaki said, “We have to get you out of there,” Lu-Culligan recalls. A few months later, the young scientist abandoned more than 2 years of graduate work to start over with Iwasaki—later learning that she wasn’t the first person her new mentor had rescued from a miserable experience elsewhere.

Nearly 9 months into the pandemic, lab life has settled down—somewhat. Iwasaki’s latest passion is long-haulers who can’t shake symptoms like fatigue and brain fog. Volunteers find her via word of mouth. The project faces hurdles, though: Iwasaki is hunting for a facility to draw blood from her volunteers, who are still symptomatic and potentially contagious. With many competing studies, such space is at a premium and she hasn’t yet been able to secure any. She’s also racing to apply for grants to fund the project. 

“We really want to get to the bottom of what’s going on,” she says impatiently. Until then—along with so many other researchers—she’ll be in overdrive. 

Eye size predicts where birds breed and feed

The chestnut-crowned gnateater (Conopophaga castaneiceps) lives in the dark understory of tropical cloud forests and has relatively large eyes.

IAN AUSPREY/FLORIDA MUSEUM OF NATURAL HISTORY

When Ian Ausprey outfitted dozens of birds with photosensor-containing backpacks, the University of Florida graduate student was hoping to learn how light affected their behavior. The unusual study, which tracked 15 species in Peru’s cloud forest, has now found that eye size can help predict where birds breed and feed—the bigger the eye, the smaller the prey or the darker the environment. The study also suggests birds with big eyes are especially at risk as humans convert forests into farmland.  

The study reveals a “fascinating new area of sensory biology,” says Richard Prum, an evolutionary biologist at Yale University who was not involved in the new work. It also shows the size of a bird’s eye says a lot about its owner, adds Matthew Walsh, an evolutionary ecologist at the University of Texas, Arlington, also not involved with the work.

Light matters—not just for plants, but also for animals. Large eyes have long been associated with the need to see in dim conditions, but very little research has looked in depth at light’s impact on behavior. Recently, scientists have shown that the relative size of frogs’ eyes corresponds to where they live, hunt, and breed. And several studies published in the past 3 years suggest the eyes of killifish and water fleas vary in size depending on the presence of predators. With no predators, even slightly larger eyes offer a potential survival advantage.

To find out how eye size might matter for birds, Ausprey and his adviser, Scott Robinson, an ecologist at the Florida Museum of Natural History, turned to the 240 species they had identified in one of Peru’s many cloud forests. The study area included a range of habitats—dense stands of trees, farms with fencerows, shrubby areas, and open ground. Because light can vary considerably by height—for example, in the tropics, the forest floor can have just 1% of the light at the tops of the trees—they included species living from the ground to the treetops.

Researchers temporarily mounted a light sensor (see arrow) to the back of this chestnut-capped brush finch (Arremon brunneinucha) and other birds to learn how light affected behavior.

IAN AUSPREY/FLORIDA MUSEUM OF NATURAL HISTORY

Over 4 years, the researchers measured eye width in 192 netted bird species, and estimated the size of the remaining species’ eyes’ from photographs. Larger birds tend to have larger eyes, so they used relative eye size for their subsequent analyses. They divided the birds into two groups based on hunting habits: those that typically grab morsels from their perch (and tend to be near-sighted) and those that usually pounce or dive to grab their meals. The team then documented roughly where these birds spend most of their time.

They also put commercially available light detectors on 71 birds from 15 species, attaching them to tiny backpacks with a medical adhesive that lasted several weeks. Once they fell off, Ausprey used a pack’s radio signal to track it down and retrieve the data. The light measurements tracked the light the birds were experiencing. “It’s amazing that they were able to glue little things on the birds,” says Jeffry Dudycha, an evolutionary biologist at the University of South Carolina, Columbia, who was not involved with the work.

After analyzing the data, Ausprey and his colleagues determined that eye size predicted not only where the birds spent their time, but also what they ate, they report this month in Ecology. As one might expect, birds that live deep in forests or needed to chase down insects from afar, like flycatchers, had relatively large eyes. Birds that lived in the brightest environments, such as the blue-capped tanager, have comparatively small eyes.

Moreover, the birds tended to stay where their eyes worked the best, which could explain the rise and fall of some species as humans clear forests for farming and development. Species with smaller eyes are thriving in pastures, fields, and tree plantations, Ausprey and his colleagues found. But larger eyed species that avoid bright light may be threatened as their forest habitat becomes fragmented and they cannot travel as far as they need to successfully reproduce or hunt. “Light can have an impact,” Ausprey says, on which species survive where.

Meanwhile, Prum predicts more researchers will start to look at the impact of light on their favorite organisms. And that pleases Ausprey. “It’s been a real privilege getting to share an entirely new dimension in ecology.”

Delete offensive language? Change recommendations? Some editors say it’s OK to alter peer reviews

ISTOCK.COM/AndreyPopov

Fiona Fidler, a metaresearcher at the University of Melbourne, was outraged. She had discovered that her appraisal of a submitted paper had been changed before being sent to the author, sometimes drastically. The words “very sympathetic” had become “generally sympathetic.” “This one is a good example” ended up as “this one still needs work.” Worst of all, she felt that the bottom line of her peer-review report to the journal Educational and Psychological Measurement, recommending that it accept the paper with minor revisions, was misrepresented in the editor’s rejection letter to the author.

“I had never experienced anything like this before,” Fidler says about the 2012 incident. She demanded explanations from the journal editor. And she later partnered with the snubbed paper author, Rink Hoekstra, a psychologist at the University of Groningen, to find out how widespread this practice was.

With colleagues, they’ve now surveyed 322 editors at high-impact journals across ecology, economics, medicine, physics, and psychology on when they think altering peer-review reports is justified. Published as a preprint earlier this year at the Open Science Framework and now under review at eLife, the survey reports that 91% of the respondents identified at least one situation in which they would edit a report. More than 80% said they would do so if a reviewer used offensive language or made inappropriate personal comments about the authors. But 8% said they would change the reviewer’s overall recommendation—even without their permission, a finding that shocked Hoekstra. He believes that’s probably an underestimate, given the stigma of admitting to such dubious behavior in a survey. “I think there are probably even more who actually do it.”

The survey comes amid a wider push for consistent guidelines. There’s little dispute that editors should intervene when peer-review comments are hostile. Such comments have a disproportionate impact on minorities and other marginalized groups, inducing self-doubt and harming productivity, according to a 2019 PeerJ paper. It’s not just ethical to edit such review reports—it’s essential, says Seth Leopold, editor-in-chief of Clinical Orthopaedics and Related Research.

Jane Alfred, director of Catalyst Editorial, which offers training on research integrity and publication ethics, thinks it’s best to return reports containing hostile language and ask the reviewer to change it. Reviewers are often grateful for the chance to revise ill-considered comments, she says. But Leopold says this may be impractical at fast-paced journals, and trying to educate reviewers who make unprofessional comments is likely futile. It’s better, he says, not to ask that person to review again.

Changing a reviewer’s recommendation is another matter, says Howard Browman, a council member of the nonprofit Committee on Publication Ethics, which is developing guidance on how to navigate the ethics of editing reviewers’ comments. “It’s so obviously something you wouldn’t do,” he says.

Red lines

A survey of 322 editors at high-impact journals has found a wide range of attitudes toward altering peer-review reports. About 8% believe it’s OK to change the reviewer’s recommendation, even without permission.

When a reviewer identifies themself in a blinded peer-review framework (N=276)When a reviewer has used inappropriate or offensive language (N=291)When the reviewer has made an inappropriate reference to an author’s gender, age, etc. (N=290)When there are spelling and/or grammatical errors in the review (N=294)When the review has English language problems (N=292)When the reviewer has left in their comments to the editor (N=290)When the editor disagrees with the reviewer’s recommendation (N=293)34%39%27%15%58%26%17%56%27%35%48%17%33%42%25%17%62%21%81%8%11%Never acceptable to edit the reportAcceptable to edit without reviewer’s permissionAcceptable to edit, but only with reviewer’s permission

HAMILTON ET AL., METAARXIV, 10.31222/OSF.IO/QKJY4 (2020), ADAPTED BY A. CUADRA/SCIENCE

Yet it apparently happened to Fidler, who stumbled on the changes to her report by accident. Although the review process was double-blinded, she recognized the paper as Hoekstra’s because she had seen him present the work, on Ph.D. students’ statistical reasoning, at a conference in Slovenia. So after sending in her review, she emailed him to congratulate him and tell him that her review was nitpicky but positive.

That same day, Hoekstra’s paper was rejected by the journal. “The reviewers have spoken in nearly a single voice in their recommendation to me that I decline publication of the paper in its current form,” wrote the editor-in-chief, George Marcoulides, a research methodologist at the University of California, Santa Barbara. Although editors may override reviewer recommendations, the normal practice is to explain this in the decision letter. Hoekstra wrote back to Fidler, attaching the two reviews he got from the journal and asking for suggestions of other journals that might publish the work.

When she saw the reviews, Fidler cottoned on. “I think we have a controversy on our hands,” she wrote to Hoekstra. She downloaded her review from the online journal system, and compared it, word by word, with the review Hoekstra received. Her sentence saying her concerns were minor had been deleted. Other sentences criticizing Hoekstra’s methods had been added. She emailed Marcoulides, who replied that the journal computer system sometimes blended and distorted reviewer comments.

Fidler calls that explanation “preposterous,” saying it would be impossible for a technical glitch to create “perfectly grammatical sentences that are exactly opposite in meaning.” She reached out to contacts at SAGE, the journal’s publisher, who said they would investigate, but she heard no more from them. In an email to Science, a SAGE spokesperson wrote that the publisher “addressed the issue directly with the editor at the time” and that Marcoulides now double-checks reviewer comments for consistency.

Later in 2012, Marcoulides invited Hoekstra to resubmit his paper. This time, Fidler’s review made it through intact, and Hoekstra’s paper was accepted—pivotal for him winning a permanent job at Groningen. In an email to Science, Marcoulides wrote that the reviewer comments automatically attached to his decision letter were “distorted” and his edits were intended to clarify his interpretation of Fidler’s assessment. “In hindsight, I should have contacted her rather than attempting to resolve the problem on my own,” he wrote. He added that he still sometimes edits reports for clarity or to remove inappropriate language.

Few journals offer explicit guidance on when editing peer-review reports is and isn’t permissible. Alfred says they ought to, and should also allow reviewers to opt out from being edited. No matter how well-intentioned editors may be, she says, clear policies will ensure a transparent and unbiased process. Many journals have a safeguard: They share all reviews and the editorial decision with reviewers, allowing them to see how their comments were communicated to the authors. But about 20% of the editors in the survey report that their journals do not send out either the reports or the decision letters to reviewers.

Simine Vazire, editor-in-chief of Collabra: Psychology and a colleague of Fidler’s, argues for a bright line on the question: no edits without reviewer permission. Her journal has no policy on the issue, but she is considering proposing one. Without clear boundaries, she says, it becomes easy to rationalize changes, adding that journal editors have lots of power and little accountability. “There’s no one watching over editors,” she says. “I think it’s especially important that they have really hard and fast rules for themselves.”

‘Another piece of populist propaganda’: Critics slam the Brazilian government’s new COVID-19 drug

Brazilian President Jair Bolsonaro at a 19 October ceremony to announce results from a clinical trial with nitazoxanide

Andre Borges/NurPhoto via AP

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

On 19 October, the Brazilian government organized a high-profile ceremony to announce what it billed as a new breakthrough in the fight against the COVID-19 pandemic: the antiparasitic drug nitazoxanide. President Jair Bolsonaro was present, as were several other Cabinet members. “We are announcing something that will begin to change the history of the pandemic,” science minister Marcos Pontes said.

Only one thing was missing from the presentation: the evidence. And when it emerged 4 days later, scientists were decidedly underwhelmed.

Bolsonaro has been a tireless advocate of hydroxychloroquine to treat COVID-19, even after large clinical trials showed it didn’t work. Now, his government is promoting nitazoxanide, which has been tested in a clinical trial led by Patricia Rocco, a respiratory physiology researcher at the Federal University of Rio de Janeiro, Rio de Janeiro, and sponsored by the Ministry of Science, Technology, and Innovation. Given early, nitazoxanide significantly reduces virus levels in patients with mild COVID-19 infection, Rocco said at the meeting, lowering the risk they pass the virus on to others or develop more serious disease.

In vitro studies have shown that the drug—used primarily to treat helminth and protozoan infections—slows replication of SARS-CoV-2. And as Pontes pointed out at the ceremony, nitazoxanide is cheap, easy to produce, and has few side effects. It has been available in Brazil since 1996 and can be purchased at any pharmacy.

Rocco didn’t present any numbers, tables, or charts to support her claims that nitazoxanide works in humans, however. The data could not be shown, she said, because they are under review at a journal. But announcing the findings was the right thing to do because hundreds are still dying of COVID-19 in Brazil every day. “Would it be correct to omit this information and wait for 14,000 people to be dead within a month?” she asked. The only “data” available, shown in a slick video, was a generic animated bar chart, plucked from Shutterstock, with an arrow pointing downward and the text “NITAZOXANIDE IS EFFECTIVE!”

Four days after the ceremony Rocco and her colleagues, under pressure from the scientific community, decided to post the study as a preprint on medRxiv ahead of its publication. After inspecting the data, many researchers concluded it didn’t mean much—and certainly would not change the history of the pandemic.

The paper presents data for 392 patients with mild disease, half of whom were given nitazoxanide, on average 5 days after symptom onset; the other half received a placebo. The study’s “primary outcome” was relief of cough, fever, and fatigue after 5 days of treatment. Nitazoxanide did not make a difference there; neither did it prevent hospitalization or cause any change in blood biomarkers of the disease. But the viral load—the amount of virus RNA detected in nasopharyngeal samples using a polymerase chain reaction (PCR) test—was “significantly” lower in the treated group; 30% tested negative for SARS-CoV-2 at the end of the 5-day treatment, versus 18% in the placebo group. “This effect may have an epidemiological impact, potentially decreasing community spread of SARS-CoV-2, morbidity, and mortality,” the authors write.

Treatment ended on day five, but the 95 patients who still had symptoms were contacted by telephone 1 week later. At that time, 78% of patients in the treatment group reported being symptom-free, versus 57% in the control group.

Scientists cannot omit data during a pandemic; all knowledge must be revealed and is part of a constructive process.

Patricia Rocco, Federal University of Rio de Janeiro, Rio de Janeiro

None of that impressed critics. A lower viral load has little meaning if it doesn’t make the patient feel better, scientists say, and it’s unlikely to reduce transmission of the disease 10 days after the onset of symptoms. “Everyone who examined the data said this reduction in viral load doesn’t have any clinical or epidemiological implications,” adds Renato Sabbatini, a retired medical sciences professor at the University of Campinas. Other researchers note that, at that stage in a mild COVID-19 case, the patient has already mounted an immune response and what the PCR test is measuring are mostly fragments of viral genetic material that don’t come from active virus.

The modest benefit in symptoms 1 week after treatment ended—and up to 17 days after onset of symptoms—is hardly cause for celebration either, says Glória Teixeira, an epidemiologist at the Federal University of Bahia, Ondina. “The results of this study do not justify prescription of this drug for treatment of COVID-19,” she says.

The government is using the study as “another piece of populist propaganda, meant to create a false impression that the situation is under control, the pandemic is not that serious, and everything is going to be OK,” says Natalia Pasternak Taschner, president of the Science Question Institute, a private organization that promotes scientific integrity.

Rocco, in an email to Science, wrote that criticism is a normal and healthy aspect of scientific debate, but she lamented that “some colleagues, apparently eager to contribute” had come to “premature conclusions” about the study. She added that both the primary and secondary outcomes are important in a clinical trial, and cited other studies to defend her assessment that a lower viral load does have clinical and epidemiological relevance. “Scientists cannot omit data during a pandemic; all knowledge must be revealed and is part of a constructive process,” Rocco wrote. Asked whether she thought nitazoxanide could help prevent the 14,000 deaths she mentioned on 19 October, she did not answer.

For critics, the episode is yet another example of how politics trumps science in the Bolsonaro administration. In his speech at the event, the president railed against compulsory vaccination for COVID-19 and once again touted hydroxychloroquine as a treatment. Pontes, in a press conference afterward, boasted that the study was relevant to “the entire planet” and broke into tears as he thanked the scientists for their “tireless work for Brazil and to help save lives.”

Antibody-producing yeast vanquishes deadly gut infection in mice

A type of yeast has been engineered to battle the bacterium Clostridioides difficile (above).

Kari Lounatmaa/Science Source

When people take antibiotics for one infection, another can swoop in to take its place: the bacterium Clostridioides difficile, which causes severe, recurring colon infections that kill nearly 30,000 people annually in the United States, most over the age of 65. Now, researchers have a new idea for battling C. diff: They have modified yeast to produce and deliver antibodies that defang the bacterium’s two toxins and spur recovery in infected mice.

If it works in people, the genetically engineered yeast, derived from a strain used in a popular probiotic, could be taken as a daily pill to ward off or treat C. diff infections. Study leader Hanping Feng, a microbiologist at the University of Maryland School of Dentistry, calls the proposed method “inexpensive, very easy to manufacture, and a convenient route” for delivery. “The real advance is that they have a living delivery system” for the therapeutic antibodies, says physician and microbiologist Vincent Young of the University of Michigan, Ann Arbor.

C. diff infections occur most often in elderly people who receive antibiotics for an unrelated illness. The drugs wipe out much of a person’s protective gut microbiota, which makes them vulnerable to infection from C. diff spores lingering in a nursing home or hospital. Although most people given antibiotics targeting C. diff recover, the bacterium returns in one in six cases. Sometimes it comes back repeatedly, with deadly results.

Recently, fecal transplants from healthy people have been shown to quell stubborn C. diff infections by replacing the missing beneficial gut microbes. But they remain experimental and can be risky. Despite screening, the samples sometimes contain other pathogens; the fecal transplants also can’t be given with antibiotics.

Another potential treatment involves immune proteins called monoclonal antibodies that neutralize C. diff’s two toxins. But they normally must be given as an intravenous injection that moves from the bloodstream into the gut. Feng’s team wanted to get around the high cost of manufacturing such antibodies and deliver them directly to the gut. So his group turned to Saccharomyces boulardii, a type of yeast considered safe by the U.S. Food and Drug Administration (FDA) as a probiotic to improve gut health.

The group first designed its own antibody for C. diff, a potent four-pronged protein with two prongs for each of the bacterium’s two toxins. When the researchers injected this antibody followed by C. diff toxins into the abdomens of mice, all of the mice survived; those that got another antibody treatment or a saline solution died.

To test whether the modified S. boulardii could protect mice from C. diff, Feng and colleagues gave mice antibiotics to disrupt their normal gut microbes, and then infected them with the bacteria’s spores. Mice that had begun to receive a weeklong, daily dose of the antibodymaking S. boulardii starting 3 days before C. diff infection all survived the illness, but 60% of those receiving a control yeast strain or saline died within 4 days, the team reports today in Science Translational Medicine. The colon tissue of yeast-treated mice also had less inflammation and none of the tissue damage from C. diff toxins seen in control mice.

 The researchers then tested their daily yeast treatment in mice that already had a C. diff infection, dosing them for 4 days. About 70% survived, whereas two-thirds of those receiving control yeast or saline soon died. The results were similar for mice with recurring C. diff infections. In both experiments, the sick mice receiving the modified S. boulardii also regained lost weight faster and had less diarrhea, Feng’s team reports

“It’s really exciting,” says structural biologist Borden Lacy of Vanderbilt University, who studies C. diff toxins. “A lot of what we need to do is give people a window of time in which they can recover a healthy microbiome before toxins cause a lot of damage. This helps extend that window,” Lacy says.

Feng has started a company to develop the yeast for testing in people. FDA will need to weigh in on the safety of the genetically modified yeast, which would be the first drug of that kind, and his company also needs to raise funding from investors. “Unfortunately, it takes a long time,” Feng says. He hopes a clinical trial will begin within 3 years.

Controlling monkey brains with light could get easier thanks to open data project

Methods to influence rodent neurons using light have not translated smoothly into primate brains.

JOHN SERRAO/SCIENCE SOURCE

When neuroscientist Sébastien Tremblay set out to manipulate monkeys’ brains with light, colleagues had sobering advice: “It’s more difficult than it sounds.” Tremblay, who works in neuroscientist Michael Platt’s lab at the University of Pennsylvania, uses light to activate or silence precise groups of neurons and probe their role in brain function. The method, called optogenetics, works well in rodents, but studies in nonhuman primates are critical if it’s ever going to become a therapy for humans—to suppress seizures, for example, disrupt tremors in Parkinson’s disease, or even project images into the brain of a blind person.

But in spite of more than 10 years of work, progress has been slow. The tools for rendering cells light sensitive were largely refined in rodents and behave unpredictably in monkeys. It’s hard to illuminate enough tissue in large primate brains to reliably change animals’ behavior. Researchers have devised their approaches by trial and error, often without knowing what had or hadn’t worked for others.

Tremblay, Platt, and colleagues from 45 primate optogenetics labs in nine countries hope to change that with the Nonhuman Primate Optogenetics Open Database, which published its first results last week. The database contains minute details of successes and failures, many of which have gone unpublished. And if it can be sustained, it may soon include tests in monkeys of promising new optogenetic tools. The open-data approach “is tremendously powerful, tremendously useful to the community,” says Hongkui Zeng, a neuroscientist who develops optogenetic tools for mice at the Allen Institute for Brain Science and was not involved in the project.

In optogenetics, researchers endow brain cells with a gene for one of several opsins, light-sensitive proteins from microbes. These proteins can influence the flow of ions in and out of a neuron to control whether it fires an electrical signal. Depending on the opsin, researchers can excite or inhibit neurons by shining light on them, usually via an implanted optical fiber.

Strains of mice have been genetically engineered to express opsins in their brains from birth. But for now, getting an opsin into monkey neurons means infecting the cells with a virus injected through a hole in the skull. Along with opsin DNA, the virus typically carries a sequence called a promoter, which restricts the opsin’s expression to certain cell types.

There’s no proven formula for getting monkey brain cells to make opsins. In the hunt for the right combination of viral strains and promoters, “we kind of entered this voodoo land,” says Arash Afraz, a neuroscientist at the U.S. National Institute of Mental Health. Scientists relied on rumors of other labs’ successes and failures, he says, and were afraid to vary a recipe once they got it working. Unlike with plentiful mice, researchers couldn’t afford to use lots of monkeys to hone their technique, he adds. “We value them more. They have names. We view them as our colleagues, in a sense.”

Afraz hopes the database, which he contributed to, will minimize wasted effort by pooling the field’s failures. It catalogs 1042 viral injections performed in nonhuman primates, 552 of them previously unpublished. Seven-tenths of the experiments were in rhesus macaque monkeys. Tremblay can’t be sure the database is exhaustive, but the 66 groups he invited to contribute—identified through publications and referrals from colleagues—represent the majority of labs active in the field, he says.

In a 19 October paper in Neuron introducing the database, the team estimates the success rate of the most commonly used vectors, promoters, and opsins in the data set. About half of the experiments in monkey brains looked for changes in neural activity after cells were hit with light; 69% found a strong effect. Of the 20% of experiments that aimed to influence an animal’s behavior—to prompt an eye or hand movement, for example—nearly half saw a weak effect or none at all.

Scaling up

Monkey brains have been harder to manipulate with light than mouse brains, in part because they’re much larger.

MacaqueMouseOptical fiber

C. BICKEL/SCIENCE

Failure likely discouraged some researchers from publishing studies, says Julio Martinez-Trujillo, a neurophysiologist at Western University and contributor to the project. His group has tried, without success, to evoke eye movements in one macaque and to impair working memory function in another. “This is the first paper that shows our experience,” he says.

Such attempts probably fail in part because the virus doesn’t reach enough of the brain, Tremblay says. A single injection can infect about 1 cubic millimeter of tissue—a broad swath of a mouse’s brain, but a puny fraction of a monkey’s. And scientists want to avoid multiple injections that could cause excessive tissue damage. Instead, some labs are trying to send the virus farther by injecting it at high volumes and pressures, a technique called convection-enhanced delivery.

Others hope to eliminate the need for brain injections by designing viruses that are small enough to cross into the brain via its tiny capillaries after being infused into a vein. In a June preprint on bioRxiv, neuroscientist and bioengineer Viviana Gradinaru and her team at the California Institute of Technology describe such an engineered virus that selectively infects the neurons of a marmoset.

Delivering light to large brains is a hurdle as well. “Say I am using a 200-micron-diameter fiber optic for stimulating my mouse brain,” Afraz explains. “To scale that up, I’d have to stick a flashlight in the monkey’s head.” In a bioRxiv preprint last month, Afraz and colleagues describe a possible alternative: a 5-square-millimeter array of 24 light-emitting diodes (LEDs), each of which can produce as much light as a typical optical fiber. By laying this array over a monkey’s cortex, researchers might illuminate a relatively broad brain area without multiple implanted fibers, Afraz says. They can also use individual LEDs to excite separate parts of the cortex in precise patterns.

Other groups are developing more sensitive opsins so that weaker light can affect more distant tissue. In a study in mice reported on 5 October in Nature Biotechnology, a group led by Stanford University neuroscientist Karl Deisseroth—one of the original developers of optogenetics—used a highly sensitive opsin called ChRmine to activate neurons several millimeters below the brain’s surface with light from outside the rodent’s skull.

“I can’t wait to test them,” Laval University molecular biologist Marie-Ève Paquet says of these ultrasensitive opsins. She’s part of a Canadian collaboration that tests and disseminates emerging optogenetics tools. As opsins, promoters, and viruses make their way to participating research groups, Paquet’s team plans to upload its results to the new database.

To keep the database up to date, she says, “the community really has to be motivated,” especially because she expects the next few years to bring a boom in studies to influence and understand the brain circuits of some of our closest animal relatives.

The ‘very, very bad look’ of remdesivir, the first FDA-approved COVID-19 drug

President Donald Trump and Food and Drug Administration Commissioner Stephen Hahn (right) met with Daniel O’Day (left), CEO of Gilead Sciences, when remdesivir received an emergency use authorization in May.

AP Photo/Alex Brandon

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

October was a good month for Gilead Sciences, the giant manufacturer of antivirals headquartered in Foster City, California. On 8 October, the company inked an agreement to supply the European Union with its drug remdesivir as a treatment for COVID-19—a deal potentially worth more than $1 billion. Two weeks later, on 22 October, the U.S. Food and Drug Administration (FDA) approved remdesivir for use against the pandemic coronavirus SARS-CoV-2 in the United States—the first drug to receive that status. The EU and U.S. decisions pave the way for Gilead’s drug into two major markets, both with soaring COVID-19 cases.

But both decisions baffled scientists who have closely watched the clinical trials of remdesivir unfold over the past 6 months—and who have many questions about remdesivir’s worth. At best, one large, well-designed study found remdesivir modestly reduced the time to recover from COVID-19 in hospitalized patients with severe illness. A few smaller studies found no impact of treatment on the disease whatsoever. Then, on 15 October—in this month’s decidedly unfavorable news for Gilead—the fourth and largest controlled study delivered what some believed was a coup de grâce: The World Health Organization’s (WHO’s) Solidarity trial showed that remdesivir does not reduce mortality or the time COVID-19 patients take to recover.

Science has learned that both FDA’s decision and the EU deal came about under unusual circumstances that gave the company important advantages. FDA never consulted a group of outside experts that it has at the ready to weigh in on complicated antiviral drug issues. That group, the Antimicrobial Drugs Advisory Committee (AMDAC), mixes infectious disease clinicians with biostatisticians, pharmacists, and a consumer representative to review all available data on experimental treatments and make recommendations to FDA about drug approvals—yet it has not convened once during the pandemic.

The European Union, meanwhile, decided to settle on the remdesivir pricing exactly 1 week before the disappointing Solidarity trial results came out. It was unaware of those results, although Gilead, having donated remdesivir to the trial, was informed of the data on 23 September and knew the trial was a bust.

“This is a very, very bad look for the FDA, and the dealings between Gilead and EU make it another layer of badness,” says Eric Topol, a cardiologist at the Scripps Research Translational Institute who objected to remdesivir’s FDA approval.

FDA has no obligation to convene outside panels for its decisions, stresses AMDAC member David Hardy, an HIV/AIDS scientist of the University of California, Los Angeles. Yet the agency often does so for tricky drug approvals and Hardy is “amazed” the agency didn’t consult the panel in this case. “This sets the standard for the first COVID-19 antiviral,” he says. “When it comes to the point of giving pharmaceutical companies exclusive marketing rights in this area, that really is something that’s very, very important. And there does need to be more than just governmental input.”

FDA did not respond to Science’s request to discuss why it opted against convening the committee, noting only that it is “at the discretion” of division directors. But FDA’s inaction stands in sharp contrast to its handling of potential COVID-19 vaccines. Last week, the agency convened an advisory group to discuss the mere possibility of such a vaccine passing regulatory muster.

As to the EU agreement, Gilead confirmed to Science that WHO in “late September” provided the company with a manuscript about the study results, but a spokesperson for the European Commission, the EU executive arm, said these weren’t revealed during its negotiations. The company has aggressively called into question the validity of the Solidarity data, in part because the study was carried out in vastly different countries around the world with different health care standards. In a 15 October statement, Gilead went so far as to say “it is unclear if any conclusive findings can be drawn from the study results.”

That criticism has angered investigators in the Solidarity study, including Marie-Paule Kieny, director of research at the French medical research agency INSERM and a former WHO officer. “It’s appalling to see how Gilead tries to badmouth the Solidarity trial,” Kieny says. “Pretending the trial has no value because it is in low-income countries is just prejudice.”

Disappointing trials

On 10 January, 2 days after SARS-CoV-2 was proved to be the cause of COVID-19, researchers published a study in Nature Communications that showed remdesivir had powerful inhibitory effects in both test tube and mouse studies on the related coronavirus that is responsible for Middle East respiratory syndrome. Two weeks later, doctors treated the first confirmed case of COVID-19 in the United States with the drug and reported that the 35-year-old man improved rapidly.

An interim analysis from a large-scale, placebo-controlled clinical trial carried out by the National Institutes of Health (NIH), announced on 29 April, tempered expectations but also emphasized that remdesivir had promise. The drug reduced the median time that severely ill, hospitalized COVID-19 patients took to recover from 15 days to 11 days. It was a modest gain, but NIH noted in a press release that treated patients “had a 31% faster time to recovery than those who received placebo.” Remdesivir, which must be repeatedly infused intravenously, also seemed to lower the risk of death, but that difference could have arisen by chance. (A peer-reviewed, final report of the study published 8 October in The New England Journal of Medicine reduced the time to recovery for the 531 treated patients to 10 days.)

A second, smaller placebo-controlled study of remdesivir on hospitalized COVID-19 patients in China, published online by The Lancet also on 29 April, found no statistically significant benefit from the treatment—and the antiviral surprisingly had no impact on levels of the coronavirus.

Two days after the results from China and the United States came out, FDA granted remdesivir an emergency use authorization (EUA)—a temporary status that is far from full approval—for use in severe COVID-19 patients. The agency cited the NIH trial data, but not the other study. President Donald Trump praised the EUA in an Oval Office press event with Daniel O’Day, CEO of Gilead.

It’s appalling to see how Gilead tries to badmouth the Solidarity trial. Pretending the trial has no value because it is in low-income countries is just prejudice.

Marie-Paule Kieny, INSERM

On 21 August, a Gilead-sponsored study published online in JAMA compared hospitalized COVID-19 patients with moderate pneumonia who received remdesivir for 5 days or 10 days versus those treated with the standard of care. The 5-day remdesivir group improved more quickly, but, oddly, the 10-day group did not. (An earlier published study sponsored by Gilead found no difference between the two treatment courses.)

The next week, FDA expanded remdesivir’s EUA to include all hospitalized COVID-19 patients. That led Topol to publish a scathing open letter to FDA Commissioner Stephen Hahn on Medscape, a popular medical website of which Topol is editor-in-chief. Under the headline “Tell the Truth or Resign,” Topol lumped the decision together with heavily criticized EUAs issued earlier for the malaria drug hydroxychloroquine—which the agency later rescinded—and antibody-rich “convalescent” plasma obtained from the blood of recovered COVID-19 patients. “These repeated breaches demonstrate your willingness to ignore the lack of scientific evidence, and to be complicit with the Trump Administration’s politicization of America’s healthcare institutions,” Topol wrote.

Debating the evidence

WHO’s Solidarity trial, conducted in 405 hospitals in 30 countries, is about three times as large as the other three trials together and many scientists expected it to better resolve remdesivir’s worth. Solidarity did not use a placebo, but instead compared remdesivir and three other repurposed drugs with each other and the standard of care. The Solidarity trial investigators described the study results to FDA representatives on 10 October and posted a preprint on them on medRxiv 5 days later. Solidarity mainly aimed to determine whether the drugs lowered mortality among hospitalized COVID-19 patients, which none of them did. The researchers also noted that remdesivir did not affect “the duration of hospitalization” or whether COVID-19 patients required ventilators, which are only used when people advance to very serious disease.

The release of the Solidarity data has triggered a fresh debate about the relative value of each remdesivir trial—and whether FDA should have aired that discussion in public instead of weighing the data privately. In its review that recommended remdesivir’s approval, the agency only included data from three trials: the NIH study and two Gilead-sponsored trials, ignoring the Solidarity data as well as the findings from the other placebo-controlled trial in China.

That infuriated the Solidarity team. “The mantra I’ve always heard as a joke about the FDA is that they say ‘In God we trust, everyone else has to provide data,’” Kieny says. “So look at all the data.”

As far as Gilead is concerned, the Solidarity data should not play an important role. “We are concerned that the data from this open-label global trial have not undergone the rigorous review required to allow for constructive scientific discussion, particularly given the limitations of the trial design,” the company wrote in its statement.

The argument that the earlier you use it, the better is great until you realize what the implications of that are: You won’t save many lives, and you’ll have to treat a lot of patients. It’s very inconvenient, and it’ll cost you a fortune.

Martin Landray, University of Oxford

Gilead Chief Medical Officer Merdad Parsey wrote in an open letter posted the day of FDA’s remdesivir approval that Solidarity “does not negate other study results—particularly from a trial designed with the strictest of scientific standards, as is the case with” NIH’s study. Gilead has also raised questions about the availability of Solidarity’s data, telling Science it has requested from WHO, but has yet to receive, “the underlying data sets or statistical analysis plan” for the trial.

WHO counters that Gilead knew the statistical analysis plan before joining the trial and will receive the full data set once the study is complete. It does not matter that the data have not yet been peer reviewed, WHO scientists say, because FDA traditionally reviews all available data, including unpublished findings. As to the disparity in health systems that Gilead cites as a confounding factor in Solidarity’s findings, WHO’s chief scientist, Soumya Swaminathan, notes that 50% of the 2750 patients who received remdesivir in the trial were from Canada and Europe, places recognized for high-quality health care. And she stresses that the other participating countries do not necessarily have substandard care.

Clifford Lane of the National Institute of Allergy and Infectious Diseases, who helped run the NIH study, says its main difference with Solidarity is “the degree of granularity” of the analyses of subgroups that may have benefited. “I think the Solidarity data are fine,” Lane says. “It’s a very large study and it has a very robust endpoint.”

Martin Landray of the University of Oxford, who is co-leading the world’s largest study of various COVID-19 treatments, says remdesivir “definitely doesn’t work in the sickest patients where the biggest gains would be” but might help people at earlier stages of disease. Further complicating the matter, most people infected with SARS-CoV-2 recover without any intervention. “The argument that the earlier you use it the better is great until you realize what the implications of that are: You won’t save many lives, and you’ll have to treat a lot of patients,” Landray says. “It’s very inconvenient, and it’ll cost you a fortune.”

Questions have also arisen about the potential of remdesivir to do harm. WHO has a regular overview of possible adverse drug events related to COVID-19 treatments. In late August it noted a disproportionately high number of reports of liver and kidney problems in patients receiving remdesivir compared with patients receiving other drugs for COVID-19. The European Medicines Agency (EMA) also announced this month that its safety committee had started a review to assess reports of acute kidney injuries in some patients taking remdesivir.

Gilead Sciences’s remdesivir has become part of the standard of care for many COVID-19 patients in the United States and the company has been increasing production of the antiviral to meet increasing demand.

Gilead

Many researchers point out that another crucial piece of data is missing entirely from FDA’s statement on remdesivir’s approval: evidence the drug reduces the amount of SARS-CoV-2 in the body, the viral load. “I’ve been working in antivirals for 30 years. Every time you study an antiviral, you show an effect on the virus and you publish it,” says Andrew Hill, a clinical pharmacologist at the University of Liverpool. “Surely Gilead has done that. Where are the data? It is very, very strange.”

Richard Peto, an Oxford statistician and epidemiologist who helped design Solidarity and analyze the data, stresses that the WHO trial cannot prove whether remdesivir has zero benefit for COVID-19. “Trials produce confidence intervals, not just point estimates and this is actually the difficulty in trying to discuss this,” Peto says. “Gilead and the FDA have sort of maneuvered us into a position where we’re being asked to try and prove remdesivir does nothing rather than asking the usual way round, which is, ‘Can the manufacturers prove it does something?’”

To many scientists, such complexities underscore that FDA should have consulted ADAC, its panel of outside experts, for a vigorous debate. It could have “elevated the discussion,” says ADAC Chair Lindsey Baden, an infectious disease specialist at Brigham and Women’s Hospital. “Hydroxychloroquine, convalescent plasma, remdesivir—these are complicated decisions given the imperfect nature of the data upon which the decisions are being made, and the urgency of the clinical use gives all the more reasons to have an open discussion,” says Baden, whose group last met in October 2019.

“This was not a straightforward approval and this is not an ordinary time,” adds Luciana Borio, a former acting chief scientist at FDA who now works at a not-for-profit venture capital firm. “It would have been helpful to have a public discussion on the matter.”

Georgetown University’s Jesse Goodman, a former chief scientist at FDA, notes that it is complicated to organize advisory committee meetings, but adds that the agency obviously just arranged one for COVID-19 vaccines. “Although it’s a pandemic and everybody is super busy, it’s something … you can do virtually,” he says. “It would have been an opportunity to make clear publicly the rationale and their risk-benefit assessment.”

European Commission in the dark

EMA, Europe’s FDA counterpart, in July gave “conditional approval” to remdesivir—which is similar to an EUA—but it has yet to give its full blessing. The European Union nevertheless has negotiated a “joint procurement agreement” with Gilead that offers 500,000 treatment courses over the next 6 months for $1.2 billion. A spokesperson of the Commission confirms to Science it was not informed of the drug’s failure in the Solidarity trial until the day after the new contract was signed on 8 October.

“The Commission became aware of the results of the Solidarity trial on 9 October from the reporting of [EMA] at the COVID task force meeting on the same day,” the spokesperson says. “There was no discussion with WHO about the ongoing study prior to signing the contract with Gilead.”

When Science asked Gilead why it didn’t disclose the Solidarity data during its negotiations with the Commission, the company acknowledged it received a draft manuscript from WHO in late September but said it was “heavily redacted.” WHO says the only information blacked out was results relating to the other drugs used in the trial because of confidentiality agreements with their manufacturers.

This was not a straightforward approval and this is not an ordinary time. It would have been helpful to have a public discussion on the matter.

Luciana Borio, former acting chief scientist at FDA

Although the agreement with Gilead locks EU members into a price of about $2400 for a full course of remdesivir, it does not obligate any countries to purchase the drug, the Commission spokesperson tells Science. “The EU needs to publish the deal with Gilead,” says Yannis Natsis of the nonprofit European Public Health Alliance. “It should at least renegotiate the volume of the doses and the price per treatment.” Gilead says it doesn’t plan to adjust its negotiated price in the wake of the Solidarity data.

Kieny says it’s an “enormous” waste for EU countries to invest in remdesivir based on the idea that it might help a small subset of patients. “You can always say, ‘OK, now, if I disaggregate the population and if I take only those who have a blue eye and a wooden leg, maybe this is very effective,’” she says.

Indeed, some advocates of remdesivir point to analyses of Solidarity patient subgroups that suggest a mortality benefit in those who received supplemental oxygen but were not on ventilators. But accepting that would also mean accepting that remdesivir harmed those who were on ventilators, Hill says. “You can’t do a subgroup analysis and only believe half the story.”

The bottom line from the trials so far is there simply isn’t enough evidence that remdesivir works, says Jason Pogue, a University of Michigan, Ann Arbor, researcher who is president of the Society of Infectious Diseases Pharmacists. Pogue believes FDA made a mistake and, unless more data emerge, EMA should not give the drug full approval. “There are more questions than answers about the efficacy of remdesivir in hospitalized patients,” he says.

*Correction, 30 October, noon: An earlier version of this story incorrectly stated that Gilead was the sponsor of the Solidarity trial. It has been corrected to note that the company supported the study by donating the drug.

The universe teems with weird black holes, gravitational wave hunters find

The orientation of merging black holes’ spins helps reveal how the pair of black holes formed, and physicists have now probed the spin distribution statistically.

LIGO/Caltech/MIT/Sonoma State (Aurore Simonnet)

Less than 5 years ago, physicists rocked the scientific world when they first spotted gravitational waves—fleeting ripples in space and time—set off when two gargantuan black holes billions of light-years away swirled into each other. Since then, scientists have detected a scad of similar events, mostly reported event by event. Today, however, researchers with a global network of gravitational wave detectors announced the first major statistical analyses of their data so far, 50 events in all. Posted online in four papers, the analyses show that black holes—ghostly ultraintense gravitational fields left behind when massive stars collapse—are both more common and stranger than expected. They also shed light on mysteries such as how such black holes pair up before merging.

The new studies, posted on the physics preprint server arXiv, “are superimportant,” says Carl Rodriguez, an astrophysicist at Carnegie Mellon University who was not involved in the work. “With an individual event, there’s only so much you can do in comparing to astrophysics models. But with a catalog you can not only begin to constrain the theory, you can start to understand the landscape.” Selma de Mink, an astrophysicist at Harvard University, says she and her colleagues have been waiting to do their own analyses of the data trove. “There will definitely be a flurry of papers that are rushing to take the first stabs at the data.”

The observations come from three huge L-shaped optical instruments called interferometers that can measure the infinitesimal stretching of space itself by a passing gravitational wave. Two of those detectors belong to the Laser Interferometer Gravitational-Wave Observatory (LIGO), a pair of detectors with arms 4 kilometers long in Louisiana and Washington that spotted the first gravitational waves in 2015. The third detector is Virgo, an interferometer near Pisa, Italy, that has 3-kilometer-long arms and joined the hunt for gravitational waves in 2017.

LIGO and Virgo had already spotted 11 events, including one merger of neutron stars, an event that may shed light on how the universe forges heavy elements. Now, the team has cataloged 37 additional black hole mergers, one likely neutron star merger, and one possible merger of a black hole and neutron star from the first half of its third observing run, from April through September 2019.

Analyses of all 50 events show that when it comes to black holes, “the diversity is surprisingly large,” says Frank Ohme, a gravitational wave astronomer at the Max Planck Institute for Gravitational Physics. From details of the mergers’ chirplike signals, scientists can calculate the masses of the colliding black holes. They expected to find a “mass gap” between about 45 and 135 solar masses—the result of particle physics processes that should blow apart stars within a certain mass range before they can collapse into black holes.

However, LIGO and Virgo have now spotted mergers involving black holes squarely within the gap, including one with a mass of roughly 85 solar masses. De Mink, who models the evolution of black hole pairs from binary star systems, says accounting for the interlopers will be challenging. The mass gap is “such a clear prediction from the models that it’s hard to believe that there’s not a feature there” in the mass spectrum, she says.

Similarly, scientists expected another forbidden range below five solar masses, based on previous observations of individual black holes peacefully orbiting normal stars. But at least one hole in the catalog appears to fall below that limit. “How do you describe the boundaries of this population?” Ohme asks. “It’s not such a clear picture anymore.”.

Their new ability to take a census of black holes has also enabled researchers to probe whether black holes in a merging pair point in the same direction as they orbit each other—a potential clue to how the pair came together in the first place. If the spins align with the orbital axis, the black holes might have formed from a pair of stars that were born together, naturally acquired matching spins, and remained companions after they collapsed. If the spins point in different directions, the black holes might have formed first and then somehow paired later. Which formation channel dominates is a subject of intense debate.

In particular, if one of the black holes spins in the opposite sense of the orbit, the pair would more likely come from the mingling of black holes that had already formed. But it’s very hard to tell for sure whether that’s happening from the warble of a single signal, says Maya Fishbach, an astrophysicist and LIGO member from Northwestern University. However, by analyzing the events en masse, scientists have teased out evidence that at least some of the mergers involve reversed spins. That result in turn suggests that black hole pairs form in more than one way, Fishbach says. “It seems like there might be multiple things going on.” 

Rodriguez notes that the overall rate of black hole mergers that LIGO and Virgo see seems to roughly match the rate he predicted in his model, in which already formed black holes find each other and pair in knots of old stars called globular clusters. “I shouldn’t toot my own horn—but I totally am going to,” he says. But, he adds, the data are also consistent with such a mechanism producing just onequarter of the mergers.

Researchers have even been able to probe how the number of black hole mergers may have changed over cosmic time, Fishbach says. The rate is expected to be higher in the early universe, when the pace of star formation was also higher. But previous data allowed that rate to be up to 100,000 times higher than it is now. Now, scientists have seen enough far-flung events to say that the rate of mergers 8 billion years ago was no more than 10 times what it is now, Fishbach says. 

LIGO and Virgo scientists owe their scientific bounty to the increasing sensitivity of their detectors, which has enabled them to spot ever fainter and more distant events. Now, they are eager to build up their catalog even further. With more events, they find a correlation between spin alignment and the masses of the black holes that could help reveal whether the heaviest might themselves have formed through mergers. (If the two black holes’ spins aren’t aligned, then they may not have formed from an isolated pair of stars, and theorists wouldn’t necessarily have to explain how a collapsing star could produce such a heavy black hole.) “We’ve answered a lot of questions we didn’t even know we had,” Fishbach says, “but we raised even more. This is just the beginning of the science.”

India’s COVID-19 cases have declined rapidly—but herd immunity is still far away, scientists say

A health worker takes a swab sample from a man to test for COVID-19 outside a garment shop in Mumbai.

AP Photo/Rajanish Kakade

Sciences COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.

MUMBAI—Last week, a panel of leading scientists appointed by the Indian government delivered a startlingly optimistic message: The world’s second largest COVID-19 epidemic has rounded a corner. India’s daily number of daily new cases has almost halved the past six weeks, and a new mathematical model suggests “we may have reached herd immunity,” some members of the panel wrote in a paper published online by The Indian Journal of Medical Research. Assuming measures such as social distancing, wearing masks, and hand washing remain in place, the group said the pandemic could be “controlled by early next year.”

But other scientists say the model overestimates the number of people already infected and warn that with colder temperatures and several religious holidays approaching, India may well see a second wave. The positive national trends hide a more complex picture, suggests Giridhar Babu, an epidemiologist with the Public Health Foundation of India. He believes the virus may have burned through large, densely packed populations but will continue to spread in rural areas, at a lower rate, for many months: “We still have large numbers of people for the virus to go through.”

Daily new infections in India have fallen from a high of 90,000 a day in mid-September to fewer than 50,000 this week. Deaths have also gone down, from a peak of 1275 per day in mid-September to about 500 now.

The encouraging projections come from the National Supermodel Committee, which modeled the past and future of India’s epidemic at the government’s request. Its work suggests 380 million Indians had already been infected by mid-September and that there might be “minimal active symptomatic infections” by late February 2021 if control measures continue. (The study also concluded that by flattening the curve, India’s lockdown last spring saved up to 2.6 million lives.)

But the model did not take regional differences in viral spread into account, and most cases are still concentrated in less than half of India’s 28 states, including those that have large cities where the virus first entered the country, such as Mumbai. Babu notes that serological surveys—which test for antibodies in a population to gauge the fraction already infected—have found much higher infection rates in cities, and in particular in slum areas. Studies in August, for example, found antibodies in 41% of residents of Mumbai’s slums, compared with 18% elsewhere in the city. “Many dense pockets that can be easily infected have [likely] already been infected,” Babu says. That could help explain the slowdown in new infections but suggests many more people remain vulnerable.

Gautam Menon of Ashoka University, a co-author on several COVID-19 modeling studies, adds that the model suffers from “a lack of epidemiological realism” because it assumes an unusually large fraction of infected people remains asymptomatic. Other models for the Indian pandemic are “better rooted in reality than this one,” says Menon, who believes 200 million to 300 million is a better estimate for the number of infected people.

Experts agree that spread in rural areas, home to more than half of the population, is a challenge to both fight and monitor. The health infrastructure in these areas is weaker, making it harder to treat patients. And testing isn’t easily available in many small towns and villages. Serosurveys suggest official testing, now at 1 million per day, vastly undercounts actual cases. Some states rely heavily on so-called rapid antigen tests, which range widely in sensitivity. Such tests comprise about 90% of testing in the most populous and rural state of Bihar, for instance, which has reported relatively few cases; in the state with the most reported cases, Maharashtra, two-thirds of tests are still done using the more reliable polymerase chain reaction assay.

More granular data might help scientists better understand the pandemic’s trajectory. The national epidemic is a “figment of statistical imagination,” says T. Jacob John, former head of the department of virology at Christian Medical College; instead, “There are 100 or more small epidemics in different states and cities, rising and falling at different times.”

There are 100 or more small epidemics in different states and cities, rising and falling at different times.

T. Jacob John, Christian Medical College

More detailed data could also shed more light on India’s perplexingly low mortality rates, often touted by the government. The total death toll stands at a little over 100,000, less than half that of the United States, which has roughly one-quarter of India’s population. India’s fatality rate has decreased in the past few months and is now about 1.5%, compared with 2.8% in the United States.

Explanations for the low death rates have ranged from the country’s young population to unproven factors such as cross-immunity from other viruses. But if age is the driving factor, India’s mortality rate would be lower than it actually is, according to a study by researchers at the U.S. National Bureau of Economic Research who used a model to predict mortality in India based on age-specific mortality rates in other countries. For instance, if India’s age-specific fatality rates were similar to South Koreas, its overall fatality rate would have been only 0.74% in July, when it was still 2.7%.

In reality, the number of COVID-19 deaths is almost certainly higher. Death registration rates are not 100% in many states to begin with. And investigations have shown that some states are not including suspected or probable COVID-19 deaths.

Ramanan Laxminarayan, director of the Center for Disease Dynamics, Economics & Policy, and others have found surprising patterns in the mortality data. A study of confirmed cases in two Indian states showed that deaths among people over age 85 were lower than in the United States, perhaps because of what Laxminarayan calls “survivorship bias”: Life expectancy is lower in India, and those who live beyond 75 in the first place are likely to be in better health and of better socioeconomic status, he says.

On the other hand, the study found surprisingly high death rates in younger cohorts. For instance, 9% of COVID-19 patients aged between 40 and 50 died, compared with about 2% in the United States. Underlying conditions could be one reason, Laxminarayan says: “There is a lot of hidden diabetes and hypertension in the country.” Air pollution may also be driving up mortality, he says. A study published this week estimated that long-term exposure to air pollution is linked to 15% of COVID-19 deaths globally.

The effect of air pollution will be more clearly seen in the next few months, as north India enters its traditionally smoggy winter. Meanwhile, further loosening of travel and economic restrictions may trigger an uptick in cases. Religious festivals have already spurred fresh surges in Kerala and other states that were successful in curbing infections early on. Even the National Supermodel Committee warns that cases could surge in December if precautions aren’t taken. 

Babu warns against complacency. “The decline [in cases] is real and valid, but no one should rejoice yet,” he says. “It only means that the first set of formidable challenges is over, and the next set is beginning.”

Fleet of robotic probes will monitor global warming’s impact on microscopic ocean life

Since 2014, researchers have deployed more than 150 biogeochemical Argo floats in the Southern Ocean.

GRETA SHUM/SOCCOM

A single drop of seawater holds millions of phytoplankton, a mix of algae, bacteria, and protocellular creatures. Across the world’s oceans these photosynthesizing microbes pump out more than half of the planet’s oxygen, while slowing climate change by capturing an estimated 25% of the carbon dioxide (CO2) released from humanity’s burning of fossil fuels. But the scale of this vital chemistry is mostly a guess, and there’s little sense of how it will change as temperatures rise. “What’s happening out there? We have no idea really,” says Susan Wijffels, a physical oceanographer at the Woods Hole Oceanographic Institution.

Soon, 500 drifting ocean floats studded with biogeochemical sensors will deliver answers. Today, the National Science Foundation (NSF) announced it will spend $53 million to fund the new floats, marking the first major expansion of the Argo array, a set of 4000 floats that for 15 years has tracked rising ocean temperatures. “This is going to be revolutionary,” says Wijffels, a leader of the original Argo program.

The biogeochemical (BGC) Argo floats, in development for nearly as long as Argo itself, will operate much like their forerunners. After being tossed off a ship, each of the skinny, 1-meter-tall floats drifts with deep ocean currents 1000 meters down. Every 10 days or so, it uses an oil-filled bladder to change its density, dropping to 2000 meters and then slowly rising to the surface, where it beams the resulting profile home. Although instruments lowered from ships can make deeper and more precise measurements, ship campaigns are expensive, and often limited to common ocean trade routes, says Ken Johnson, a chemical oceanographer at the Monterey Bay Aquarium Research Institute and a leader of the new program. The floats, he says, are “not as good as a ship, but they’re there all the time.”

In addition to standard Argo measurements of temperature and salinity, the new floats will have sensors measuring oxygen, sunlight, particles, chlorophyll (a gauge of phytoplankton abundance), nitrate (a key nutrient), and pH (acidity). Researchers will be watching that last reading closely, because acidity reflects both the ocean’s uptake of CO2 and its pernicious effect. When the gas dissolves in seawater, it forms carbonic acid that eventually splits into bicarbonate and hydrogen ions, the latter increasing the water’s acidity. Ecologists are concerned that acidification, already 30% worse in surface waters than preindustrial times, will make it more difficult for some phytoplankton, corals, bivalves, and many other species to assemble their shells of calcium carbonate.

Researchers have been testing more than 150 prototype BGC floats in the Southern Ocean since 2014, and the findings are tantalizing. This ocean, encircling Antarctica, is home to two seasonally contrasting CO2 fluxes. In the summer, algae draw down CO2. But in the winter, ancient carbon, stashed away for centuries in deep currents traveling south from the Atlantic and Pacific oceans, wells up, some escaping into the atmosphere. Scientists have long assumed that the carbon absorption dominates, with the Southern Ocean accounting for a significant share of the oceans’ global CO2 storage. But because almost no ships ventured to the stormy, cold Southern Ocean, they couldn’t check whether the winter release really was smaller.

In the past few years, Alison Gray, an oceanographer at the University of Washington, Seattle, and her colleagues have used the trial BGC floats to show that the winter exhalation of CO2comes close to canceling out the summer’s gains. She is now seeking to understand why the outgassing seems to peak on the Pacific side of the ocean. Surface winds or currents smashing into undersea ridges might sweep up more of the deep waters there. Another explanation is biological: The region’s phytoplankton might be less capable than their Atlantic counterparts at staunching the CO2 outflow.

The BGC floats could also shed light on a less-known ocean trend: a slow drop in oxygen. Since the mid–20th century, it has declined by some 2%. Much of the loss takes place in anoxic dead zones like one in the Gulf of Mexico, where nutrient runoffs from overfertilized lands lead to algal blooms, and, eventually, bacterial surges that use up oxygen in a frenzy of aerobic decomposition, suffocating fish. But researchers have also found that vast tracts of open ocean are losing oxygen because of warming, which limits water’s ability to hold oxygen, and decreased downward mixing. BGC-Argo could reveal the true extent of these minimum zones. “If you eat seafood or care about sea life, you should care about deoxygenation,” Gray says.

The floats aren’t only useful for large-scale trends. For instance, the trial floats discovered massive phytoplankton blooms in the Southern Ocean, far from typical nutrient sources like melting sea ice, suggesting a seafloor hydrothermal vent was providing the nutrients. The floats should also be able to detect short-lived phenomena such as the oxygen loss after a hurricane’s upheaval, or the injection of nutrients for species in the North Atlantic twilight zone, up to 1000 meters down, that come from late-winter plunges of surface water. “The ability to observe these biogeochemical properties in three dimensions is going to be huge,” says Katja Fennel, an oceanographer at Dalhousie University, who is pushing for Canada to add 40 floats to BGC-Argo.

Researchers plan to begin deploying the new floats next year in the equatorial Pacific, where El Niño and La Niña drive large temperature swings every year or two. The floats could show how the swings affect the ability of phytoplankton to soak up carbon, offering clues to how a warming climate will change the ocean’s overall carbon uptake.

After the first 5 years of NSF financing, Johnson and his colleagues would likely need support from the National Oceanic and Atmospheric Administration, which pays for much of the main U.S. Argo fleet. Expanding to 1000 floats, as the team hopes, would require funding from France, Australia, Canada, China, and other countries. At some point, they hope the Argo fleet will be bolstered by 1200 deep Argo floats, which can sink to 6000 meters without crushing. But money for upgrading the fleet, which would remain at 4000 total floats, has been elusive—even though Argo is a relative bargain compared with ships.

If anything, the pandemic has underscored that point, Johnson says. “We’re all sitting at home now,” he says. Yet out in the ocean, the robotic fleet calls home week after week, capturing otherwise invisible changes. “Ten years ago, the ship was the observing platform,” Johnson says. “Now, it’s the tender.”

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