(Image caption: Abnormalities in the cholesterol transport protein ABCA13 have been shown to lead to schizophrenia in a mouse model. Credit: ©Mindy Takamiya/Kyoto University iCeMS)
Large transporter protein linked to schizophrenia
Scientists have suspected mutations in a cellular cholesterol transport protein are associated with psychiatric disorders, but have found it difficult to prove this and to pinpoint how it happens. Now, Kazumitsu Ueda of Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS) and colleagues in Japan have provided evidence that mice with disrupted ABCA13 protein demonstrate a hallmark behaviour of schizophrenia. The team investigated ABCA13’s functions and published their findings in the Journal of Biological Chemistry.
ABCA13 belongs to a family of cellular transporter proteins called ATP-binding cassette (ABC) proteins, which are involved in moving cholesterol and other molecules into and out of cells. Ueda and his team have been studying ABC proteins for 35 years, giving them extra leverage for uncovering the elusive roles of what is suspected to be the largest of these proteins, ABCA13.
The scientists studied ABCA13 in different types of human cells. They also turned off the gene that codes for the protein in mice. Finally, they investigated the effects of mutated ABCA13 proteins in human cells. The team found that ABCA13 was a large protein localized in cellular vesicles, and helps transport cholesterol from the cell’s membrane into the vesicles.
“We found that ABCA13 accelerates the internalization of cholesterol in cells and that its loss of function is associated with the pathophysiology of some psychiatric disorders,” says Ueda.
Mice lacking ABCA13 looked normal and had a normal lifespan. But a series of behavioural investigations showed abnormal results for the ‘startle response and prepulse inhibition test’. Normally, a weak ‘prepulse’ stimulus, like a sound, can reduce the feeling of being startled by a subsequent stronger stimulus. However, people with some psychiatric disorders, still feel startled by a main stimulus despite being preceded by a prepulse. The scientists found that both normal mice and the mice lacking ABCA13 had a normal startle response. But only the engineered mice were startled when the startling stimulus was preceded by a prepulse.
The scientists further wanted to know how ABCA1 deletion affected nerve cells in the brain. They found that vesicles in brain nerve endings in the mice that lacked ABCA1 did not accumulate cholesterol. Synaptic nerve vesicles are vital for the transmission of information from one nerve to another, so this malfunction could contribute to the pathophysiology of psychiatric disorders, the researchers say.
Finally, the scientists studied human cells containing mutated versions of ABCA13 thought to be associated with some psychiatric disorders. They found the mutations impaired ABCA13’s functions and ability to locate within cellular vesicles.
The team suggests further studies on ABCA13 functions could lead to the development of novel therapeutic strategies for psychiatric disorders like schizophrenia, bipolar disorder and major depression.
61 notes · View notes
Africa’s Covid Crisis Deepens, but Vaccines Are Still Far Off
Africa is now in the deadliest stage of its pandemic, and there is little prospect of relief in sight. The Delta variant is sweeping across the continent. Namibia and Tunisia are reporting more deaths per capita than any other country. Hospitals across the continent are filling up, oxygen supplies and medical workers are stretched thin and recorded deaths jumped 40 percent last week alone.
But only about 1 percent of Africans have been fully vaccinated. And even the African Union’s modest goal of getting 20 percent of the population vaccinated by the end of 2021 seems out of reach.
Rich nations have bought up most doses long into the future, often far more than they could conceivably need. Hundreds of millions of shots from a global vaccine-sharing effort have failed to materialize.
“The blame squarely lies with the rich countries,” said Dr. Githinji Gitahi, a commissioner with Africa Covid-19 Response, a continental task force. “A vaccine delayed is a vaccine denied.” Unable to strike early deals for vaccines, African nations relied on Covax, a global partnership, to deliver free doses to countries that needed them. But Covax deliveries ground to a halt after India imposed export restrictions on the AstraZeneca vaccine as it dealt with its own resurgence this year.
There is little room for African countries to buy doses on their own: Almost all of the vaccines forecast to be made in 2021 have already been sold, according to data from Airfinity, an analytics firm. Most of the surplus supply includes Chinese vaccines and an Indian vaccine, Covaxin.
Some of the world’s richest countries will have 1.9 billion doses more than they need to vaccinate their populations by the end of August, according to the One campaign. The size of their excess supply has drawn the ire of African leaders, scientists and rights groups, who have called for accountability and warned that protectionism and stockpiling would only contribute to prolonging the pandemic.
“Covax is a really lovely idea,” said Andrea Taylor, an assistant director at the Duke Global Health Innovation Center. But, she added: “It didn’t take into account how human behavior actually works in real life. It didn’t assume that wealthy countries would act in their own self-interest, and it should have done so.”
Africa’s grim vaccine prognosis
The pace of vaccination remains far slower in Africa than in the rest of the world. Europe and South America are dispensing vaccines nearly 20 times faster than Africa, adjusted for population. About three-quarters of the 70 million doses African countries have received have already been administered, according to the W.H.O.
At the current pace of inoculation, only eight small African nations are set to meet a global target to vaccinate at least 10 percent of each country’s population by September, the W.H.O. says. Vaccine deliveries to Africa are not expected to ramp up until then, according to Covax.
Even Africa’s modest vaccination goals this year appear out of reach. The African Union, aware of the challenge of obtaining enough vaccines, hoped to immunize 20 percent of its population by year’s end. The International Monetary Fund proposed a more ambitious goal: 40 percent immunization this year, and 60 percent by mid-next year. But reaching either of those goals would require a huge change in current vaccination rates.
Logistical roadblocks to vaccine delivery
India’s decision in March to significantly cut back on its vaccine exports — particularly the supplies from the Serum Institute of India that Covax relied on — disrupted Africa’s vaccine rollouts. As stocks were depleted, immunization campaigns in Africa slowed down or were suspended altogether in May, even as a brutal third wave was getting underway.
Restrictions on vaccine exports and raw materials in the United States and the European Union have also undermined efforts to produce and deliver vaccines.
One lesson from this crisis was that Africa could not “be dependent on another sovereign state” for supplies, Dr. Gitahi said. The postponement in deliveries, he said, left many frontline workers and families vulnerable to infection and death. A recent study found that those who suffer from severe Covid in Africa are more likely to die than patients in other parts of the world because of scarcity in intensive care unit equipment and the prevalence of chronic conditions like H.I.V. and diabetes.
Yet even when vaccines arrived, some African nations struggled to distribute them. From the start, many nations lacked the requisite planning, funding, work force, refrigeration and transportation network needed to get their citizens inoculated.
The ultra-cold storage requirements of some vaccines have posed a challenge on the continent, too. Only a few African countries, like Rwanda, initially had the capacity to receive the Pfizer-BioNTech vaccine, which at the time had to be stored at temperatures well below freezing, after it became the first to receive W.H.O. emergency authorization last December. Even the electricity needed to refrigerate vaccines can be hard to come by: Only 28 percent of health-care facilities in sub-Saharan Africa have reliable electricity, according to the World Bank. Ensuring this equipment will arrive in time to transport doses into rural areas and hard-to-reach zones remains a concern, said Hitesh Hurkchand, a senior adviser to the World Food Program who is advising the African Union on cold-storage logistics and vaccine supply chains.
Hesitancy and misinformation
Even in areas where vaccine doses may be available soon, some Africans are hesitant about taking them. About 68 percent of people surveyed expressed concerns around vaccine safety in a 15-country study released in March by the Africa Centers for Disease Control and Prevention. And while the willingness to accept vaccines varied from country to country, over half of those surveyed said they were “not very well or not at all informed about vaccine development.”
Health officials say vaccinations have increased as more doses have arrived on the continent. Still, Dr. Marina Joubert, a senior science communication researcher at the Stellenbosch University in South Africa, warned that conspiracy theories continue to persist, stoking unfounded fears, for example, that Covid-19 vaccines cause infertility or that Africans are being used as “guinea pigs” to test vaccine safety and efficacy.
What could speed up vaccinations
The W.H.O. and the Africa C.D.C. have said they are hopeful vaccine deliveries — both bilateral donations and those from Covax — would gather momentum in the coming weeks. Aurélia Nguyen, the managing director of Covax, said last week that it expected to deliver 520 million vaccines to Africa by the end of the year, and 850 million by the end of the first quarter of 2022.
In the meantime, wealthy nations with excess doses have started sharing vaccines. In coordination with the African Union, Covax will soon deliver more than 20 million Johnson & Johnson and Pfizer-BioNTech vaccines donated by the United States to 49 African countries. France and Denmark have cumulatively donated hundreds of thousands of doses, while donations from Norway and Sweden are set to arrive in the coming weeks, Dr. Moeti said. G7 nations also announced in June their intention to share at least 870 million doses with low-income nations, including those in Africa.
Some nations are also looking to manufacturing to boost vaccine availability. Only seven African countries have companies operating in the vaccine-manufacturing chain, a recent study shows. Kenya has announced plans to build a plant that would package Covid-19 vaccines and distribute them regionally. Moroccan and Egyptian companies aim to start producing China’s Sinopharm and Sinovac vaccines, respectively, while Rwanda signed a deal with the European Union to bolster its vaccine manufacturing capabilities. A joint American-European plan would invest more than $700 million for a South African plant to produce more than 500 million doses of the Johnson & Johnson vaccine by the end of 2022.
The availability of more vaccine varieties globally could help curb the virus in Africa, said Ms. Taylor of the Duke Global Health Innovation Center. Novavax, based in the United States, announced last month that its two-dose inoculation provides protection against the virus. There’s also Corbevax, from the Indian firm Biological E, which has enormous manufacturing capacity and promising provisional data, she said.
But even as more people get inoculated, the efficacy of the particular vaccines being delivered to African countries remains a concern. That is the case in Seychelles, which raced to vaccinate its population of just over 100,000 with China’s Sinopharm, only to face a surge in coronavirus infections. While the W.H.O. and the Africa C.D.C. have said they are studying the situation in Seychelles, both institutions have for now encouraged countries to continue using any of the Covid-19 vaccines listed for emergency use.
By Abdi Latif Dahir and Josh Holder (The New York Times)
31 notes · View notes