Culture

In 1986, cellular biochemist Kazumitsu Ueda, currently at Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS), discovered that a protein called ABCB1 could transport multiple chemotherapeutics out of some cancer cells, making them resistant to treatment. How it did this has remained a mystery for the past 35 years. Now, his team has published a review in the journal FEBS Letters, summarizing what they have learned following years of research on this and other ATP-binding cassette (ABC) transporter proteins.

ABC transporter proteins are very similar across species and have various transportation roles: importing nutrients into cells, exporting toxic compounds outside them, and regulating lipid concentrations within cell membranes.

ABCB1 is one of these proteins, and is responsible for exporting toxic compounds out of the cell in vital organs such as the brain, testes, and placenta. Sometimes, though, it can also export chemotherapeutic drugs from cancer cells, making them resistant to treatment. The protein lies across the cell membrane, with one end reaching into the cell and the other poking out into the surrounding space. Even though scientists have known its roles and structure for years, exactly how it functions has been unclear.

Ueda and his team crystalized the ABCB1 protein before and after it exported a compound. They then conducted X-ray tests to determine the differences between the two structures. They also conducted analyses using ABCB1 fused with fluorescent proteins to monitor the conformational changes during transport.

They found that compounds destined for export access ABCB1's cavity through a gate in the part of the protein lying inside of the cell membrane. The compound rests at the top of the cavity, where it attaches to molecules, triggering a structural change in the protein. This change requires energy, which is derived from the energy-carrying molecule adenosine triphosphate (ATP). When magnesium ions bind to ATP, the part of ABCB1 inside the cell packs tightly in on itself and tilts, causing its cavity to shrink and then close. This opens the protein's exit gate. ATP is also involved in making ABCB1 progressively rigid from its bottom to its top, leading to a twist and squeeze motion that expels the compound into the extracellular space.

"This mechanism is distinct from those of other transporter proteins," says Ueda. "We expect our work will facilitate the study of other ABC proteins, such as those involved in cholesterol homeostasis."

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.

Philadelphia, December 29, 2020 - Posttraumatic stress disorder (PTSD) is a complex psychiatric disorder brought on by physical and/or psychological trauma. How its symptoms, including anxiety, depression and cognitive disturbances arise remains incompletely understood and unpredictable. Treatments and outcomes could potentially be improved if doctors could better predict who would develop PTSD. Now, researchers using magnetic resonance imaging (MRI) have found potential brain biomarkers of PTSD in people with traumatic brain injury (TBI).

The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

"The relationship between TBI and PTSD has garnered increased attention in recent years as studies have shown considerable overlap in risk factors and symptoms," said lead author Murray Stein, MD, MPH, FRCPC, a Distinguished Professor of Psychiatry and Family Medicine & Public Health at the University of California San Diego, San Diego, La Jolla, CA, USA. "In this study, we were able to use data from TRACK-TBI, a large longitudinal study of patients who present in the Emergency Department with TBIs serious enough to warrant CT (computed tomography) scans."

The researchers followed over 400 such TBI patients, assessing them for PTSD at 3 and 6 months after their brain injury. At 3 months, 77 participants, or 18 percent, had likely PTSD; at 6 months, 70 participants or 16 percent did. All subjects underwent brain imaging after injury.

"MRI studies conducted within two weeks of injury were used to measure volumes of key structures in the brain thought to be involved in PTSD," said Dr. Stein. "We found that the volume of several of these structures were predictive of PTSD 3-months post-injury."

Specifically, smaller volume in brain regions called the cingulate cortex, the superior frontal cortex, and the insula predicted PTSD at 3 months. The regions are associated with arousal, attention and emotional regulation. The structural imaging did not predict PTSD at 6 months.

The findings are in line with previous studies showing smaller volume in several of these brain regions in people with PTSD and studies suggesting that the reduced cortical volume may be a risk factor for developing PTSD. Together, the findings suggest that a "brain reserve," or higher cortical volumes, may provide some resilience against PTSD.

Although the biomarker of brain volume differences is not yet robust enough to provide clinical guidance, Dr. Stein said, "it does pave the way for future studies to look even more closely at how these brain regions may contribute to (or protect against) mental health problems such as PTSD."

Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, said of the work, "This very important study uses magnetic resonance imaging to take the field a step closer to understanding why some people develop PTSD after trauma and others do not. It also lays the groundwork for future research aimed at using brain imaging to help predict that a person is at increased risk and may benefit from targeted interventions to reduce the clinical impact of a traumatic event."

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. Review concludes universal mask use by lay persons reduces the spread of viral infections including SARS-CoV-2
Findings affirm policy promised by President-Elect Biden, who will ask Americans on Inauguration Day to wear masks for 100 days

A new narrative review of over 100 research articles concludes that masks and face coverings worn by members of the public reduce the spread of respiratory viral infections including SARS-CoV-2, the virus that causes Covid-19. The virus travels in the air in tiny droplets and particles, which are blocked to some extent even by 'imperfect' cloth face coverings. Wearing a face covering in a crowded indoor space reduces the chance that an infected person will pass the virus on to others. Even small reductions in the transmission rate can lead to large reductions in the number of people becoming infected over time. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-6625.

According to the authors from the University of Oxford, Institute for Advanced Studies, Vienna, Austria, and London School of Economics there is no evidence that masks and face coverings cause serious harm, though they can cause discomfort. There is also no evidence that wearing a mask leads to people stopping other protective behaviors, such as hand-washing. Resistance to mask-wearing is influenced by cultural norms and expectations; in some but not all cultures, the mask symbolizes the loss of autonomy and a threat to individual freedom. In such circumstances, mandated masking should be introduced only if the virus is spreading and cannot be controlled by other means.

The authors say this review is published at a critical time in the pandemic, as over 80 million people are known to have been infected with the virus and at least 1.75 million have so far died. Currently, over half a million people are becoming infected every day. While masks aren't a perfect barrier to the virus, the data strongly support wide-spread mask mandates, as observational studies suggest universal masking reduces transmission.

Media contacts: A PDF for this article is not yet available. Please click the link to read the full text. The lead corresponding author, Thomas Czypionka can be reached at czypionk@ihs.ac.at.

2. Update to 'living review' summarizes latest evidence on mask use among laypersons and health care workers
Researchers from Oregon Health & Sciences University published a fourth update to their living rapid review of evidence evaluating the use of masks among lay persons in the community and health care workers for preventing the spread of respiratory virus infections, including SARS-CoV-2, the virus that causes COVID-19. The update includes 739 citations that were published from early October to early December 2020 using the same search strategies as the original review. One study on the use of masks and the prevention of SARS-CoV-2 infection in a community setting (the DANMASK trial) and two studies in health care settings were added for the update. Read the full text: https://www.acpjournals.org/doi/10.7326/L20-1429.

The DANMASK trial, a good-quality, open-label trial of 6,024 community-dwelling adults in Denmark evaluated the effects of wearing a surgical mask outside of the house, at a time when mask wearing in the community was neither recommended nor common. The trial found that the incidence of SARS-CoV-2 infection among participants was 2.0%. Mask use versus no mask use was associated with a small, non-statistically significant reduction in risk for SARS-CoV-2 infection. The trial was not designed to assess the effects of mask use as source control; in addition, high adherence to other infection control measures (for example, physical distancing and handwashing) could have attenuated potential benefits.

The evidence on mask use in health care settings and risk for SARS-CoV-2 infection was previously assessed as insufficient on the basis of three studies with methodological limitations. Two new cohort studies, both done in the United States, reported on mask use in health care settings. One study of 16,397 health care workers and first responders (86% health care workers) found that use of an N95 or surgical mask all of the time versus not all of the time was associated with a decreased risk for infection. In the second study, done in 20,614 asymptomatic health care workers, risk for infection was reduced with any mask use versus no mask use. An N95 mask was associated with decreased risk versus a surgical mask. However, both studies had methodological limitations, so evidence for various comparisons about mask use in health care settings and risk for SARS-CoV-2 remains insufficient.

Media contacts: A PDF for this article is not yet available. Please click the link to read the full text. The lead corresponding author, Roger Chou, MD, can be reached through the Oregon Health & Sciences newsroom at news@ohsu.edu.

The loss and return of consciousness is linked to the same network of brain regions for both sleep and anesthesia, according to new research published in JNeurosci.

The biological basis of consciousness has confounded scientists for centuries. Our experimental techniques falter, as the effects of sleep and anesthetic drugs alter brain activity beyond changes in consciousness. In addition, behavior does not always reveal someone's state of consciousness. An unresponsive person might still be aware of their surroundings (connected), or unaware but still experiencing their internal world (disconnected).

Scheinin et al. sought networks associated with human consciousness by measuring the brain activity of adult males with PET as they fell asleep and went under anesthesia. The research team woke participants mid-experiment to interview them and confirm their state of connectedness. Changes in connectedness corresponded to the activity of a network comprised of regions deep inside the brain: the thalamus, anterior and posterior cingulate cortex, and angular gyri. These regions exhibited less blood flow when a participant lost connectedness and more blood flow when they regained it. The pattern held true for both sleep and anesthesia, indicating the changes corresponded to connectedness rather than the effects of sleep or drugs, and that the network may be imperative for human consciousness.

To effectively combat an infection, the body first has to sense it's been invaded, then the affected tissue must send out signals to corral resources to fight the intruder. Knowing more about these early stages of pathogen recognition and response may provide scientists with crucial clues when it comes to preventing infections or treating inflammatory diseases resulting from overactive immunity.

That was the intent behind a new study, led by researchers at the University of Pennsylvania School of Veterinary Medicine, examining infection with the parasite Cryptosporidium. When the team looked for the very first "danger" signals emitted by a host infected with the parasite, they traced them not to an immune cell, as might have been expected, but to epithelial cells lining the intestines, where Cryptosporidium sets up shop during an infection. Known as enterocytes, these cells take up nutrients from the gut, and here they were shown to alert the body to danger via the molecular receptor NLRP6, which is a component of what's known as the inflammasome.

"You can think about the inflammasome as an alarm system in a house," says Boris Striepen, a professor in the Department of Pathobiology at Penn Vet and senior author on the paper, which is publishing in the journal Proceedings of the National Academy of Sciences. "It has various components--like a camera that watches the door, and sensors on the windows--and once triggered it amplifies those first signals to warn of danger and send a call for help. Cells have these different components as well, and now we've provided maybe the clearest example yet of how a particular receptor in the gut is acting as a sensor for an important intestinal infection."

Typically, Striepen says, researchers have focused on immune cells, like macrophages and dendritic cells, as being the first to detect foreign invaders, but this new finding underscores that cells not normally thought of as part of the immune system--in this case intestinal epithelial cells--are playing key roles in how how an immune response gets launched.

"There is a growing body of literature that is really appreciating what epithelial cells are doing to help the immune system sense pathogens," says Adam Sateriale, first author on the paper who was a postdoc in Striepen's lab and now leads his own lab at the Francis Crick Institute in London. "They seem to be a first line of defense against infection."

Striepen's lab has devoted considerable attention to Cryptosporidium, which is a leading cause of diarrheal disease that can be deadly in young children in resource-poor areas around the world. Cryptosporidium is also a threat to people in well-resourced environments, causing half of all water-borne disease outbreaks in the United States. In veterinary medicine, it's known for infecting calves, stunting their growth. These infections have no effective treatment and no vaccine.

In the current work, Striepen, Sateriale and colleagues took advantage of a naturally occurring species of mouse Cryptosporidium that they recently discovered mimics human infection in many respects. While the researchers knew T cells help control the parasite in later stages of infection, they began looking for clues as to what happens first.

One important clue is the unfortunate linkage between malnutrition and Cryptosporidium infection. Early infection with Cryptosporidium and the inflammation of the intestine that goes along with it predisposes children to malnutrition and stunted growth; at the same time, children who are malnourished are more susceptible to infection. This can lead to a downward spiral, putting children at greater risk of deadly infections. The mechanisms behind this phenomenon are not well understood.

"That led us to think that maybe some of the danger-sensing mechanisms that can drive inflammation in the gut also play a role in the larger context of this infection," adds Striepen.

Together these linkages inspired the research team to look more closely at the inflammasome and its impact on the course of infection in their mouse model. They did so by removing a key component of the inflammasome, an enzyme called caspase-1. "It turns out that animals that are missing this had much higher levels of infection," Sateriale says.

Further work demonstrated that mice lacking caspase-1 just in intestinal epithelial cells suffered infections as high as those lacking it completely, demonstrationg the crucial role of the epithelial cell.

Consistent with this idea, the Penn Vet-led team showed that, out of a variety of candidate receptors, only loss of the NLRP6 receptor lead to failure to control the infection. NLRP6 is a receptor restricted to epithelial barriers previously linked to sensing and maintaining the intestinal microbiome, bacteria that naturally colonize the gut. However, experiments revealed that mice never exposed to bacteria, and thus lacked a microbiome, also activated their inflammasome upon infection with Cryptosporidium--a sign that this aspect of danger signalling occurs in direct response to parasite infection and independent of the gut bacterial community.

To trace how triggering the intestinal inflammasome led to an effective response, the researchers looked at some of the signalling molecules, or cytokines, typically associated with inflammasome activation. They found that infection leads to release of IL-18, with those animals that lack this cytokine or the ability to release it showing more severe infection.

"And when you add back IL-18, you can rescue these mice," Sateriale says, nearly reversing the effects of infection.

Striepen, Sateriale, and colleagues believe there's a lot more work to be done to find a vaccine against Cryptosporidium. But they say their findings help illuminate important aspects of the interplay between the parasite, the immune system, and the inflammatory response, relationships that may inform these translational goals.

Moving forward, they are looking to the later stages of Cryptosporidium infection to see how the host successfully tamps it down. "Now that we understand how infection is detected, we'd like to understand the mechanisms by which it is controlled," Sateriale says. "After the system senses a parasite, what is done to restrict their growth and kill them?"

To control mosquito populations and prevent them from transmitting diseases such as malaria, many researchers are pursuing strategies in mosquito genetic engineering. A new Texas A&M AgriLife Research project aims to enable temporary "test runs" of proposed genetic changes in mosquitoes, after which the changes remove themselves from the mosquitoes' genetic code.

The project's first results were published on Dec. 28 in Philosophical Transactions of the Royal Society B, titled "Making gene drive biodegradable."

Zach Adelman, Ph.D, and Kevin Myles, Ph.D., both professors in the Texas A&M College of Agriculture and Life Sciences Department of Entomology are the principal investigators. Over five years, the team will receive $3.9 million in funding from the National Institute of Allergy and Infectious Diseases to test and fine-tune the self-deleting gene technology.

"People are wary of transgenes spreading in the environment in an uncontrolled manner. We feel that ours is a strategy to potentially prevent that from happening," Adelman said. "The idea is, can we program a transgene to remove itself? Then, the gene won't persist in the environment.

"What it really comes down to is, how do you test a gene drive in a real-world scenario?" he added. "What if a problem emerges? We think ours is one possible way to be able to do risk assessment and field testing."

A crucial target for mosquito control

Many genetic engineering proposals revolve around inserting into mosquitoes a select set of new genes along with a "gene drive." A gene drive is a genetic component that forces the new genes to spread in the population.

"A number of high-profile publications have talked about using a gene drive to control mosquitoes, either to change them so they can't transmit malaria parasites anymore, or to kill off all the females so the population dies out," Adelman said.

An often-voiced worry is that such genetic changes could carry unintended or harmful consequences.

One plan makes the cut

In the project's first publication, the colleagues describe three ways for an introduced genetic change to remove itself after a designated period of time. The time period could, for instance, be 20 generations of mosquitoes, or about a year. The team modeled how the genes would spread among mosquitoes based on generation times and parameters of an average mosquito's life. Of the three methods, the team has chosen one to pursue further.

This method takes advantage of a process all animals use to repair damaged DNA, Adelman said. Inside cell nuclei, repair enzymes search for repeated genetic sequences around broken DNA strands. The repair enzymes then delete what's between the repeats, he said.

So, Adelman and Myles' team plans to test in fruit flies and mosquitoes a gene drive, a DNA-cutting enzyme and a small repeat of the insect's own DNA.

Once the introduced enzyme cuts the DNA, the insect's own repair tools should jump into action. The repair tools will cut out the genes for the gene drive and the other added sequences. At least, that's what should happen in theory.

Failure is not just an option, it's part of the plan

The team has already started lab work to test different gene drives and determine how long they last in flies and mosquitoes. The goal is to see a gene drive spread rapidly through a lab insect population. After a few generations, the added genes should disappear and the population should again consist of wild-type individuals.

"We assigned various rates of failure for how often the mechanism does not work as expected," Adelman said. "The models predict that even with a very high rate of failure, if it succeeds just 5% of the time, that's still enough to get rid of the transgene."

What The Patient Page Says: We have all lived with COVID-19 for about a year now. Overall, we have learned that children get sick less often than adults, but a few children have gotten severely sick. This update summarizes the current understanding of how children are affected and gives ways to keep families safe as children continue to grow and thrive.

Authors: Lindsay A. Thompson, M.D., M.S., and Sonja A. Rasmussen, M.D., M.S., of the University of Florida College of Medicine in Gainesville, are the authors.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2020.5817)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: This observational study examined whether lasting change in sweetened beverage prices or the volume sold was associated with the implementation and repeal of a sweetened beverage tax in Cook County, Illinois, where Chicago is.

Authors: Lisa M. Powell, Ph.D., of the University of Illinois Chicago, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamanetworkopen.2020.31083)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Angiosarcomas are clinically aggressive tumours that are more prevalent in Asian populations

Study led by Singapore clinician-scientists has found a way to classify angiosarcomas into three subtypes, allowing for more targeted treatment, better outcomes for patients and the development of new therapies

Findings were published in The Journal of Clinical Investigation in October this year

Singapore, 29 December 2020 - A new study led by clinician-scientists from the National Cancer Centre Singapore (NCCS), with collaborators from research institutions worldwide, has found that angiosarcomas have unique genomic and immune profiles which allow them to be classified into three different subtypes. With this new and improved classification system, patients can be treated using a personalised-medicine approach and it will encourage the development of novel treatments.

Angiosarcomas, a type of cancer that forms in the lining of the blood and lymph vessels, are more commonly found in Asia making up 7% of all sarcoma diagnoses. Angiosarcomas are aggressive and can spread to various regions of the body and most often occur on the scalp and face.

For angiosarcomas that have not spread, a combined approach using surgery, radiotherapy and/or chemotherapy is often the course of action for treatment. Once the cancer has metastasised, various chemotherapy treatments are typically administered, which often have poor clinical efficacy and little benefit. As a result, angiosarcomas present a challenge for clinicians and patients because treatment options are limited and prognosis is bleak.

"At NCCS, we treat around 100 patients with sarcomas a year. With a deeper understanding of the tumours, we can better treat these group of patients," said Clinical Assistant Professor Jason Chan, first author of the study and Consultant Medical Oncologist, Division of Medical Oncology, NCCS.

For the study, 68 patients diagnosed with angiosarcoma at NCCS and Singapore General Hospital between 2000 to 2015 were identified. The research team analysed the tumour samples using multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence.

Multiomic sequencing, which is used to find associations or pinpoint biomarkers in biological entities, like an angiosarcoma, found that 50% of the head and neck angiosarcomas exhibited higher tumour mutation burden (TMB) and UV mutational signatures. This indicated that half of the head and neck angiosarcomas may have developed as a result of UV exposure, and are likely to respond to a type of cancer treatment known as immune checkpoint inhibitors.

NanoString profiling, a technology that profiles gene expression in tumours, revealed that patients with angiosarcomas were grouped into three clusters. Patients in the third cluster had specific enrichment of immune cells and genes involved in immune-related signalling. Tumour inflammation signature (TIS) scores were also highest in this third cluster. Cluster one, like cluster three, was found to be predominantly head and neck angiosarcomas although with a lower inflammation footprint. Cluster two exhibited higher expression of genes that typically promote tumour growth and spread. They were also mainly secondary sarcomas, meaning they had previous exposure to certain environmental or genetic risk factors.

Recent clinical studies have shown that treating tumours with high TMB and TIS scores with immune checkpoint inhibitors showed promising results. By stratifying these 68 angiosarcoma patients, the study results suggest that checkpoint immunotherapy can be used for clusters one and three, while the tumour-promoting genes that are highly expressed in cluster two could be explored as potential treatment targets using targeted therapies.

"Our results are very promising, as they show that we can potentially use existing modes of therapy, like immunotherapy to treat a subset of angiosarcoma patients," said Clin Asst Prof Chan. "The next step will be to perform further molecular and immunological dissection of angiosarcomas to get more insight into how we can best use precision medicine to target these cancers."

The findings, published in The Journal of Clinical Investigation in October of this year, is testament that research can directly improve patient care.

"Understanding angiosarcomas will allow oncologists to treat their patients in a more targeted way and it is also a confirmation that NCCS is continuously conducting cutting edge, translational research that has an impact on patients," said Professor Soo Khee Chee, senior author of the study and Founding Director, NCCS.

The research team plans to further the study by investigating the molecular and genomic profiles of other sarcoma subtypes. This study is part of a plan to investigate rare cancers and establish NCCS as a leading global cancer centre.

Quantum computer: One of the obstacles for progress in the quest for a working quantum computer has been that the working devices that go into a quantum computer and perform the actual calculations, the qubits, have hitherto been made by universities and in small numbers. But in recent years, a pan-European collaboration, in partnership with French microelectronics leader CEA-Leti, has been exploring everyday transistors--that are present in billions in all our mobile phones--for their use as qubits. The French company Leti makes giant wafers full of devices, and, after measuring, researchers at the Niels Bohr Institute, University of Copenhagen, have found these industrially produced devices to be suitable as a qubit platform capable of moving to the second dimension, a significant step for a working quantum computer. The result is now published in Nature Communications.

Quantum dots in two dimensional array is a leap ahead

One of the key features of the devices is the two-dimensional array of quantum dot. Or more precisely, a two by two lattice of quantum dots. "What we have shown is that we can realize single electron control in every single one of these quantum dots. This is very important for the development of a qubit, because one of the possible ways of making qubits is to use the spin of a single electron. So reaching this goal of controlling the single electrons and doing it in a 2D array of quantum dots was very important for us", says Fabio Ansaloni, former PhD student, now postdoc at center for Quantum Devices, NBI.

Using electron spins has proven to be advantageous for the implementation of qubits. In fact, their "quiet" nature makes spins weakly interacting with the noisy environment, an important requirement to obtain highly performing qubits.

Extending quantum computers processors to the second dimension has been proven to be essential for a more efficient implementation of quantum error correction routines. Quantum error correction will enable future quantum computers to be fault tolerant against individual qubit failures during the computations.

The importance of industry scale production

Assistant Professor at Center for Quantum Devices, NBI, Anasua Chatterjee adds: "The original idea was to make an array of spin qubits, get down to single electrons and become able to control them and move them around. In that sense it is really great that Leti was able to deliver the samples we have used, which in turn made it possible for us to attain this result. A lot of credit goes to the pan-European project consortium, and generous funding from the EU, helping us to slowly move from the level of a single quantum dot with a single electron to having two electrons, and now moving on to the two dimensional arrays. Two dimensional arrays is a really big goal, because that's beginning to look like something you absolutely need to build a quantum computer. So Leti has been involved with a series of projects over the years, which have all contributed to this result."

The credit for getting this far belongs to many projects across Europe

The development has been gradual. In 2015, researchers in Grenoble succeeded in making the first spin qubit, but this was based on holes, not electrons. Back then, the performance of the devices made in the "hole regime" were not optimal, and the technology has advanced so that the devices now at NBI can have two dimensional arrays in the single electron regime. The progress is threefold, the researchers explain: "First, producing the devices in an industrial foundry is a necessity. The scalability of a modern, industrial process is essential as we start to make bigger arrays, for example for small quantum simulators. Second, when making a quantum computer, you need an array in two dimensions, and you need a way of connecting the external world to each qubit. If you have 4-5 connections for each qubit, you quickly end up with a unrealistic number of wires going out of the low-temperature setup. But what we have managed to show is that we can have one gate per electron, and you can read and control with the same gate. And lastly, using these tools we were able to move and swap single electrons in a controlled way around the array, a challenge in itself."

Two dimensional arrays can control errors

Controlling errors occurring in the devices is a chapter in itself. The computers we use today produce plenty of errors, but they are corrected through what is called the repetition code. In a conventional computer, you can have information in either a 0 or a 1. In order to be sure that the outcome of a calculation is correct, the computer repeats the calculation and if one transistor makes an error, it is corrected through simple majority. If the majority of the calculations performed in other transistors point to 1 and not 0, then 1 is chosen as the result. This is not possible in a quantum computer since you cannot make an exact copy of a qubit, so quantum error correction works in another way: State-of-the-art physical qubits do not have low error rate yet, but if enough of them are combined in the 2D array, they can keep each other in check, so to speak. This is another advantage of the now realized 2D array.

The next step from this milestone

The result realized at the Niels Bohr Institute shows that it is now possible to control single electrons, and perform the experiment in the absence of a magnetic field. So the next step will be to look for spins - spin signatures - in the presence of a magnetic field. This will be essential to implement single and two qubit gates between the single qubits in the array. Theory has shown that a handful of single and two qubit gates, called a complete set of quantum gates, are enough to enable universal quantum computation.

BOSTON - Some police departments in the United States continue to teach officers that neck restraints are a safe method for controlling agitated or aggressive people, but that's a dangerous myth, according to a Viewpoint written by three neurologists at Massachusetts General Hospital (MGH) in JAMA Neurology.

The killing of George Floyd, a Black man who died while being arrested in May 2020 after a police officer pressed a knee to his neck for more than eight minutes, helped spark a national conversation about racial injustice in the United States. Floyd's death made headlines, as did that of Eric Garner in 2014 after police placed him in a chokehold. Yet a number of other Americans have died during confrontations with police officers who used neck restraints, says MGH neurologist Altaf Saadi, MD, senior author of the Viewpoint column.

Along with coauthors Jillian M. Berkman, MD, and Joseph A. Rosenthal, MD, PhD, Saadi was disturbed by the use of neck restraints by police departments in the United States. They found that some prohibit chokeholds and other neck restraints, but others teach the techniques for the purpose of subduing allegedly uncooperative people during encounters. Notably, some police agencies advise that carotid restraint--compressing the two large blood vessels on either side of the neck, which is known as a stranglehold--is a safe, nonlethal tactic that temporarily renders a person unconscious by reducing blood flow to the brain.

"As a neurologist, I know that there is never a scenario where stopping the flow of blood and oxygen to the brain is medically appropriate," says Saadi. "What shocked me most was that much of the literature supporting these techniques hides behind medical language, but lacks a real understanding of the pathophysiology of the significant harm they cause to an individual. As neurologists, we are taught that 'time is brain,' because there's such a rapid loss of human nervous tissue when the flow of blood and oxygen to the brain is reduced or stopped."

In their Viewpoint, Saadi and her colleagues describe how carotid compression--which can occur with as few as 6 kilograms (13 pounds) of force, or about the weight of a typical house cat--can result in stroke, seizure and death. They call for the creation of a system for reporting on law enforcement's use of neck restraints, including how often the technique is used and if it results in death or disability.

"It's in the public's best interest to have this data," says Saadi. She believes that increasing awareness about the impact of neck restraints could help curb their use. Ultimately, says Saadi, there is no medical justification for neck restraints in policing.

Certain bacteria, known as plant-growth-promoting bacteria (PGPB), can improve plant health or protect them from pathogens and are used commercially to help crops. To further improve agricultural yields, it is helpful to identify factors that can improve PGPB behavior.

Many PGPB form sticky communities of cells, known as biofilms, that help them adhere to plant roots. A group of scientists in North Carolina and Massachusetts were interested in finding other plant-associated bacteria that could help PGPB better adhere to plant roots, with the hope that increasing the number of PGPB cells attached to roots would increase their beneficial activities.

Using a liquid-growth-based method, they identified multiple bacterial strains that increased the adherence of PGPB to plant roots over time. These results indicate that the physical or chemical interactions between these different bacterial species result in better long-term maintenance of PGPB on roots.

"Our results highlight how bacteria can use each other for their own benefit. These findings could be used to create groups of bacteria that are able to work together to better protect crop plants and improve their growth," said Elizabeth Shank, the senior scientist involved with this research. "The results of this research might also be used to better understand and design microbial treatments that could improve crop yields in agricultural settings."

To conduct this research, Shank and her colleagues performed a high-throughput screen of bacteria originally obtained from the roots of wild-grown plants, ensuring that identified bacteria might naturally come into contact on the roots of plants in native soil environments. They also looked at how other native microbes might alter the behavior of each PGPB strain, emphasizing the importance of understanding how groups of plant-associated microbes affect plants.

This research specifically focused on a PGPB currently used in agricultural treatments so that their findings related to commercial interventions. According to Shank, "One important impact of our work may be further encouraging agricultural biotechnology companies to consider using groups of multiple bacteria (rather than a single isolate) in their search for better and longer-lasting biological treatments to improve crop yield and help increase food production."

About one in 100 children has a common brain disorder called Chiari 1 malformation, but most of the time such children grow up normally and no one suspects a problem. But in about one in 10 of those children, the condition causes headaches, neck pain, hearing, vision and balance disturbances, or other neurological symptoms.

In some cases, the disorder may run in families, but scientists have understood little about the genetic alterations that contribute to the condition. In new research, scientists at Washington University School of Medicine in St. Louis have shown that Chiari 1 malformation can be caused by variations in two genes involved in brain development.

The condition occurs when the lowest parts of the brain are found below the base of the skull. The study also revealed that children with unusually large heads are four times more likely to be diagnosed with Chiari 1 malformation than their peers with normal head circumference.

The findings, published Dec. 21 in the American Journal of Human Genetics, could lead to new ways to identify people at risk of developing Chiari 1 malformation before the most serious symptoms arise. It also sheds light on the development of the common but poorly understood condition.

"A lot of times people have recurrent headaches, but they don't realize a Chiari malformation is the cause of their headaches," Haller said. "And even if they do, not everyone is willing to have brain surgery to fix it. We need better treatments, and the first step to better treatments is a better understanding of the underlying causes."

If people start experiencing severe symptoms like chronic headaches, pain, abnormal sensations or loss of sensation, or weakness, the malformation is treated with surgery to decompress the Chiari malformation.

"There's an increased risk for Chiari malformations within families, which suggests a genetic underpinning, but nobody had really identified a causal gene," said senior author Gabriel Haller, PhD, an assistant professor of neurosurgery, of neurology and of genetics. "We were able to identify two causal genes, and we also discovered that people with Chiari have larger head circumference than expected. It's a significant factor, and easy to measure. If you have a child with an enlarged head, it might be worth checking with your pediatrician."

To identify genes that cause Chiari 1 malformation, Haller and colleagues sequenced all the genes of 668 people with the condition, as well as 232 of their relatives. Of these relatives, 76 also had Chiari 1 malformation and 156 were unaffected. The research team included first author Brooke Sadler, PhD, an instructor in pediatrics, and co-authors David D. Limbrick, Jr., MD, PhD, a professor of neurosurgery and director of the Division of Pediatric Neurosurgery, and Christina Gurnett, MD, PhD, a professor of neurology and director of the Division of Pediatric and Developmental Neurology, among others.

Sequencing revealed that people with Chiari 1 malformation were significantly more likely to carry mutations in a family of genes known as chromodomain genes. Several of the mutations were de novo, meaning the mutation had occurred in the affected person during fetal development and was not present in his or her relatives. In particular, the chromodomain genes CHD3 and CHD8 included numerous variants associated with the malformation.

Further experiments in tiny, transparent zebrafish showed that the gene CHD8 is involved in regulating brain size. When the researchers inactivated one copy of the fish's chd8 gene, the animals developed unusually large brains, with no change in their overall body size.

Chromodomain genes help control access to long stretches of DNA, thereby regulating expression of whole sets of genes. Since appropriate gene expression is crucial for normal brain development, variations in chromodomain genes have been linked to neurodevelopmental conditions such as autism spectrum disorders, developmental delays, and unusually large or small heads.

"It's not well known how chromodomain genes function since they have such a wide scope of activity and they are affecting so many things at once," Haller said. "But they are very intriguing candidates for molecular studies, to understand how specific mutations lead to autism or developmental delay or, as in many of our Chiari patients, just to increased brain size without cognitive or intellectual symptoms. We'd like to figure out the effects of each of these mutations so that in the future, if we know a child has a specific mutation, we'll be able to predict whether that variant is going to have a harmful effect and what kind."

The association between chromodomain genes and head size inspired Haller and colleagues to measure the heads of children with Chiari malformations, comparing them to age-matched controls and to population averages provided by the Centers for Disease Control and Prevention. Children with Chiari tended to have larger than average heads. Those children with the largest heads - bigger than 95% of children of the same age - were four times more likely to be diagnosed with the malformation.

The findings suggest that children with larger heads or people with other neurodevelopmental disorders linked to chromodomain genes may benefit from screening for Chiari malformation.

"A lot of kids that have autism or developmental disorders associated with chromodomain genes may have undiscovered Chiari malformations," Haller said. "The only treatment right now is surgery. Discovering the condition early would allow us to watch, knowing the potential for serious symptoms is there, and perform that surgery as soon as it's necessary."

Our understanding of biological proteins does not always correlate with how common or important they are. Half of all proteins, molecules that play an integral role in cell processes, are intrinsically disordered, which means many of the standard techniques for probing biomolecules don't work on them. Now researchers at Kanazawa University in Japan have shown that their home-grown high-speed atomic force microscopy technology can provide information not just on the structures of these proteins but also their dynamics.

Understanding how a protein is put together provides valuable clues to its functions. The development of protein crystallography in the 1930s and 1950s brought several protein structures into view for the first time, but it gradually became apparent that a large fraction of proteins lack a single set structure making them intractable to xray crystallography. As they are too thin for electron microscopy, the only viable alternatives for many of these intrinsically disorderd proteins (IDPs) are nuclear magnetic resonance imaging and small angle xray scattering. Data collected from these techniques are averaged over ensembles and so give no clear indication of individual protein conformations or how often they occur. Atomic force microscopy on the other hand is capable of nanoscale resolution biological imaging at high-speed, so it can capture dynamics as well as protein structures.

In this latest work researchers at Kanazawa University alongside collaborators in Japan, France and Italy applied the technique to the study of several IDPs and identified parameters defining the shape, size and chain length of protein regions, as well as a power law relating the protein size to the protein length, and a quantitative description of the effect of the mica surface on protein dimensions. The dynamics of the protein conformations captured thanks to the high-speed capabilities of the technique revealed globules that appear and disappear, and transformations between fully unstructured and loosely folded conformations in segments up to 160 amino acids long.

Studies of the measles virus nucleoprotein in particular helped identify not just the shape and dimensions but also characteristics of the order-disorder transitions in the region responsible for molecular recognition, which allows viruses to identify host factors so that they can reproduce. They could also determine larger scale structures of the virus's phosphoprotein that are not accessible to nuclear magnetic resonance (which can only give an indication of distances between amino acides separated by less than 2 nm). The researchers suggest that the formation of certain compact shapes observed may explain the resistance to proteolysis - protein breakdown.

In their report of the work, the researchers highlight that as well as a powerful tool in its own right, "When all molecular features revealed by HS-AFM are combined with the folded local structure given by NMR, the combined information allows a quantitative delineation of the structural and dynamic characters of IDPs, in a more realistic manner compared to the pictures depicted individually, as demonstrated for PNT [measles virus phosphoprotein]."

[Background]

High-speed atomic force microscopy

Atomic force microscopy was developed in the 1980s and brought the atomic scale resolution achieved by scanning tunnelling microscopy (which won the 1986 Nobel Prize for Physics) to non-conducting samples. It works using a tiny cantilever with a nanoscale tip at the end, which either feels the surface much like a vinyl record needle or taps it. Whether by adjusting the tip height or the resonant frequency of the tapping, the interactions between tip and surface provide a signal that can be used to generate an image.

While AFM images brought huge benefits to biological research, these studies were able to move up a gear again when Toshio Ando and his team at Kanazawa University reported an atomic force microscope that operated at high speed. Atomic scale resolution images became movies bringing not just structures but also dynamics within grasp. Previous work on ordered proteins, which are reasonably well understood, as well as the IDP facilitates chromatin transcription (FACT) protein, has established that the technique can be used to image these biomolecules without effects from contact between tip and sample distorting the data.

Intrinsically disordered proteins

The arrival of xray crystallography gave researchers a clear view of vast numbers of biomolecule structures for the first time. But with the hundreds of thousands of biomolecule structures analysed using protein crystallography since the technique first came into use in the 1930s and 1950s, a mounting body of evidence began to build that not all proteins have a single set structure. The observations ran counter to the prevailing paradigm of protein function determined by a fixed structure.

Over the past ten to twenty years the ubiquity of these intrinsically disorderd proteins and their importance in cell functions from signalling to the regulation of transcription and subsequent translation has become widely recognized. In the current work the researchers study IDPs including polyglutamine tract binding protein-1 (PQBP-1, involved in different processes, such as pre-mRNA splicing, transcription regulation, innate immunity and neuron development), autophagy proteins (which are invovolved in removing dysfunctional cell components) containing intrinsically disordered regions (IDRs) and the measles virus nucleoprotein.