The Norwegian mountains can be pretty darn inhospitable during the colder months. Nevertheless, there are plants that cope splendidly with the biting temperatures. They include the dwarf birch Betula nana and the black crowberry Empetrum hermaphroditum. Both thrive in arctic-alpine conditions; this makes them typical representatives of tundra vegetation.

Up until now, it has been unclear how the growth of dwarf birch and crowberry is influenced by specific environmental conditions. In the alpine regions of Norway, a project has been underway for 30 years that aims to change that. “We wired up some of the plants here and fitted them with so-called data loggers that record the measurements,” explains Prof. Dr. Jörg Löffler from the Department of Geography at the University of Bonn. A pin-like sensor records the diameter of the trunk — minute by minute, 365 days a year, to an accuracy of less than a thousandth of a millimeter. At the same time, the researchers measure solar radiation, temperature in the root zone and just above the soil surface, and soil moisture.

Shrinkage against frost damage

In the current study, researchers analyzed nearly 500 million measurements from 40 plants between 2015 and 2019. “We mainly studied how the microclimate, that is, the conditions encountered by the individual plant, affects its growth,” says Svenja Dobbert, who is doing her doctorate in Prof. Löffler’s research group. This revealed a striking rhythm in both dwarf birch and crowberry: During the colder months, their trunk diameter shrank significantly in each case — a process that was reversed in the spring. However, it was not until late summer that the deficits were made up to such an extent that actual growth began.

“Due to low temperatures in the colder months, there is hardly any liquid water available for the plants,” Dobbert says, explaining the finding. “They also reduce their trunk diameter by even actively reducing the water content of their cells to avoid frost damage.” Just how important this strategy is for both species to thrive is demonstrated by another observation: Plants that shrank very little during the winter often showed little or no growth the following summer.

A second important finding: The deciduous dwarf birches usually grew better after a mild winter. They therefore seem to generally benefit from warmer winters. With the evergreen crowberries it was the other way around. “In cold winters, there is usually less snowfall,” Löffler says. “This could be an advantage for evergreen species because they can then keep up photosynthetic activity for longer and hence enter the growth phase earlier in the spring.” It is therefore possible that climate change is causing an increasing spread of deciduous species and a concomitant displacement of evergreen species. Since the leaves of deciduous plants have a comparatively large surface area (in contrast, those of evergreen species are usually needle-like), this effect could contribute to the further greening of arctic-alpine regions.

The microclimate is crucial

“However, our results also show that microclimatic conditions can be extremely different depending on the location,” explains Löffler. For instance, at exposed, windy locations, snow cover tends to be very thin. The deciduous dwarf birch however requires a sufficiently thick insulating layer of snow in winter. It then has to use fewer resources to protect itself from frost. Without this warming blanket, the dwarf birch has a difficult time. The evergreen crowberry, in contrast, benefits from the extra sunlight during such snow-free periods. “Overall, our measurements prove that global climate data provide little valid evidence for local vegetation effects,” emphasizes the geographer. “Studies like ours can potentially help us better model such complex effects and in turn better predict the effects of climate change on plant life.”

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In people with type 2 diabetes, the body no longer efficiently uses insulin to control blood sugar. Dipeptidyl peptidase-4 inhibitors, also known as gliptins, can be prescribed when other diabetes drugs do not work. They help control blood sugar when combined with diet and exercise.

“People with diabetes have been shown to have a higher risk of Alzheimer’s disease, possibly due to high blood sugar levels, which have been linked to the buildup of amyloid beta in the brain,” said study author Phil Hyu Lee, MD, PhD, of Yonsei University College of Medicine in Seoul, South Korea. “Not only did our study show that people taking dipeptidyl peptidase-4 inhibitors to lower blood sugar levels had less amyloid in their brains overall, it also showed lower levels in areas of the brain involved in Alzheimer’s disease.”

The study involved 282 people with an average age of 76 who were followed up to six years. All had been diagnosed with either pre-clinical, early or probable Alzheimer’s disease. Of the group, 70 people had diabetes and were being treated with dipeptidyl peptidase-4 inhibitors, 71 had diabetes but were not being treated with the drugs and 141 did not have diabetes. Those without diabetes were matched to those with diabetes for age, sex, and education levels. All had similar scores on cognitive tests at the start of the study.

Participants had brain scans to measure the amount of amyloid in the brain.

Researchers found that people with diabetes who took the drugs had lower average amounts of amyloid plaques in the brain compared to people with diabetes who did not take the drugs and compared to people who did not have diabetes.

All participants took a common thinking and memory test called the Mini-Mental State Exam (MMSE) on average, every 12 months for 2.5 years. Questions include asking a person to count backward from 100 by sevens or copying a picture on a piece of paper. Scores on the test range from zero to 30.

Researchers found that people with diabetes who took the drugs had an average annual decline of 0.87 points on their MMSE score, while people with diabetes who did not take the drugs had an average annual decline of 1.65 points. People without diabetes scored an average annual decline of 1.48 points.

When researchers adjusted for other factors that could affect test scores, they found that the scores of the people taking the drug declined by 0.77 points per year more slowly than the people who did not take the drug.

“Our results showing less amyloid in the brains of people taking these medications and less cognitive decline, when compared to people without diabetes raises the possibility that these medications may also be beneficial for people without diabetes who have thinking and memory problems,” said Lee. “More research is needed to demonstrate whether these drugs may have neuroprotective properties in all people.”

A limitation of the study was that data were not available to show the accumulation of amyloid in participants’ brains over time. This study does not show cause and effect. It only shows an association.

The study was supported by the Korean Healthy Industry Development Institute and the Korean Ministry of Health & Welfare.

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Materials provided by American Academy of Neurology. Note: Content may be edited for style and length.

“Malaria continues to be a major cause of illness and death in many regions of the world, especially in infants and young children; therefore, new tools are needed to prevent this deadly disease,” said NIAID Director Anthony S. Fauci, M.D. “The results reported today suggest that a single infusion of a monoclonal antibody can protect people from malaria for at least 9 months. Additional research is needed, however, to confirm and extend this finding.”

According to the World Health Organization, an estimated 229 million cases of malaria occurred worldwide in 2019, resulting in an estimated 409,000 deaths, mostly in children in sub-Saharan Africa. So far, no licensed or experimental malaria vaccines provide more than 50% protection from the disease over the course of a year or longer.

Malaria is caused by Plasmodium parasites, which are transmitted to people through the bite of an infected mosquito. The mosquito injects the parasites in a form called sporozoites into the skin and bloodstream. These travel to the liver, where they mature and multiply. Then the mature parasite spreads throughout the body via the bloodstream to cause illness. P. falciparum is the Plasmodium species most likely to result in severe malaria infections, which, if not promptly treated, may lead to death.

Laboratory and animal studies have demonstrated that antibodies can prevent malaria by neutralizing the sporozoites of P. falciparum in the skin and blood before they can infect liver cells. The NIAID trial tested whether a neutralizing monoclonal antibody called CIS43LS could safely provide a high level of protection from malaria in adults following careful, voluntary, laboratory-based exposure to infected mosquitos in the United States.

CIS43LS was derived from a naturally occurring neutralizing antibody called CIS43. Researchers led by Robert A. Seder, M.D., chief of the Cellular Immunology Section of the VRC Immunology Laboratory, isolated CIS43 from the blood of a volunteer who had received an investigational malaria vaccine. The scientists found that CIS43 binds to a unique site on a parasite surface protein that is important for facilitating malaria infection and is the same on all variants of P. falciparum sporozoites worldwide. The researchers subsequently modified this antibody to extend the amount of time it would remain in the bloodstream, creating CIS43LS.

After animal studies of CIS43LS for malaria prevention yielded promising results, VRC investigators launched a Phase 1 clinical trial of the experimental antibody with 40 healthy adults ages 18 to 50 years who had never had malaria or been vaccinated for the disease. The trial was led by Martin Gaudinski, M.D., medical director of the VRC Clinical Trials Program, and was conducted at the NIH Clinical Center in Bethesda, Maryland, and the Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Maryland.

During the first half of the trial, the study team gave 21 participants one dose of CIS43LS by either an intravenous infusion or an injection under the skin. The infusions ranged from 5 to 40 milligrams per kilogram (mg/kg) of body weight, and the subcutaneous injections were 5 mg/kg. Investigators followed the participants for 6 months to learn whether the infusions and subcutaneous injections of the various doses of the experimental antibody were safe and well tolerated. In addition, they measured the amount of CIS43LS in the blood to determine its durability over time.

In the second half of the trial, six participants who had received an intravenous infusion during the first half of the trial continued to participate. Four of these participants received a second antibody infusion while the other two did not. In addition, four new participants joined the study and received a single intravenous infusion of CIS43LS. Another seven people joined the study as controls who did not receive the antibody.

All participants in the second half of the trial provided informed consent to be exposed to the malaria parasite in what is known as a controlled human malaria infection (CHMI). In this procedure, volunteers are exposed to P. falciparum through bites of infected mosquitos in a carefully controlled setting, then are closely monitored by medical staff for several weeks and promptly treated if they develop malaria. CHMI has been used for decades to generate information about the safety and protective effect of malaria vaccine candidates and potential antimalarial drugs.

Nine participants who had received CIS43LS and six participants who served as controls voluntarily underwent CHMI and were closely monitored for 21 days. Within that period, none of the nine participants who had received CIS43LS developed malaria, but five of the six controls did. The participants with malaria received standard therapy to eliminate the infection.

Among the nine participants who received CIS43LS and were protected, seven underwent CHMI approximately 4 weeks after their infusion. The other two participants had received their sole infusion during the first half of the study and were infected approximately 9 months later. These results indicate that just one dose of the experimental antibody can prevent malaria for 1 to 9 months after infusion. Collectively, these data provide the first evidence that administration of an anti-malaria monoclonal antibody is safe and can prevent malaria infection in humans.

To build on this finding, a larger Phase 2 clinical trial is underway in Mali to evaluate the safety and efficacy of CIS43LS at preventing malaria infection in adults during a six-month malaria season. The trial is being led by Peter D. Crompton, M.D., M.P.H., chief of the Malaria Infection Biology and Immunity Section in the NIAID Laboratory of Immunogenetics, and Kassoum Kayentao, M.D., M.P.H., Ph.D., a professor at the University of Sciences, Techniques and Technologies of Bamako, Mali. NIAID is sponsoring and funding the trial. Results are expected in early 2022.

In addition, VRC scientists are conducting further research on CIS43LS in the United States to determine the lowest dose that protects people from malaria infection.

“Monoclonal antibodies may represent a new approach for preventing malaria in travelers, military personnel and health care workers traveling to malaria-endemic regions,” said Dr. Seder. “Further research will determine whether monoclonal antibodies can also be used for the seasonal control of malaria in Africa and ultimately for malaria-elimination campaigns.”

For more information about the completed Phase 1 trial, please go to ClinicalTrials.gov and search under study identifier NCT04206332. For information about the ongoing Phase 2 trial in Mali, please go to ClinicalTrials.gov and search under study identifier NCT04329104.

Reference: MR Gaudinski et al. A monoclonal antibody for malaria prevention. New England Journal of Medicine DOI: 10.1056/NEJMoa2034031 (2021).

“We knew from previous studies, that two doses were not enough to produce a good immune response against COVID-19 in transplant patients,” says Dr. Deepali Kumar, Director of Transplant Infectious Diseases, UHN and joint-Senior Author of the study published today in the New England Journal of Medicine.

“Based on our study, a third dose of COVID vaccine is definitely the best way to increase protection in transplant recipients.”

The study enrolled 120 transplant patients between May 25^th and June 3^rd. None of them had COVID previously and all of them had received two doses of the Moderna vaccine. Half of the participants received a third shot of the vaccine (at the 2-month mark after their second dose) and the other half received placebo.

The primary outcome was based on antibody level greater than 100 U/ml against the spike protein of the virus. In the placebo group — after three doses (where the third dose was placebo), the response rate was only 18% whereas in the Moderna three-dose group, the response rate was 55%.

“This is an important win for our patients because the results are quite conclusive,” says Dr. Atul Humar, Medical Director of the Ajmera Transplant Centre, UHN and the joint-Senior Author of the clinical trial. “The third dose was safe and well tolerated and should lead to a change in practice of giving third doses to this vulnerable population.”

Neutralizing antibodies and T-cell response

In addition to its primary outcome, this study also looked at the effectiveness of neutralizing antibodies — antibodies that neutralize the virus — and in this case, 60% of the patients in the Moderna group developed neutralizing antibodies versus 25% in the placebo group.

The study also found a big difference in T-cell response between the two groups. T-cells are another arm of the immune system that functions to prevent severe disease, and there was a substantial improvement in the ability of the three-dose Moderna group to allow the patients to develop a robust T-cell response against the virus.

The randomized double-blind placebo-controlled study is considered the gold standard in medicine, for showing whether something truly works or not. This study showed a definitively positive response in both major arms of the immune system: the antibody arm and the T-cell arm.

Additionally, the third booster vaccine was very well tolerated with only mild side effects and did not cause acute organ rejections — an important finding, as there were concerns that repeated vaccinations could increase the incidence of organ rejection in transplant recipients.

Fast-tracking science amid a pandemic

Normally a study of this kind would take at least one year, but the team at the Ajmera Transplant Centre executed a rigorous and successful protocol in just a few months.

“We were able to do this because our team worked non-stop for months,” says Dr. Humar. “And we are in a global emergency, lucky enough to have generous philanthropic donors and an existing vaccine trials infrastructure already set up.”

The results have been shared with regulatory bodies and decision-makers including the United States Food and Drug Administration (FDA), The Canadian National Advisory Committee on Immunization (NACI), the American Society of Transplantation, and others. The research team hopes for an expedited approval to benefit as many transplant patients as possible.

Funding and next steps

Research into the effectiveness of COVID-19 vaccines in transplant recipients has recently received a boost in funding for a national study. The Government of Canada, through its COVID-19 Immunity Task Force (CITF) and Vaccine Surveillance Reference Group (VSRG), is investing over $2.8 million so that Dr. Kumar’s team can further study the effectiveness of COVID vaccines across multiple transplant centres in Canada.

“Our goal is to help coordinate the efforts of provincial and national organizations that are involved in public health and vaccination research and facilitate information sharing among public health agencies and patient partners,” says Dr. Kumar.

This work was supported by the UHN Ajmera Transplant Centre, the Di Poce Transplant Fund, and by the generous donors of UHN Foundation.

Mast cells regulate immune responses. But too many mast cells can result in a number of diseases, the most serious of which are mast cell leukemia and mast cell sarcoma. A gene known as c-KIT produces a protein, KIT, which is associated with mast cell survival and proliferation. C-KIT mutations can increase proliferation of mast cells in multiple organs, leading to mast cell cancers.

“Current treatments for mast cell cancers target signaling from the receptor encoded by the c-KIT gene, and the efficacy of current therapies can be negatively affected by c-KIT mutations associated with disease development,” says Glenn Cruse, assistant professor of immunology at North Carolina State University and corresponding author of the research. “We are targeting the gene itself, regardless of mutation. If we target the gene that drives progression, then we can target the disease.”

Cruse and a team of researchers from NC State and the National Institutes of Health (NIH) used a technique known as exon skipping to produce the frameshift mutation.

Before a gene or protein is produced, the pre-mRNA, which is composed of both coding and non-coding regions called exons and introns, is spliced so that introns are removed and only the exons — a gene’s “production instructions” — remain. The resulting mature mRNA then delivers its instructions and the gene or protein is produced. If something goes wrong or a mutation occurs, a stop codon — a short sequence in the mRNA — stops production of the faulty protein by causing that strand of the mRNA to be degraded or destroyed.

The researchers used this mechanism to their advantage by binding a short RNA molecule called an oligonucleotide to exon 4 within the c-KIT pre-mRNA, effectively fooling the splicing proteins into thinking the exon was an intron, and removing it. The missing, or skipped, exon creates a frameshift in the reading frame of the mRNA, causing it to be recognized as a mutant and degraded.

“We are altering the message that makes the protein — flipping an ‘on’ switch to ‘off,'” Cruse says. “If you get mRNA to produce a protein that is mutated and severely truncated, your cell will recognize that and degrade the message so that the protein isn’t produced.”

The researchers used their frameshifted c-KIT mRNA approach on mast cell leukemia cells in vitro and found that KIT protein expression, signaling and function were reduced. The cancer cells stopped proliferating and began dying within hours. In a mouse model, tumor growth and infiltration of other organs were reduced and tumor cell death increased when the frameshifted c-KIT mRNA was induced.

“The other advantage to our technique is that it solves the problem of degradation evasion,” Cruse says. “Occasionally faulty messages will evade degradation and their mutated proteins get produced anyway. But proteins produced by the frameshifted c-KIT mRNA are inert, or non-functional. So even if they get produced, they cannot cause more harm.”

The research appears in Molecular Therapy and is supported by the National Institutes of Health. NC State postdoctoral researcher Douglas Snider is first author. The technology described in the paper has been licensed by Hoth Therapeutics.

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Materials provided by North Carolina State University. Original written by Tracey Peake. Note: Content may be edited for style and length.

Initial energy

“We need to see these electrons at their initial energy rather than when they are fully grown and moving at near the speed of light,” said PPPL physicist Luis Delgado-Aparicio, who led the experiment that detected the early runaways on the Madison Symmetric Torus (MST) at the University of Wisconsin-Madison. “The next step is to optimize ways to stop them before the runaway electron population can grow into an avalanche,” said Delgado-Aparicio, lead author of a first paper that details the findings in the Review of Scientific Instruments.

Fusion reactions produce vast amounts of energy by combining light elements in the form of plasma — the hot, charged state of matter composed of free electrons and atomic nuclei that makes up 99 percent of the visible universe. Scientists the world over are seeking to produce and control fusion on Earth for a virtually inexhaustible supply of safe and clean power for generating electricity.

PPPL collaborated with the University of Wisconsin to install the multi-energy pinhole camera on MST, which served as a testbed for the camera’s capabilities. The diagnostic upgrades and redesigns a camera that PPPL had previously installed on the now-shuttered Alcator C-Mod tokamak at the Massachusetts Institute of Technology (MIT), and is unique in its ability to record not only the properties of the plasma in time and space but its energy distribution as well.

That prowess enables researchers to characterize both the evolution of the superhot plasma as well as the birth of runaway electrons, which begin at low energy. “If we understand the energy content I can tell you what is the density and temperature of the background plasma as well as the amount of runaway electrons,” Delgado Aparicio said. “So by adding this new energy variable we can find out several quantities of the plasma and use it as a diagnostic.”

Novel camera

Use of the novel camera moves technology forward. “This certainly has been a great scientific collaboration,” said physicist Carey Forest, a University of Wisconsin professor who oversees the MST, which he describes as “a very robust machine that can produce runaway electrons that don’t endanger its operation.”

As a result, Forest said, “Luis’s ability to diagnose not only the birth location and initial linear growth phase of the electrons as they are accelerated, and then to follow how they are transported from the outside in, is fascinating. Comparing his diagnosis to modeling will be the next step and of course a better understanding may lead to new mitigation techniques in the future.”

Delgado-Aparicio is already looking ahead. “I want to take all the expertise that we have developed on MST and apply it to a large tokamak,” he said. Two post-doctoral researchers who Delgado-Aparicio oversees can build upon the MST findings but at WEST, the Tungsten (W) Environment in Steady-state Tokamak operated by the French Alternative Energies and Atomic Energy Commission (CEA) in Cadarache, France.

“What I want to do with my post-docs is to use cameras for a lot of different things including particle transport, confinement, radio-frequency heating and also this new twist, the diagnosis and study of runaway electrons,” Delgado-Aparicio said. “We basically would like to figure out how to give the electrons a soft landing, and that could be a very safe way to deal with them.”

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Materials provided by DOE/Princeton Plasma Physics Laboratory. Original written by John Greenwald. Note: Content may be edited for style and length.