Culture

A survey of star formation activity in the Orion Nebula Cluster found similar mass distributions for newborn stars and dense gas cores, which may evolve into stars. Counterintuitively, this means that the amount of gas a core accretes as it develops, and not the initial mass of the core, is the key factor in deciding the final mass of the produced star.

The Universe is populated with stars of various masses. Dense cores in clouds of interstellar gas collapse under their own gravity to form stars, but what determines the final mass of the star remains an open question. There are two competing theories. In the core-collapse model, larger stars form from larger cores. In the competitive accretion model, all cores start out about the same mass but accrete different amounts of gas from the surroundings as they grow.

To distinguish between these two scenarios, a research team led by Hideaki Takemura at the National Astronomical Observatory of Japan created a map of the Orion Nebula Cluster where new stars are forming, based on data from the American CARMA interferometer and NAOJ's own Nobeyama 45-m Radio Telescope. Thanks to the unprecedent high resolution of the map, the team was able to compare the masses of the newly formed stars and gravitationally collapsing dense cores. They found that the mass distributions are similar for the two populations. They also found many smaller cores which don't have strong enough gravity to contract into stars.

One would think that similar mass distributions for prestellar cores and newborn stars would favor the core-collapse model, but actually because it is impossible for a core to impart all of its mass to a new star, this shows that continued gas inflow is an important factor, favoring the competitive accretion model.

Now the team will expand their map using additional data from CARMA and the Nobeyama 45-m Radio Telescope to see if the results from the Orion Nebula Cluster hold true for other regions.

The nervous system is the internet of the human body and can in the same way transfer signals over long distances very quickly. Some of the most important elements in this signaling are the axons. They are projections of the nerve cells which send signals to other nerve cells or muscles. For instance, axons that jut out from nerve cells in the spinal cord can be over one meter long.

Researchers from the Faculty of Health and Medical Sciences at the University of Copenhagen have now in a new study examined how signal molecules are transported in the axons.

"We have found out, that the protein Rab2 has to be present and functioning properly in order for the nerve cells to send effective signals between the central nervous system and the body. When we remove the protein in fruit flies we can see that the signal molecules are accumulate in the axons like in a traffic jam," explains visiting researchers Viktor Karlovich Lund from the Department of Neuroscience.

Same or similar mechanism in humans

The researchers investigate the transport of signal molecules in axons because there are multiple illnesses in humans where the transport is inhibited. This is true for neurodegenerative diseases such as Alzheimer's and Parkinson's disease, Amyotrophic lateral sclerosis (ALS) and neuropathy. Changes in the Rab2 gene are also connected to autism spectrum disorders.

Even though one has to be careful drawing conclusions between species, the researchers think that they have good reason to believe that their discovery is also relevant in humans.

"We share around 75 percent of disease-related genes with fruit flies. Beyond that, we know that the genes coding for Rab2 look alike in many different species - they have a high degree of evolutionary conservation. This makes us quite convinced that the same mechanism or one very similar exists in the human nervous system," says Ole Kjærulff, Associate Professor at the Department of Neuroscience.

The glue between cargo and engine

The signaling works by signaling molecules being transferred from one end of the axons to other nerve cells.

"Some types of signals require that the signal molecules first travel very far in the same cell. They are packaged into small organelles with a membrane around them and then they are transported op to one meter or more. This requires a complex machinery where everything needs to run smoothly," says Ole Kjærulff.

Inside the axons the 'cargo' is pulled by motor proteins that can be compared to small locomotives.

"Our best guess is that the Rab2 protein is the link between the motor proteins driving forward and the cargo being pulled. Almost like a molecular glue holding everything together," says Viktor Karlovich Lund.

The researchers hope that their new discovery can be the foundation for new attempts to create drugs targeting neurodegenerative diseases and neuropathy.

A candidate vaccine that could provide protection against the COVID-19 virus and other coronaviruses has shown promising results in early animal testing.

The candidate coronavirus vaccines, created by Virginia Tech's University Distinguished Professor X.J. Meng and UVA Health's Professor Steven L. Zeichner, prevented pigs from being becoming ill with a pig coronavirus, porcine epidemic diarrhea virus (PEDV).

The researchers have recently published their findings in the Proceedings of the National Academy of Sciences.

"The candidate vaccine was developed using an innovative vaccine platform targeting a highly conserved genomic region of coronaviruses," said Meng, a University Distinguished Professor in the Department of Biomedical Sciences and Pathobiology in the Virginia-Maryland College of Veterinary Medicine. "The new vaccine platform utilizes a genome-reduced bacteria to express the coronavirus vaccine antigen on its surface. Such a vaccine platform can be manufactured with low cost in existing facilities around the world, which could meet the pandemic demand."

Their coronavirus vaccine offers several advantages that could overcome major obstacles to global vaccination efforts. It would be easy to store and transport, even in remote areas of the world, and could be produced in mass quantities using existing vaccine-manufacturing factories.

"Our new platform offers a new route to rapidly produce vaccines at very low cost that can be manufactured in existing facilities around the world, which should be particularly helpful for pandemic response," said Zeichner.

A new vaccine-development approach

The new vaccine-production platform involves synthesizing DNA that directs the production of a piece of the virus that can instruct the immune system how to mount a protective immune response against a virus.

That DNA is inserted into another small circle of DNA called a plasmid that can reproduce within bacteria. The plasmid is then introduced into bacteria, instructing the bacteria to place pieces of proteins on their surfaces. The technique uses the common bacteria E. coli.

One major innovation is that the E. coli have had a large number of its genes deleted. Removing many of the bacteria's genes, including genes that make up part of its exterior surface or outer membrane, appears to substantially increase the ability of the immune system to recognize and respond to the vaccine antigen placed on the surface of the bacteria. To produce the vaccine, the bacteria expressing the vaccine antigen are simply grown in a fermenter, much like the fermenters used in common microbial industrial processes like brewing, and then killed with a low concentration of formalin.

"Killed whole-cell vaccines are currently in widespread use to protect against deadly diseases like cholera and pertussis. Factories in many low-to-middle-income countries around the world are making hundreds of millions of doses of those vaccines per year now, for a $1 per dose or less," Zeichner said. "It may be possible to adapt those factories to make this new vaccine. Since the technology is very similar, the cost should be similar too."

The entire process, from identifying a potential vaccine target to producing the gene-deleted bacteria that have the vaccine antigens on their surfaces, can take place very quickly, in only two to three weeks, making the platform ideal for responding to a pandemic.

Targeting COVID-19

The team's candidate vaccines take an unusual approach in that it targets a part of the spike protein of the virus, the "viral fusion peptide," that is highly universal among coronaviruses. The fusion peptide has not been observed to differ at all in the many genetic sequences of SARS-CoV-2, the virus that causes COVID-19, that have been obtained from thousands of patients around the world during the course of the pandemic.

"With the emergence of various SARS-CoV-2 variants, a vaccine targeting a conserved region of all coronaviruses, such as the fusion peptide, may potentially lead to a broadly protective candidate vaccine. Such a vaccine, if successful, would be of significant value against variant virus strains," said Meng, who is also the founding director of the Center for Emerging, Zoonotic, and Arthropod-borne Pathogens in the Fralin Life Sciences Institute at Virginia Tech.

To create their vaccine, the researchers used the new vaccine platform, synthesizing the DNA with the instructions to make the fusion peptide and engineered bacteria to place the proteins on the surface of the bacteria that had a large number of its genes removed, then grew and inactivated the bacteria to make the candidate coronavirus vaccine.

Meng and Zeichner made two vaccines, one designed to protect against COVID-19, and another designed to protect against the pig coronavirus, PEDV. PEDV and SARS-CoV-2, the virus that causes COVID-19, are both coronaviruses, but they are distant relatives. PEDV and SARS-CoV-2, like all coronaviruses, share a number of core amino acids that constitute the fusion peptide. PEDV infects pigs, causing diarrhea, vomiting, and high fever and has been a large burden on pig farmers around the world. When PEDV first appeared in pig herds in the U.S. in 2013, it killed millions of pigs in the United States alone.

One advantage of studying PEDV in pigs is the researchers could study the ability of the vaccines to offer protection against a coronavirus infection in its native host -- in this case, pigs. The other models that have been used to test COVID-19 vaccines study SARS-CoV-2 in nonnative hosts, such as monkeys or hamsters, or in mice that have been genetically engineered to enable them to be infected with SARS-CoV-2. Pigs are also very similar in physiology and immunology to people - they may be the closest animal models to people other than primates.

In some unexpected results, Meng and Zeichner observed that both the candidate vaccine against PEDV and the candidate vaccine against SARS-CoV-2 protected the pigs against illness caused by PEDV. The vaccines did not prevent infection, but they protected the pigs from developing severe symptoms, much like the observations made when primates were tested with candidate COVID-19 vaccines. The vaccines also primed the immune system of the pigs to mount a much more vigorous immune response to the infection. If both the PEDV and the COVID-19 vaccines protected the pigs against disease caused by PEDV and primed the immune system to fight the disease, it is reasonable to think that the COVID-19 vaccine would also protect people against severe COVID-19 disease.

Next steps

Additional testing - including human trials - would be required before the COVID-19 vaccine could be approved by the federal Food and Drug Administration or other regulatory agencies around the world for use in people, but the collaborators are pleased by the early successes of the vaccine-development platform.

"Although the initial results in the animal study are promising, more work is needed to refine both the vaccine platform using different genome-reduced bacterial strains and the fusion peptide vaccine target," said Meng. "It will also be important to test the fusion peptide vaccine in a monkey model against SARS-CoV-2 infection."

Zeichner added that he was encouraged that a collaboration between UVA and Virginia Tech, schools with a well-known sports rivalry, has produced such promising results.

"If UVA and Virginia Tech scientists can work together to try to do something positive to address the pandemic, then maybe there is some hope for collaboration and cooperation in the country at large," said Zeichner.

Angiogenesis is a process of new vessel formation that is activated both in physiological (tissue repair, reproduction, etc.) and pathological (myocardial infarction, diabetic retinopathy, cancer, etc.) conditions. The process is carried out by endothelial cells and includes their proliferation, migration and arrangement in tubes. Angiogenesis regulation is precise and is mainly mediated by pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), which in turn promote different signalling pathways leading to an increase of intracellular Ca2+ concentrations.

The researchers from the Cardiovascular Pathophysiology group at the Institute of Biomedicine of Seville (IBiS) focused on precisely this point, demonstrating that the inhibition of certain proteins involved in the pathway's regulation drastically affects the proper development of blood vessels. Specifically, these researchers demonstrated, for the first time, the involvement of SARAF, a SOCE regulatory protein, and Orai1, a subunit that forms the pore of the SOCE channel, in the VEGF-mediated activation of endothelial cells. Likewise, the research group has shown the importance of this Ca2+ pathway in the formation of new vessels and in the development of retinal vascularisation in neonatal mice. Thus, Orai1 and SARAF can be viewed as targets for the design of therapeutic strategies that could control angiogenesis in pathological situations such as cancer or retinopathies, or physiological situations such as post-infarction cardiac neovascularisation.

The study was funded by Spain's Agencia Estatal de Investigación (State Research Agency) and was the result of collaboration with Dr. Rosado of the University of Extremadura, and with Dr. Khatib of the University of Bordeaux - LAMC INSERM 1029, France.

Russian scientists have proposed a theory of phase transformation in polymer gels. It explains the mechanisms of the dramatic reduction in volume of zwitterionic hydrogels when they are cooled. The results are published in the journal Chemical Communications (ChemComm).

Polymer gels have unusual properties, including the ability to absorb water in volumes hundreds of times greater than their own. For example, some hydrogels are capable of holding up to two kilograms of water per gram of dry gel. By changing the temperature or adding solvents, various desired properties can be achieved. This is why polymer gels are used in industry and biomedicine, including for the targeted delivery of medication, creation of artificial skin, children's toys, etc.

If you take a gel containing a high volume of solvent and gradually lower its temperature, when a certain temperature threshold is reached, there will be a sharp decrease in the volume of the gel and a large amount of liquid will be squeezed out of it--the gel will collapse (contract).

The theory of gel collapse was first proposed by the American physicists and chemists Paul Flory and John Rehner, Jr. in 1943 and subsequently developed by the Japanese scientist Tsuyoshi Tanaka. A shortcoming of classical theory is that it does not take into account the peculiarities of the molecular structure of polymer links. The new theory was proposed by a team of Russian scientists consisting of Yury Budkov, Professor at MIEM HSE (HSE Tikhonov Moscow Institute of Electronics and Mathematics), Nikolai Kalikin, a PhD student at the Krestov Institute of Solution Chemistry of the Russian Academy of Sciences, and Andrei Kolesnikov, a research fellow at the Institute of Non-Classical Chemistry in Leipzig. The researchers developed a microscopic theory of polymer gel, each link of which carries an electric dipole --two electric charges equal in magnitude, but opposite in sign.

This molecular structure is most commonly found in zwitterionic polymers, whose units carry both positively and negatively charged ion groups.

The authors have shown that at sufficiently low temperatures it is the electrostatic interaction of polymer units that leads to gel collapse. They also named the main parameters influencing the transition temperature from expanded to contracted state: the dipole moment value (the product of the charge per dipole length) and the ratio of the bond length between adjacent links of the polymer chain to the dipole length.

The latter result is a significant advance in gel theory compared to the classical Flory-Rehner-Tanaka theory, which does not take into account the specific molecular structure of polymer links.

'In practice, we cannot control the molecular properties of polymer links, but thanks to our theory chemists will be able to create polymers with suitable properties in advance and control the collapse temperature,' comments Yury Budkov, professor at MIEM HSE.

The scientists note that the theoretical evaluations made will be useful in modern applications of zwitterionic gels, such as superabsorbents, molecular nanoreactors, antibacterial coatings, electrically conductive membranes for chemical current sources, artificial skin, artificial muscles and others.

Every year, the ChemComm editorial board shortlists young researchers from around the world working in different areas of chemistry and invites them to publish in a special Emerging Investigators issue. This year, Yury Budkov was among the invited young scientists in the field of Theoretical and Physical Chemistry.

Rare diseases are sometimes the most difficult to treat because of a lack of research and fewer participants to study.

An example would be those who have Pompe disease, a genetic condition when a body can't make a protein that breaks down a complex sugar, called glycogen, for energy. Too much glycogen builds up and damages muscles and organs. The disease causes muscle weakness and trouble breathing and can affect the heart and muscles.

In the case of Pompe disease, however, University of Cincinnati researchers have found a newer, more effective treatment for the rare condition that could become the new standard of care.

Hani Kushlaf, MD, an associate professor in both the Department of Neurology and Rehabilitation Medicine and the Department of Pathology and Laboratory Medicine at UC and principal investigator of a study led at UC, will present findings on this new treatment virtually at the American Academy of Neurology on April 20.

Kushlaf, a UC Health physician, says Pompe disease affects about 1 in 40,000 people in the United States. It can impact children, but it can also present later in life as well. Left untreated, it can result in progressive loss of function of muscles in limbs and respiration leading to the need for wheelchair use and respiratory support.

"In this clinical trial, we tested a new drug, or enzyme replacement therapy (avalglucosidase alfa), to see if it was more effective and safer than the currently approved therapy, also an enzyme replacement therapy, in patients with late-onset Pompe disease," he says. "It turns out that it is safer and more effective than the current FDA-approved therapy. This new enzyme will likely become the standard of care for patients with the disease and has already been submitted for Food and Drug Administration approval. This is a big deal for patients with this rare disease, as t-PA was for stroke."

This study was double-blinded, meaning neither the participants nor the researchers knew which treatment was being administered via an infusion. In 51 patients who received the new treatment, researchers saw an improvement in respiratory muscle function, endurance and muscle strength, in addition to an overall better quality of life, when compared to patients on the current standard of care therapy.

"These results are extremely promising for finding a new and effective treatment for this disease," adds Kushlaf, who is also a member of the UC Gardner Neuroscience Institute. "With these results, we can take the next steps in having it used widely in this patient population, improving their outcomes and giving them a better life."

COVID-19 needs no introduction. Last year, the disease, which is caused by the virus SARS-CoV-2, reached every continent across the globe. By the end of March 2021, there had been an estimated 128 million cases recorded with almost three million of these being fatal. As scientists' race to develop vaccines and politicians coordinate their distribution, fundamental research on what makes this virus so successful is also being carried out.

Within the Mathematics, Mechanics, and Materials Unit at the Okinawa Institute of Science and Technology Graduate University (OIST), postdoctoral researcher, Dr. Vikash Chaurasia, and Professor Eliot Fried have been using energy minimization techniques to look at charged proteins on biological particles. Previously they researched cholesterol molecules but when the pandemic hit, they realized that with the methods they had developed could be applied to the new virus. They collaborated with researchers Mona Kanso and Professor Jeffrey Giacomin, from Queen's University in Canada, to take a close look at SARS-CoV-2 and see how the shape of the virus' 'spikes' (which are officially called peplomers) aid its success at spreading so prolifically. Their study was recently published in Physics of Fluids.

"When one envisions a single coronavirus particle, it is common to think of a sphere with many spikes or smaller spheres distributed across its surface," said Dr. Chaurasia. "This is the way the virus was originally modeled. But this model is a rough sketch and over the last year, we've come to learn much more about what the virus looks like."

Instead, Dr. Chaurasia pointed out, the 'spikes' of the coronavirus particle are actually shaped like three small spheres stacked together to form a triangular shape. This is an important consideration because the shape of a viral particle can influence its ability to disperse.

To understand this, imagine a ball moving through space. The ball will follow a curve but, as it does this, it will also rotate. The speed at which the ball rotates is called its rotational diffusivity. A particle of SARS-CoV-2 moves in a similar way to this ball although its suspended in fluid (specifically, tiny droplets of saliva). The rotational diffusivity of the particle impacts how well it can align with and attach itself to objects (such as a person's tissues or cells) and this has been key in its ability to successfully spread from person to person so quickly. A higher rotational diffusivity will mean that the particle shakes and jitters as it follows a trajectory - and thus may have difficulty attaching to objects or efficiently bouncing off an object to continue to move through the air. Whereas a lower rotational diffusivity has the opposite effect.

Another consideration was the charge of each spike. The researchers assumed that each is equally charged. The same charges always repel each other so if there are only two spikes on a particle and they have equal charges, they'll be situated at either pole (as far away from each other as possible). As more equally charged spikes are added, they become evenly distributed across the surface of the sphere. This provided the researchers with a geometrical arrangement from which they could calculate the rotational diffusivity.

Previously, the researchers looked at a viral particle with 74 spikes. For this new study, they used the same particle but switched out the single-bead spikes for the three-bead triangles. When they did this, the rotational diffusivity of the particle was found to decrease by 39%. Moreover, this trend was found to continue with the addition of more spikes.

This was an important finding - having a lower rotational diffusivity means that the virus particles can better align and attach themselves to objects and people. Thus, this study suggests that the triangular shaped spikes have contributed to the success of SARS-CoV-2.

"We know it's more complicated than this," explained Dr. Chaurasia. "The spikes might not be equally charged. Or they might be flexible and able to twist themselves. Also, the 'body' of the particle might not be a sphere. So, we plan to do more research in this area."

An additional interesting feature of this research is its connection to a question asked more than a century ago by physicist J. J. Thomson, who explored how a set number of charges will be distributed across a sphere.

"I find it fascinating that a problem considered more than 100 years ago has such relevance for the situation we're in today," said Professor Eliot Fried. "Although this question was first posed primarily from a standpoint of curiosity and intellectual interest, it has turned out to be applicable in unexpected ways. This shows why we mustn't lose site of the importance of fundamental research."

The scientists at OIST and at Queen's University intend to continue to collaborate on this kind of research to shed light on the success of SARS-CoV-2. The researchers at Queen's University have just been awarded a Mitacs Globalink Research Award to allow for lead author Mona Kanso to travel between Canada and Japan and work more closely with OIST.

Researchers from University of British Columbia, Emory University, and New York University published a new paper in the Journal of Marketing that investigates the relationship between branding and counter-marketing in the cigarette industry.

The study, forthcoming in the Journal of Marketing, is titled "Investigating the Effects of Excise Taxes, Public Usage Restrictions, and Anti-Smoking Ads across Cigarette Brands" and is authored by Yanwen Wang, Michael Lewis, and Vishal Singh.

While the goal of marketing is usually to boost purchase rates and strengthen relationships between consumers and brands, counter-marketing is an increasingly common strategy for reducing the consumption of "vice" goods such as cigarettes. Counter-marketing activities may include excise taxes that increase consumer costs, usage constraints that restrict public consumption, and advertising that highlights product dangers. A notable feature of many vice categories is that they are dominated by very strong or high-equity brands such as Coca-Cola, McDonald's, Budweiser, and Marlboro.

The researchers assembled a data set that includes a consumer panel of cigarette purchases for a six-year period from 2005 to 2010, retail scanner data from 2006 to 2010, and a comprehensive data set on state-level cigarette taxes, state-level smoke-free restrictions, and national anti-smoking advertising campaigns. They modeled each smoker's monthly brand and quantity decisions and evaluated if and how cigarette excise taxes, smoke-free restrictions, and anti-smoking advertising campaigns influenced cigarette purchase decisions asymmetrically across a variety of brands and composites of brands based on price tier. The research also includes an analysis of tax passthrough, highlighting the role of brand positioning and channel characteristics.

Results show that the effects of anti-smoking interventions vary significantly across brands. Marlboro, the category leader, for example, is relatively less affected by tax increases, but relatively more affected by usage restrictions. The resistance to taxes is driven by Marlboro's ability to pass through less of the tax increases than most other brands. This effect may be due to market share based on economies of scale or distribution strength that leads retailers to limit price increases of their highest-volume brand. In the case of usage restrictions, results show that high-equity brands incur more negative effects. The researchers' speculation is that public prohibitions make it more difficult for consumers to garner symbolic or image-based benefits through consumption of high-equity brands. Regarding anti-smoking advertising, these communications have relatively little effect overall, but do have a slightly above-average impact on Marlboro.

Since cigarette excise taxes have almost doubled in the past ten years, these policy experiments may partially explain why Marlboro's market shares have increased in almost every state of the U.S. As Wang explains, "The findings highlight the importance of considering brand asymmetries when applying cigarette tax hikes and smoke-free restrictions. Strong brands such as Marlboro may be better able to resist tax hikes due to lower tax passthrough rates. However, removing public consumption options may reduce the stronger brands' value because consumers can no longer benefit from using them to project a public image."

A series of policy experiments assesses the differential effects of alternative counter-marketing policies across stakeholders including regulators, consumers, and brands. "We find that a 100% tax increase yields a 30% increase in quit rate, but it imposes significant costs to consumers and only increases tax receipts by about 28%. In contrast, an aggressive smoke-free policy increases quit rates by 9% and reduces tax revenues by 6%. With usage restrictions, consumers may experience inconvenience and reduced symbolic benefits but do not incur economic costs," says Lewis.

Overall, the simulations reveal important elements of the category structure for consumers, regulators, and brands. Increased taxes and smoke-free restrictions both decrease consumption and increase quit rates. However, taxes impose significant financial burdens on consumers while providing revenues to the government, whereas smoke-free restrictions lead to a loss in tax revenue, but do not impose economic costs on consumers. In terms of brands, stronger brands tend to gain share following tax hikes, but lose share due to smoke-free policies. The research does not find a readily identifiable pattern of the effects of anti-smoking advertising across brands. In general, these effects are small or insignificant.

Regarding other categories, Singh says that "While lessons learned from tobacco control efforts are also likely to be used when designing counter-marketing tactics in categories such as fast food or soda, these findings suggest that efforts to tax soda or fast food might result in increased market shares for high-equity brands. However, this is speculation, and additional research is needed."

Categories now targeted by anti-obesity groups include exceptionally powerful brands such as McDonald's and Coca-Cola. Public relations responses are just one option for brands facing counter-marketing. Relationships between consumers and relatively weak brands may be disrupted using taxes, while for strong brands, the appropriate tactic seems to be usage restrictions that limit public consumption. For companies in these categories, these results suggest that brand building is the correct response to taxes, while usage restrictions call for other responses, such as lobbying.

New UCLA research suggests that elderly patients of female physicians are more likely than those of male physicians in the same outpatient practice to be vaccinated against the flu.

This trend holds for all racial and ethnic groups studied and could provide insight into improving vaccination rates for influenza, COVID-19 and other illnesses, according to the research letter, which is published in the peer-reviewed JAMA Internal Medicine.

Prior studies have shown that female physicians tend to spend more time with their patients, said study author Dr. Dan Ly, an assistant professor in the division of general internal medicine and health services research at the David Geffen School of Medicine at UCLA.

"Now we're trying to vaccinate against COVID-19, and we will soon get to a point where most adults who want a vaccine will get it," Ly said. "We'll then need to reach those who need more convincing in order to be vaccinated, and my research suggests that perhaps this extra time spent may be helpful in getting these patients vaccinated.

"In general, flu vaccines are 40% to 60% effective. But COVID-19 vaccines are more than 90% effective, and even more so against severe disease," he said. "This means that the time spent to convince a patient to get vaccinated against COVID-19 is time well spent, not to mention the societal benefits coming from it."

People in some racial and ethnic groups, particularly Black people, are less likely to be vaccinated for a variety of complex reasons.

Ly examined Medicare claims data from 2006 through 2016 for both male and female beneficiaries age 65 years and older from four racial and ethnic groups: white, Black, Asian and Hispanic. The research sample about included approximately 40 million patient visits to about 150,000 female physicians and 300,000 male physicians.

Ly found that patients of female physicians were vaccinated at higher rates than those of male physicians across the board:

Among white men, the vaccination rate was 52.7% for those seen by female physicians, compared with 52.0% for male physicians. For white women, the rates were 54.6% (female physician) and 53.8% (male physician).

Rates for Black men were 39.8% vs. 38.1%; for Black women, 41.6% vs. 40.3%.

Among Asian men, rates were 56.8% vs. 54.7%; for Asian women, 56.4% vs. 55.7%.

For Hispanic man, rates were 48.9% vs. 47.3%; for Hispanic women, 50.6% vs. 49.1%.

Ly also found that female physicians were more likely than male physicians to get patients with more chronic conditions and co-mordibities vaccinated.

Overall, Black patients were about 14 percentage points less likely, and Hispanics 5 percentage points less likely, than whites to be vaccinated. Differences in vaccination rates between patients of female and male physicians, Ly found, represented 10% of the white-Black gap and about 30% of the white-Hispanic gap.

Differences in communication style between female and male physicians, which have been documented in previous studies, may also contribute to the differences vaccination rates, Ly noted.

A single footprint left by a cat-sized dinosaur around 100 million years ago has been discovered in China by an international team of palaeontologists.

University of Queensland researcher Dr Anthony Romilio was part of the team that investigated the track, originally found by Associate Professor Lida Xing from the China University of Geosciences (Beijing).

"This footprint was made by a herbivorous, armoured dinosaur known broadly as a stegosaur - the family of dinosaurs that includes the famed stegosaurus," Dr Romilio said.

"Like the stegosaurus, this little dinosaur probably had spikes on its tail and bony plates along its back as an adult.

"With a footprint of less than six centimetres, this is the smallest stegosaur footprint known in the world.

"It's in strong contrast with other stegosaur prints found at the Chinese track site which measured up to 30 centimetres, and prints found in places like Broome in Western Australia where they can be up to 80 centimetres."

The tiny footprint has similar characteristics of other stegosaur footprints with three short, wide, round toe impressions.

However researchers found the print wasn't elongated like larger counterpart prints discovered at the track sites, which suggests the young stegosaur had a different behaviour.

"Stegosaurs typically walked with their heels on the ground, much like humans do, but on all fours which creates long footprints," Dr Romilio said.

"The tiny track shows that this dinosaur had been moving with its heel lifted off the ground, much like a bird or cat does today.

"We've only previously seen shortened tracks like this when dinosaurs walked on two legs."

Associate Professor Xing said that it was plausible young stegosaurs were toe-walkers.

"This could be possible as this is the ancestral condition and a posture of most dinosaurs, but the stegosaur could also have transitioned to heel-walking as it got older," Dr Xing said.

"A complete set of tracks of these tiny footprints would provide us with the answer to this question, but unfortunately we only have a single footprint."

Finding the tiny tracks on crowded track sites will be challenging for the researchers.

"The footprints made by tiny armoured dinosaur are much rarer than those formed by other groups of dinosaurs," Associate Professor Xing said.

"Now that our study has identified nine different dinosaur track sites from this locality, we will look even closer to see if we can find more of these tiny tracks."

While Black, Hispanic, Latino, Indigenous, Asian and Pacific Islander people are more likely to die of COVID-19 than white people nationwide, a recent study from Oregon State University found the risk was even greater for racial and ethnic minority groups living in rural areas compared with urban areas.

To address the disparities, researchers say the health care response to COVID-19, including the vaccine rollout, needs to allocate additional resources to rural areas that have been hardest hit, especially those where minority populations are concentrated.

Earlier studies throughout the U.S. have shown that social determinants of health like poverty, access to reliable health care, chronic health conditions and type of occupation contribute to increased risk of COVID-19 infection and fatality for racial and ethnic minorities.

But living in a rural area on top of being a member of a racial minority group acts as a "double whammy," said Kwadwo Boakye, co-author on the study and a doctoral student focusing on epidemiology in OSU's College of Public Health and Human Sciences.

"It would not be ideal to say that 'rural versus urban' is a standalone thing. It has to be intertwined with the racial and ethnic disparity as well," to account for the disparate risk levels, Boakye said.

The study, published in the Journal of Racial and Ethnic Health Disparities, examined case fatality ratios during the period of Jan. 1 through Dec. 18, 2020. Researchers found that in that time, people living in "mostly rural" and "completely rural" counties who contracted COVID-19 were 15-26% and 15-24%, respectively, more likely to die from it than people in "mostly urban" counties who contracted the virus.

When researchers broke the results down by race, they found that the more rural a county was, as determined by census data, the higher the case-fatality ratio was for minority groups, especially for Black, Hispanic and Latino people. American Indian and Asian/Pacific Islander people also saw an increased case-fatality ratio in more rural counties.

In rural areas around the country, researchers noted that counties with larger percentages of Black, Hispanic/Latino and Asian/Pacific Islander people had clusters of higher COVID-19 case fatality.

"Generally, minorities are on the lower end of the spectrum for socioeconomic status. This may result in a need for them to work in occupations where they're in contact with a lot of other people, which puts them in more circumstances that are more prone to the spread of the virus," Boakye said.

In rural areas, most blue collar jobs are in agriculture, which means workers can't work from the safety of home during a pandemic, he said.

This study highlighted the impact that socioeconomic disparities and structural racism have had on health outcomes for racial and ethnic minorities over the decades, Boakye said.

"We are seeing with the COVID pandemic that minorities are at a larger risk of getting the disease, and also have a higher risk of mortality from the disease compared to other ethnic groups," he said.

"Compare living in a rural area, where you don't have a state-of-the-art medical facility with plenty of ventilators, to someone who is living in the city, who has access to all those facilities. We need health care facilities in these rural areas," Boakye said. "Policies should prioritize rural health and the adequate distribution of health resources to meet the needs of the minority populations, especially the distribution of COVID-19 vaccinations."

The researchers added that they were limited by the census data available; if they had been able to parse the numbers on an individual level, rather than aggregate, they could have obtained more specific results.

Prime editing (PE), a "search-and-replace" CRISPR-based genome editing technique, has great potential for gene therapy and agriculture. It can introduce desired base conversions, deletions, insertions, and combination edits into target genomic sites. Prime editors have been successfully applied in animals and plants, but their off-target effects, which can be a major hindrance to real-life application, have not been thoroughly evaluated until now.

Prof. GAO Caixia from the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences (CAS) and her research team recently performed a comprehensive and genome-wide analysis of the off-target effects of PEs in rice plants.

Off-target effects are in principle of two types: guide RNA (gRNA)-dependent and gRNA-independent. The first result from similarities between target and off-target sequences and the second from the activity of CRISPR-based tools, such as deaminase, at non-target positions in the genome.

The researchers first measured editing frequencies using pegRNAs with primer binding sites (PBSs) or spacers containing mismatches of the chosen target sequence, and found that mismatches located in seed sequence regions of the spacer (near the PAM) and near the nicking site of nCas9 (H840A) at the PBS greatly reduced the frequency of PE implying high editing specificity. They also evaluated the frequencies of editing by 12 pegRNAs at 179 endogenous off-target sites containing mismatches, and confirmed that editing rates were extremely low (0.00%~0.23%). Thus, designing pegRNAs with homology to fewer off-target sites is necessary.

The gRNA-independent effects induced by ectopic expression of functional elements in the CRISPR-based tools (which have been detected with some base editors) are not predictable by in silico methods. Gao et al. therefore used whole-genome sequencing to investigate whether ectopic expression of the prime editors induced undesired edits at the genome-wide level. They delivered PE constructs with or without pegRNA expression cassettes into rice calli via Agrobacterium-mediated transformation and obtained regenerated T0 plants (the PE group). They found the number of single nucleotide variants and indels (small insertions/deletions) in the PE group was not significantly higher than in the control group (expressing Cas9 nickase).

Moreover, mutation type analysis and mutation distribution analysis further demonstrated that the PE and control groups did not differ significantly. This result indicated that the PE system did not induce significant numbers of genome-wide pegRNA-independent off-target edits in plants.

Since M-MLV RT is a core element of the PE system, it seemed possible that overexpressing M-MLV RT might interfere with natural reverse transcription mechanisms in the cell. The researchers therefore evaluated the activities of retrotransposons and telomerase by analyzing the number of copies of the OsTos17 retrotransposon and the fidelity of telomeres, and found no effect of M-MLV reverse transcriptase on either parameter. They also evaluated the possibility that over-expression of RT might increase the risk of random reverse transcription of mRNAs and insertion of the products into the rice genome. Hence, they looked for pegRNA and mRNA insertions but detected no such events, further indicating that the M-MLV reverse transcriptase in PEs does not have nonspecific effects in plant cells. In summary, a systematic assessment demonstrated that prime editors are highly specific in plants.

It is an old-standing theory in evolutionary ecology: animal species on islands have the tendency to become either giants or dwarfs in comparison to mainland relatives. Since its formulation in the 1960s, however, the 'island rule' has been severely debated by scientists. In a new publication in Nature Ecology and Evolution on April 15, researchers solved this debate by analysing thousands of vertebrate species. They show that the island rule effects are widespread in mammals, birds and reptiles, but less evident in amphibians.

Dwarf hippos and elephants in the Mediterranean islands are examples of large species who exhibited dwarfism. On the other hand, small mainland species may have evolved into giants after colonizing islands, giving rise to such oddities as the St Kilda field mouse (twice the size of its mainland ancestor), the infamous dodo of Mauritius (a giant pigeon), and the Komodo dragon.

In 1973, Leigh van Valen was the first that formulated the theory, based on the study by mammologist J. Bristol Foster in 1964, that animal species follow an evolutionary pattern when it comes to their body sizes. Species on islands have the tendency to become either giants or dwarfs in comparison to mainland relatives. "Species are limited to the environment on an island. The level of threat from predatory animals is much lower or non-existent", says Ana Benítez-Lopez, who carried out the research at Radboud University, now researcher at Doñana Biological Station (EBD-CSIC, Spain). "But also limited resources are available." However, until now, many studies showed conflicting results which led to severe debate about this theory: is it really a pattern, or just an evolutionary coincidence?

Island rule confirmed

The team of scientists at Radboud University, Doñana Biological Station, National Museum of Natural Sciences and Imperial College London has revisited the island rule, aiming to solve this debate by performing a meta-analysis of over a thousand vertebrate species. They show that island rule effects are widespread in mammals, birds and reptiles, but less evident in amphibians, which mostly tend towards gigantism. The study also indicates that the magnitude of insular dwarfism and gigantism is more pronounced in smaller, more remote islands for mammals and reptiles.

Size is context-dependent

They also found an effect of climate and seasonality on the island rule. Small mammal and bird species grew larger and large species stayed the same size to conserve heat in colder, harsher insular environments. Furthermore, when seasons are present, availability of resources become less predictable for reptiles, leading smaller reptile species to become larger. Benítez-López: "Using a wealth of data from museum and live specimens, we were able to rigorously demonstrate for the first time that insular gigantism and dwarfism across vertebrates is a generalized pattern and not just an evolutionary coincidence."

A past COVID-19 infection does not completely protect against reinfection in young people, according to an observational study of more than 3,000 healthy members of the US Marines Corps most of whom were aged 18-20 years, published in The Lancet Respiratory Medicine journal.

The authors say that despite previous infection and the presence of antibodies, vaccination is still necessary to boost immune responses, prevent reinfection, reduce transmission, and that young people should take up the vaccine wherever possible.

In the study, between May and November 2020, around 10% (19 out of 189) of participants who were previously infected with SARS-CoV-2 (seropositive) became reinfected, compared with new infections in 50% (1,079 out of 2,247) of participants who had not previously been infected (seronegative).

Although the study was in young, fit, mostly male Marine recruits, the authors believe that the risk of reinfection found in their study will apply to many young people, but that the exact rates of reinfections will not be applicable elsewhere (owing to the crowded living conditions on a military base and close personal contact required for basic training likely contributing to a higher overall infection rate than seen elsewhere). For example, a study of 4 million people in Denmark also found that the risk of infection was five times higher in people who had not before had COVID-19, but they found that only 0.65% of people who had COVID-19 during Denmark's first wave tested positive again during the second wave, compared with 3.3% of people who tested positive after initially being negative [1]. In addition, a preprint study including British healthcare workers found that those who had been not previously infected had a five times higher risk of being reinfected than people who had a past infection [2].

Professor Stuart Sealfon, of Icahn School of Medicine at Mount Sinai, USA, and senior author of the study, says: "As vaccine roll outs continue to gain momentum it is important to remember that, despite a prior COVID-19 infection, young people can catch the virus again and may still transmit it to others. Immunity is not guaranteed by past infection, and vaccinations that provide additional protection are still needed for those who have had COVID-19." [3]

In the study, US Marine Corps recruits completed an unsupervised quarantine at home for two weeks before entering a Marine-supervised quarantine facility for another two weeks. They received antibody tests to establish whether any of the recruits were seropositive (they had previously been infected with SARS-CoV-2 and had antibodies). They were also tested for new SARS-CoV-2 infection at baseline then weeks one and two of the quarantine, and completed a questionnaire including demographic information, risk factors, medical history, and COVID-19 symptoms. Participants were excluded from the study if they tested positive for COVID-19 via PCR test during their supervised quarantine. After quarantine, recruits who did not have COVID-19 entered basic training and were tested for new SARS-CoV-2 infection by PCR tests every two weeks, for six weeks and completed follow up questionnaires about any COVID-19 symptoms.

Recruits who tested positive for a new second COVID-19 infection during the study were isolated and the study team followed up with additional testing. Levels of neutralising antibodies were also taken from subsequently infected seropositive and selected seropositive participants who were not reinfected during the study period.

Of the 2,346 Marines followed long enough for this analysis of reinfection rate, 189 were seropositive and 2,247 were seronegative at the start of the study. Across both groups of recruits, there were 1,098 (45%) new infections during the study. Among the seropositive participants, 19 (10%) tested positive for a second infection during the study. Of the recruits who were seronegative, 1,079 (48%) became infected during the study.

To understand why these reinfections occurred, the authors studied the reinfected and not infected participants' antibody responses. They found that, among the seropositive group, participants who became reinfected had lower antibody levels against the SARS-CoV-2 virus than those who did not become reinfected. In addition, in the seropositive group, neutralising antibodies were less common (neutralising antibodies were detected in 45 (83%) of 54 uninfected, and in six (32%) of 19 reinfected participants during the six weeks of observation).

Comparing new infections between seropositive and seronegative participants, the authors found that viral load (the amount of measurable SARS-CoV-2 virus) in reinfected seropositive recruits was on average only 10 times lower than in infected seronegative participants, which could mean that some reinfected individuals could still have a capacity to transmit infection, but the authors note that this will need further investigation.

In the study, most new COVID-19 cases were asymptomatic - 84% (16 out of 19 participants) in the seropositive group vs 68% (732 out of 1,079 participants) in the seronegative group - or had mild symptoms, and none were hospitalised.

Lt. Dawn Weir, of the Navy Medical Research Centre, USA, says: "Our study shows that some individuals with lower levels of neutralizing antibodies were reinfected, indicating that it is possible that previously infected and recovered people are susceptible to new SARS-CoV-2 infection at a later time. These reinfections may be asymptomatic, as observed in the majority of our participants. This is an important consideration for maintaining U.S. military operational readiness, such as preventing future COVID-19 outbreaks among Marine units or aboard Navy ships. The takeaway message for all young people, including our military service members, is clear - immunity resulting from natural infection is not guaranteed; you still need to be vaccinated even if you have had COVID-19 and recovered." [3]

The authors note some limitations to their study, including that it likely underestimates the risk of reinfection in previously infected individuals because it does not account for people with very low antibody levels following their past infection (in the study there were an unknown number of people in the seronegative group who had previously been infected but who did not have detectable levels of antibodies in their baseline antibody level test).

In the study there was a higher than usual drop-out rate of participants (a total of 566 participants - 34 recruits in the baseline seropositive group and 532 recruits in the baseline seronegative group - who began basic training and did not report for follow up two-weeks later). The study team were not told why any recruit did not return for follow up, but say that this could be a combination of individuals dropping out of the study, those who are transferred off the base for medical reasons, or who were separated from the US Marine Corps.

Lastly, the authors were unable to determine how seropositive recruits contracted their previous SARS-CoV-2 infection and confirm it by PCR test or determine how severe it was and what symptoms they had. They say they also could have missed detectable infections that occurred between the PCR testing every 2 weeks during the study.

Writing in a linked comment, María Velasco of Hospital Universitario Fundación Alcorcón, Spain, said: "This study was conducted in a closed setting but provides some interesting insights regarding the risk of subsequent SARS-CoV-2 infection in the general population or other settings. First, the rate of new SARS-CoV-2 PCR positive results is about 80% lower among seropositive individuals. These data confirm that seropositive individuals have a significant albeit limited protection for new infections [...] Second, the rate of new SARS-CoV-2 PCR detection among seropositive Marines cases is not negligible (1·1 cases per person-year), even in the young and healthy population. Globally, these results indicate that COVID-19 does not provide an almost universal and long-lasting protective immunity such as measles."

She continued: "Efforts must be made to reduce the risk of SARS-CoV-2 transmission from young oligosymptomatic individuals. Results from Letizia et al. suggest that even young individuals with a previous SARS-CoV-2 infection should also be a target of vaccination to avoid a poorly noticed source of transmission."

A number of SARS-CoV-2 variants have emerged from immunocompromised hosts, research has identified. It is thought that variants of concern - including B.1.1.7, a variant first identified in Kent - were a result of long-term infection in people with a weakened immune system.

Persistent infections in immunocompromised people could cause the virus to mutate more frequently because the person's immune system cannot clear the virus as quickly as the immune system of a healthy person.

Authors Professor Wendy Barclay, Dr Thomas Peacock, Professor Julian Hiscox and Rebekah Penrice-Randal explain the importance of monitoring genetic changes in SARS-CoV-2 for future control of the virus: "As more and more variants appear, we are getting a better picture of their shared similarities and differences and can better predict what other new variants will look like. Putting all this information together will also help us design booster vaccines that protect against as many variants as possible or design targeted diagnostics" they said.

Their review discusses where mutations have occurred, what part of the virus they affect and how the resulting variants could impact vaccination efforts. According to the authors, mutations in SARS-CoV-2 are expected, as the virus is adapting to humans. "Sequencing of human seasonal coronaviruses has not been done on a scale like SARS-CoV-2, particularly when they would have initially spread into humans. SARS-CoV-2 is at the start of its journey in humans whereas other human coronaviruses have been around, in some cases, for many decades" they said.

Variants with the same or similar mutations have emerged independently in different countries: "SARS-CoV-2 is probably still finding its way in humans in terms of optimal infection and transmission. The scale of the outbreak and the massive sequencing efforts will identify concurrent mutations; basically, the virus is undergoing the same types of selection pressures wherever you are in the world, and the outbreak was all seeded by the same original virus," explained the authors.

Mutations of particular interest include those in the spike protein. This protein allows the virus to enter host cells and is the main target of the immune system, including immunity generated by all current SARS-CoV-2 vaccines.

Mutations in the gene that codes for spike could change the shape of the protein, allowing it to no longer be recognised by the immune system. Because this protein is so important for SARS-CoV-2 entry, favourable mutations are more likely to succeed and create new, dominant variants of the virus.

Changes that give the virus an advantage can quickly become dominant. For example, one mutation, named D614G, was found in 80% of SARS-CoV-2 viruses sequenced just four months after it was first detected. Now, viruses without the D614G mutation are only commonly seen in parts of Africa.

Another mutation, N501Y, is found in the SARS-CoV-2 variant B.1.1.7. This mutation is believed to be the result of infection of an immunocompromised individual and may contribute to the virus being more contagious. Infections with this variant have a higher fatality rate. In the UK, B.1.1.7 became the dominant variant within three months and is now responsible for over 90% of infections there.

Significant spike protein mutations discussed in the review include:

D614G:

In February 2020, a mutation was detected in the spike protein of SARS-CoV-2 and named D614G. This mutation was found to makes SARS-CoV-2 more infectious, however does not make the virus more harmful. This increase in infectivity led to a significant fitness advantage and within four months, 80% of SARS-CoV-2 viruses sequenced around the world were found to have the mutation. Now, only parts of Africa have circulating viruses without the D614G mutation.

Despite initial concerns, D614G does not have an effect on vaccine efficiency and in some cases, viruses with the D614G mutation are more readily cleared by antibodies against SARS-CoV-2.

Y435F:

In mid-2020, reports of mink becoming infected by humans became frequent. In mink, the spike protein of the virus commonly developed two mutations called Y435F and N501T. These mutations allow for stronger binding of the virus to human receptor cells. Viruses with these mutations were found in a cluster of human infections in Denmark, believed to have originated from mink. Concerningly, this variant was able to infect people who had previously been infected with SARS-CoV-2 and were thought to have some immunity to the virus. As a result, 17 million mink were culled.

The mutation Y435F has also been reported to have developed in an immunocompromised person, possibly as a result of chronic infection with the virus allowing it to adapt.

N501Y:

In December 2020, a highly transmissible variant of the virus was isolated in Kent, UK. This variant, named B.1.1.7, contained a mutation in the spike protein called N501Y. Not only does this mutation make the virus more contagious, but it was also found to have a higher fatality rate. In the UK, B.1.1.7 is now the dominant variant, and is responsible for over 90% of infections.

The mutation N501Y has been found to have little effect on immunity from both vaccines and previous infections.

E484K:

The spike protein mutation E484K has emerged in recent months, once in South Africa and at least twice in Brazil. Variants with the mutation of E484K are able to evade the immune system of both vaccinated and previously infected individuals.

It is thought that this mutation was driven by high levels of population immunity, which drove mutations in the spike protein to evade the immune system. In Brazil, there have been several reports of healthcare workers and other people with antibodies against SARS-CoV-2 being reinfected with variants with the E484K mutant, raising concerns about vaccine protection against this variant.

The review also examines mutations which make changes to other parts of the virus, such as ORF8, an accessory protein that is thought to supress the host immune system. Viruses with a deletion in the gene that encodes for ORF8 has been found to cause less severe clinical disease.

The authors of the review have called for increased global efforts to monitor SARS-CoV-2 mutations. Currently the United Kingdom and Denmark perform disproportionately high sequencing of the SARS-CoV-2 genome. Regular monitoring of the virus allows early identification of emerging variants and allows researchers to identify the associated mutations.

"Although the genomic surveillance in Europe and the USA is fairly strong it is becoming clear there are large areas of the world that we simply have no idea what variants are circulating. These are starting to appear in Europe as imports or community outbreaks. Better surveillance across a broader range of countries would allow us to better risk assess what the next stage of the pandemic might look like," said the authors. "If we want to monitor the ongoing emergence, spread, and import of potential vaccine escape mutants we have to continue this effort or risk further pandemic waves and vaccine failure. Furthermore, understanding the genomic epidemiology of the virus as early as possible will allow us to rapidly develop updated vaccine boosters."

Professor Alain Kohl, Deputy Editor-in-Chief of the Journal of General Virology said "The emergence of SARS-CoV-2 variants is one of the great challenges in the ongoing pandemic. This review article summarises our current knowledge and understanding of the evolution of the virus, as well as the consequences - for example in terms of vaccination. It is of great interest to anyone wishing to learn more about the history of this virus and what the future may hold."