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PHILADELPHA--Inflammation in the blood could serve as a new biomarker to help identify patients with advanced pancreatic cancer who won't respond to the immune-stimulating drugs known as CD40 agonists, suggests a new study from researchers in the Abramson Cancer Center of the University of Pennsylvania published in JCI Insight

It is known that pancreatic cancer can cause systemic inflammation, which is readily detectable in the blood. The team found that patients with systemic inflammation had worse overall survival rates than patients without inflammation when treated with both a CD40 agonist and the chemotherapy gemcitabine.

The purpose of CD40 agonists is to help "push the gas" on the immune system both by activating antigen-presenting cells, such as dendritic cells, to "prime" T cells and by enhancing anti-tumor macrophage activity. However, CD40 agonist-combination approaches only shrink tumors in a little more than half of patients, past studies have shown. Now, identifying systemic inflammation as a mechanism of resistance could help guide treatment decisions and future studies, as well as offer up new targets for researchers to explore.

"CD40 is a really exciting target, especially in pancreatic cancer, where agonistic monoclonal antibodies have shown a lot of promise, but we know that these agonists still face obstacles in certain patients that weaken the drug's intended effects," said lead author Max M. Wattenberg, MD, a clinical instructor of Medicine in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania. "We believe we have not only identified a potentially robust biomarker, but also important players in the immune system we didn't see before that may drive mechanisms of resistance."

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and currently the third leading cause of cancer deaths in the United States. Despite the fact that it only accounts for about three percent of new cancer cases, it is responsible for more than seven percent of all cancer deaths, and just 10 percent of patients survive five years with the disease.

The researchers analyzed blood samples from 22 patients with PDAC to gain insight into the immunological mechanisms underway after treatment with chemoimmunotherapy. The team observed a depletion of B cells, monocytes, and dendritic cells as well as activation of CD4+ T cells over eight days in most patients. Surprisingly, a closer look revealed no consistent evidence of CD8+ cell activation and no association between T cell activation and outcomes. These findings challenge preclinical studies that have suggested that T cell activation sparked by CD40 agonists would associate with outcomes.

Rather, overall survival outcomes were associated with a measurable characteristic in the patients' blood found before treatment: systemic inflammation. Systemic inflammation is marked by the increased presence of neutrophils, inflammatory cytokines (including IL-6 and IL-8) and acute phase reactants in the peripheral blood, and is a known symptom of pancreatic cancer and other cancer types.

Patients with systemic inflammation before treatment with a CD40 agonist and gemcitabine, the authors report, had a median overall survival of 5.8 months versus 12.3 months for patients without inflammation from the start of treatment.

Also surprising, the data suggest that gemcitabine chemotherapy may eliminate monocytes and dendritic cells, which are fundamental to facilitating T cell immune responses. However, the team has previously shown that a CD40 agonist can sensitize PDAC to gemcitabine chemotherapy, and thus, T cells may not always be needed for successful outcomes with treatment using CD40 agonists in combination with chemotherapy.

"These latest findings support the fact that inflammation seems to place the immune system at a disadvantage and in doing so prevents the ability of immune therapies to work," said senior author Gregory L. Beatty, MD, PhD, an associate professor of Hematology-Oncology at Penn's Perelman School of Medicine. "Next, we're interested to learn how to pair a T cell immune response with a CD40 agonist, so we are studying combinations that will help make the inflammatory response less suppressive and the components of the immune system more capable of triggering a T-cell response."

This study is the first randomised control trial to rigorously test a sequential approach to treating comorbid PTSD and major depressive disorder.

Findings from a trial of 52 patients undergoing three types of treatment regime - using only Cognitive Processing Therapy (CPT), using Behavioural Activation Therapy (BA) with some CPT, or CPT with some BA - found that a combined treatment protocol resulted in meaningful reductions in PTSD and depression severity, with improvements maintained at six-month follow-up investigations.

"We sought to examine whether a protocol that specifically targeted both PTSD and comorbid depression would benefit those with this dual diagnosis compared with a solely PTSD-focused protocol," says Flinders PTSD research expert Professor Reg Nixon.

"With some qualifications, the answer to this question is yes in the case of CPT and BA."

The findings - "Comorbid posttraumatic stress disorder and major depressive disorder: The usefulness of a sequential treatment approach within a randomised design," by Samantha Angelakis, Nathan Weber, and Reg Nixon - has been published in the Journal of Anxiety Disorders.

It found that the reductions in depressive symptoms that occur when PTSD symptoms are targeted early in treatment are consolidated when closely followed with behavioural activation.

"Although the findings need to be replicated, our observation that when depression was targeted before PTSD that those individuals did not quite have as good an outcome as those in the other conditions indicates there might be a cost to delaying or putting off targeting PTSD symptoms over depressive symptoms," says Professor Nixon.

"Facing one's trauma is understandably very difficult, but our findings suggest that trying to 'ease' into this work and working on depression first might not in fact help clients as much as people would expect."

The researchers also noted that CPT alone, without any modifications, still demonstrated positive outcomes in this comorbid sample

"Our clinical view at this time is that when individuals with PTSD and MDD present for PTSD treatment, CPT should be delivered first."

Those with higher levels of depression showed greater change from treatment than those with lower levels of depression. Although symptoms tended to remain higher in these individuals after treatment than those with lower levels of depression, the findings indicated that those with high levels of depression still benefited from therapy.

You might remember you ate cereal for breakfast but forget the color of the bowl. Or recall watching your partner put the milk away but can't remember on which shelf.

A new Northwestern Medicine study improved memory of complex, realistic events similar to these by applying transcranial magnetic stimulation (TMS) to the brain network responsible for memory. The authors then had participants watch videos of realistic activities to measure how memory works during everyday tasks. The findings prove it is possible to measure and manipulate realistic types of memory.

"On a day-to-day basis we must remember complex events that involve many elements, such as different locations, people and objects," said lead author Melissa Hebscher, a postdoctoral fellow at Northwestern University Feinberg School of Medicine. "We were able to show that memory for complex, realistic events can be improved in a safe and non-invasive way using brain stimulation."

The study was conducted on healthy young adults in a controlled laboratory setting. These methods, however, also could eventually be used to improve memory in individuals with memory disorders due to brain damage or neurological disorders, Hebscher said.

The study will be published Feb. 4 in the journal Current Biology.

A new approach to studying memory: Incorporating video

The study authors used TMS with the goal of altering brain activity and memory for realistic events. Immediately following stimulation, subjects performed a memory task while having their brains scanned using functional magnetic resonance imaging (fMRI).

Instead of showing study participants pictures or lists of words - typical practices in laboratory tests that analyze memory - participants in this study watched videos of everyday activities such as such as someone folding laundry or taking out the garbage.

"Our study used video clips that more closely replicate how memory works on a day-to-day basis," Hebscher said.

Following stimulation, study participants more accurately answered questions about the content of the video clips, such as identifying the shirt color an actor was wearing or the presence of a tree in the background.

Additionally, the study found that brain stimulation led to higher quality reinstatement of memories in the brain. Reinstatement is when the brain replays or relives an original event, Hebscher said. Following stimulation, a person's brain activity while watching a video more closely resembled their brain activity when remembering that same video.

"This is why remembering can sometimes feel like 'mental time travel,'" Hebscher said. "Our findings show that stimulation enhances this 'mental time travel' in the brain and improves memory accuracy. These findings have implications for the development of safe and effective ways to improve real-world memory."

How the study worked

The study authors used a brain imaging technique called multi-voxel pattern analysis to compare patterns of brain activity when subjects were watching a video to brain activity when subjects were remembering that same video. The scientists measured the effect of stimulation by comparing memory and brain activity following stimulation of the memory network to the same measures following stimulation of a control brain region that does not belong to the memory network.

During the memory test, subjects watched a large set of video clips and later remembered them and answered true/false questions about the content of the videos. The researchers found that memory network stimulation improved the number of questions that subjects answered correctly. It also increased reinstatement of videos in brain regions associated with visual processing.

"Follow-up studies will work to gather more reliable measures of the brain network responsible for memory in healthy subjects as well as in patients with memory disorders," Hebscher said. "Having a more reliable measurement of this network will help us more easily identify reinstatement in the brain and may help improve the effectiveness of stimulation for enhancing memory."

Researchers from the international BASE collaboration at CERN, Switzerland, which is led by the RIKEN Fundamental Symmetries Laboratory, have discovered a new avenue to search for axions--a hypothetical particle that is one of the candidates of dark matter particles. The group, which usually performs ultra-high precision measurements of the fundamental properties of trapped antimatter, has for the first time used the ultra-sensitive superconducting single antiproton detection system of their advanced Penning trap experiment as a sensitive dark matter antenna.

If our current understanding of cosmology is correct, ordinary "visible" matter only makes up 5 percent of the total energy content of the universe. Another 26 percent is believed to be a mysterious substance called "cold dark matter". Because this hypothetical "dark matter" does not interact strongly with ordinary matter, it is extremely hard to detect, and as a result its exact microscopic properties have yet to be understood. One possibility is that "dark matter" is a new type of particle, called an axion. In fact, there are a number of global physics programs hunting for dark matter "axions" or "axion-like particles" using very different types of detectors.

If axions and axion-like dark matter particles (ALPs) exist, they oscillate through the galaxy at characteristic frequencies defined by their masses. In strong magnetic fields, such as those present in Penning trap experiments, the particles might convert into electromagnetically interacting photons. Like a musician hitting a string of their instrument, the converted ALPs would then excite the detection resonators of the sensitive single particle detectors causing them to reverberate, allowing the induced dark matter "sound" to be detected.

Thanks to the ultra-high sensitivity of the single-antiproton detectors used in the BASE experiment, the researchers were able to set new laboratory limits on the coupling of axion-like particles and photons. Though no ALP-induced signal was detected, the axion-to-photon coupling limits which were reached were similar to the limits derived from astrophysical searches and constitute, in a narrow mass range, the best laboratory limits derived so far. The combination of Penning-trap and single particle detection methods furthermore enables detector noise-level calibration by single-particle quantum thermometry, an elegant method that can provide model-independent calibration of coupling limits. In addition, this newly discovered avenue of using precision Penning trap experiments as axion detectors has the potential to be extended to other trap experiments, and to derive axion-photon coupling limits in much broader mass ranges. According to Stefan Ulmer, who heads the Fundamental Symmetries Laboratory, "With a purpose built-experiment, combining the already available technologies with higher magnetic fields, and lower detector temperatures, we are optimistic that we will be able to improve the limits by at least a factor of 100, and with ongoing developments, we may be able to improve the current detection bandwidth by at least a factor of 3,000."

Virtual 'exergaming' has become a popular way to exercise - especially among younger people - since the release of virtual reality (VR) fitness games on consoles such as Nintendo and Playstation.

But while VR is undoubtedly raising fitness games to a whole new level, researchers at the University of South Australia are cautioning players about the potential side effects of VR, particularly in the first hour after playing.

In a new study published in the Journal of Medical Internet Research, UniSA researchers investigated the consequences of playing one of the most popular VR exergames - Beat Saber* - finding that one in seven players still reported VR sickness 40 mins after they had finished playing.

The study tested the effect of VR exergaming on gamers' vision, nausea, and reaction times after both short (10 minute) and long (50 minute) game play, finding that while Beat Saber was mostly well-tolerated some people had longer-lasting side-effects.

Lead researcher, Dr Ancret Szpak says while VR offers promising benefits to exergaming, VR technology is only in its infancy and we still have a lot to learn.

"There's no doubt that VR provides unparalleled benefits to a range of applications, but it's important to be wary of how new technologies can affect you, both during and after play," Dr Szpak says.

"VR is particularly promising for exergaming as it keeps players absorbed in the virtual world while distracting them from feelings of physical effort of exercise. In this way, people who are not particularly excited about exercise, can still get their game on and get moving.

"For VR exergaming, the lessons are twofold: first it's always a good idea to try a brief VR session to make sure you can tolerate it before you dive into longer play; if you feel a bit dizzy after a short time, you're likely to feel worse after a longer exposure.

"Secondly, after playing any VR - exergaming or otherwise - it's always wise to wait and see how you feel before you take on any higher-risk activity, such as driving a car.

"VR is such an exciting field that can potentially provide all sorts of benefits to all sorts of people. But we must walk before we leap. And it's always best to exercise caution with the unknown."

Today's digital world generates vast amounts of data every second. Hence, there is a need for memory chips that can store more data in less space, as well as the ability to read and write that data faster while using less energy.

Researchers from the National University of Singapore (NUS), working with collaborators from the University of Oxford, Diamond Light Source (the United Kingdom's national synchrotron science facility) and University of Wisconsin Madison, have now developed an ultra-thin material with unique properties that could eventually achieve some of these goals. Their results were first published online in the journal Nature on 4 February 2021.

Storing data in anti-ferromagnets

In existing ferromagnet memory devices like hard drives, information is stored into specific patterns of atoms (called bits), within which all the little magnetic poles are oriented in the same direction. This arrangement makes them slow and susceptible to damage by stray magnetic fields. In contrast, a special class of materials called anti-ferromagnets, made up with magnetic poles on adjacent atoms aligned oppositely, are emerging to be important for future memory technology.

In particular, there is a lot of interest in creating special magnetic nano-patterns in anti-ferromagnets that are shaped as whirls or vortices. In essence, each pattern consists of many little magnetic poles winding around a central core region in a clockwise or anti-clockwise manner, very much like air circulating inside a tornado or whirlwind. When realised experimentally, combinations of these anti-ferromagnetic whirls would be quite useful, as they are very stable structures and can potentially be moved along magnetic 'race tracks' at whirlwind speeds of a few kilometres per second!

They could act as new types of information bits that not only store memory but also participate in computational operations. Hence, they would enable a new generation of chips that are significantly faster yet more energy efficient than today's devices.

Experimental discovery of whirls

To date, constructing and manipulating patterns in anti-ferromagnetic materials has been very challenging, as they appear almost non-magnetic from afar. "Standard approaches for control, such as using external fields, fail to work on these materials. Therefore, to realise these elusive anti-ferromagnetic whirls, we came up with a novel strategy that combined high-quality film synthesis from materials engineering, phase transitions from physics and topology from mathematics," explained Dr Hariom Jani, who is the lead author of the paper and a Research Fellow from the NUS Department of Physics.

To grow these materials the researchers fired a laser at an extremely common and cheap material - iron-oxide, which is the main component of rust. By using ultra-short pulses of laser, they created a hot vapour of atomic particles that formed a thin film of iron-oxide on a surface.

Professor Thirumalai Venky Venkatesan, who led the NUS group and invented the pulsed laser deposition process for making the thin film, highlighted the versatility of the team's approach. "The deposition process allows precise atom-level control during the growth, which is important for making high-quality materials. Our work points to a large class of anti-ferromagnetic material systems, containing phase transitions, in which one can study the formation and control of these whirls for eventual technological applications," he said.

Explaining the underlying mechanism, Professor Paolo Radaelli, leader of the Oxford group, shared, "We drew inspiration from a celebrated idea in cosmological physics, from nearly 50 years ago, which proposed that a phase transition in the early universe, during the expansion after the Big Bang, may have resulted in the formation of cosmic whirls. Accordingly, we investigated an analogous magnetic process occurring in high-quality iron-oxide, which allowed us to create at will a large family of anti-ferromagnetic whirls."

The team's next step is to construct innovative circuits that can electrically control the whirls.

A study published in the journal Pediatrics expands validation evidence for a new screening tool that directly engages preschool-age children during clinic visits to assess their early literacy skills. The tool, which is the first of its kind, has the potential to identify reading difficulties as early as possible, target interventions and empower families to help their child at home, according to researchers at Cincinnati Children's Hospital Medical Center.

The Reading House (TRH) is an assessment for ages 3-5 based on a specially designed children's book, which was developed by John Hutton, MD, and his team at Cincinnati Children's. Screening takes five minutes and gauges performance levels for ages 3-4 and 4-5. It addresses a significant gap in ways to efficiently and directly screen early literacy skills. The tool, which is intended to be fun for the child, could be used in primary care or preschool settings. Early screening is particularly important for children from disadvantaged backgrounds.

"While developmental screening is a mainstay of pediatric practice, there is no established standard to assess reading readiness and identify children at-risk early," said Hutton, director of the Reading & Literacy Discovery Center at Cincinnati Children's. "As a result, many children arrive at kindergarten unprepared to learn to read, especially from minority and economically impoverished backgrounds - estimated at over 50% of children from impoverished backgrounds in the U.S. and over 25% overall."

The screener measures core skills typically emerging in the preschool age range, including vocabulary, rhyming, alphabet knowledge and print concepts (how books work). All are skills predictive of reading success and often implicated in reading difficulties, according to Hutton.

After screening, the family is given the book to take home and read together, helping address the important question: "What should I do to help my child?" Possibilities include enrollment in preschool as well as building nurturing home-reading routines.

The study involved 70 healthy children--34 boys and 36 girls--between 3 and 5 years old from various socioeconomic status backgrounds. The children completed standardized assessments of important literacy skills: composite, vocabulary, rhyming and rapid automatized naming (how quickly they can access linguistic information about objects, letters or words). Fifty-two of these children also successfully completed magnetic resonance imaging (MRI), including measurement of cortical thickness, or the gray matter surface of their brains. Thicker cortex, particularly in left-sided areas supporting language and reading, has been associated with higher skills that are predictive of reading outcomes.

These findings are the first of their kind, building on a series of "firsts" involving relationships between reading and brain development in preschool-age children published by the research team from Cincinnati Children's.

"We found significantly thicker gray matter cortex in the left-sided areas of the brain in children with higher TRH scores, which align with cortical thickness patterns found in older children and adults with higher reading skills," Hutton said. "This is an important neurobiological correlate of screened skills at this formative age, when the brain is growing rapidly."

Higher scores on TRH were also strongly related to higher vocabulary, rhyming and rapid naming scores, adding to validation evidence for the TRH measure.

An additional finding involved substantial differences in cortical thickness patterns for children in poverty versus those not in poverty related to higher TRH scores.

"We found a less mature or 'strain' pattern and thinner cortex overall in the subsample of children from impoverished backgrounds, which is a potential biomarker of lower readiness and early adversity often found in such children," Hutton said. "By screening early during pediatric clinic visits, especially in practices serving disadvantaged families, we can hopefully target effective interventions that help children better prepare for kindergarten and improve reading outcomes -- literally 'shaping their brains to read.' "

Researchers from the University of Missouri School of Medicine have discovered that children who receive a seasonal flu shot are less likely to suffer symptoms from a COVID-19 infection. The finding comes from a review of more than 900 children diagnosed with COVID-19 in 2020.

"It is known that the growth of one virus can be inhibited by a previous viral infection," said Anjali Patwardhan, MD, professor of pediatric rheumatology and child health. "This phenomenon is called virus interference, and it can occur even when the first virus invader is an inactivated virus, such as the case with the flu vaccine."

Patwardhan reviewed records from 905 pediatric patients diagnosed with COVID-19 between February and August 2020 to determine each patient's influenza vaccination history. She discovered the COVID-19 positive children who received the influenza vaccine in the current flu season had lower odds of experiencing symptoms, respiratory problems or severe disease. She also found that children with COVID-19 who received the pneumococcal vaccine also had lower odds of experiencing symptomatic disease.

"Research on the pediatric population is critical because children play a significant role in influencing viral transmission," Patwardhan said. "Understanding the relationship and co-existence of other viruses alongside COVID-19 and knowing the vaccination status of the pediatric patient may help in deploying the right strategies to get the best outcomes."

Patwardhan said it will also be important to explore the connection between vaccinations and COVID-19 symptoms in a larger geographical-multiracial study.

"Based on these findings, we hypothesize that the higher incidence of COVID-19 in minority populations may also reflect their low vaccination rate apart from other health inequalities," Patwardhan said.

It is necessary to develop additional COVID-19 vaccines, as different vaccine approaches have their advantages and disadvantages and may work synergistically. Researchers at Karolinska Institutet in Sweden now report that they have developed a prototype vaccine against SARS-CoV-2 using a DNA vaccine platform that is inexpensive, stable, easy to produce, and shows a good safety profile. A study published in Scientific Reports shows that the vaccine induces potent immune responses in mice.

The vaccine, called DREP-S, is administered as DNA and is based on a DNA-launched self-amplifying RNA (DREP) platform developed at Karolinska Institutet. This means that upon delivery into host cells, the vaccine will launch an RNA replicon, which is a self-amplifying RNA molecule that produces multiple copies of a selected RNA sequence.

The platform has previously been used to develop several vaccines that are now in clinical trials towards infectious viral diseases such as HIV, Ebola, chikungunya and HPV. It is also inexpensive, stable and easy to produce. Its self-amplification feature enables administration of lower doses and consequently might induce milder side effects, according to the researchers. Two other advantages are that it does not require a cold chain during transportation and storage and that it is suitable for rapid adaptation to new virus variants.

The vaccine carries the gene encoding the external spike (S) protein of SARS-CoV-2 and was developed by Dr Inga Szurgot in Professor Peter Liljestrom's lab and colleagues in Gerald McInerney's lab at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet.

"Although several vaccines against COVID-19 have been approved for emergency use, there are still concerns regarding the durability of immune responses after vaccination," says first author Inga Szurgot. "Moreover, the vaccines that are based on mRNA molecules need to be stored and transported at ultralow temperatures. Maintaining such conditions can cause logistical problems and might not even be possible in many areas of the world where the need for vaccines is great."

In the new study, the researchers were able to show that the DREP-S vaccine is immunogenic in mice, generating high levels of SARS-CoV-2-specific IgG antibodies as well as very strong T cell responses. Importantly, the vaccine-induced antibodies were able to efficiently neutralize SARS-CoV-2 virus after a single immunization. In addition, the researchers reported that a second vaccination with a different vaccine type, containing recombinant SARS-CoV-2 spike protein resulted in even better immune responses.

"Different vaccine approaches and platforms have their distinct merits and may work synergistically in regimens where a patient receives first immunization with one type of vaccine and second with a different type," says last author Peter Liljestrom. "This approach often gives a better response and should be investigated further."

If you have a second, try typing "time management" into your favourite search engine.

You will get literally millions of results: books, tips, lessons, do's and don'ts.

It's a big industry. But as John Molson School of Business graduate researcher Brad Aeon asks in a new paper published in the journal PLoS ONE, does it actually work? Does time management correlate to professional and academic success?

To answer this question, Aeon and his colleagues Aïda Faber of Université Laval in Quebec City and Alexandra Panaccio, associate professor of management at John Molson, conducted a first-of-its-kind meta-analysis of time management literature. Their study pored over data from 158 separate studies spanning four decades, six continents and involving more than 53,000 respondents.

Their conclusion? Yes, time management does work. Though maybe not as one might initially think.

A balanced life is a satisfied life

"We found that it does have a moderate impact on work performance," Aeon says. "But we found that the relationship between time management and job performance actually increased over the years, and significantly so."

Aeon speculates that time management has become an ever-more vital skill set for an ever-more autonomous work force.

"People have more leeway in deciding how to structure their own time, so it is up to them to manage their own time as well. If they are good at it, presumably they will have a better performance," he notes. "And if they are not, they will have an even worse performance than they would have had 30 years ago, when they had more of their time managed for them."

Time management also had a positive effect on academic success, though it was not as pronounced as on work. It had no discernible effect on standardized testing results, which Aeon says depend on a fluid type of intelligence that time management cannot address.

The researchers did find a stronger relationship between time management and overall well-being, in particular life satisfaction.

"Time management helps people feel better about their lives because it helps them schedule their day-to-day around their values and beliefs, giving them a feeling of self-accomplishment," he explains. Conversely, there was a strong negative relationship between the practice and distress.

Finally, the researchers looked at the impact of time management across demographics, such as personality traits, age, gender, education and family status. They found the relationship far weaker than expected, though they had correctly anticipated that women would be slightly better at time management than men.

"The only trait that did correlate strongly with time management was conscientiousness," Aeon says. "That involves people's attention to details, their desire for organization, to be reliable and systematic. That is understandable, because there is a lot of overlap there."

They noted that people who have what they call an internal locus of control --- meaning that they feel they have the ability to change or impact their lives -- are more successful at time management than those who say they are subject to an external locus of control.

Keeping goals within reach

As the world continues to struggle through the COVID-19 pandemic, Aeon adds that it is important to avoid comparing time management with supposedly more successful people. These misguided attempts at inspiration can lead to what he calls "time management shaming."

"You see these social media posts saying, 'Yes, there's a pandemic, but I learned a new language or I woke up at 5 a.m. and accomplished more in a few hours than you will all day,'" he says. "It makes the rest of us feel bad and creates unrealistic standards as to what we can and cannot do with our time."

BUFFALO, N.Y. -- All things being equal, large, long-lived animals should have the highest risk of cancer.

The calculation is simple: Tumors grow when genetic mutations cause individual cells to reproduce too quickly. A long life creates more opportunities for those cancerous mutations to arise. So, too, does a massive body: Big creatures -- which have many more cells -- should develop tumors more frequently.

Why, then, does cancer rarely afflict elephants, with their long lifespans and gargantuan bodies? They are some of the world's largest land animals.

A new study delves into this sizeable mystery, showing that elephants possess extra copies of a wide variety of genes associated with tumor suppression.

But this phenomenon is not unique to elephants, scientists say: The research concluded that duplication of tumor suppressor genes is quite common among elephants' living and extinct relatives, including in small ones like Cape golden moles (a burrowing animal) and elephant shrews (a long-nosed insectivore). The data suggest that tumor suppression capabilities preceded or coincided with the evolution of exceptionally big bodies, facilitating this development.

The study was published on Jan. 29 in the journal eLife by biologists Vincent Lynch at the University at Buffalo and Juan Manuel Vazquez at the University of California, Berkeley.

"One of the expectations is that as you get a really big body, your burden of cancer should increase because things with big bodies have more cells," says Lynch, PhD, assistant professor in the Department of Biological Sciences in the UB College of Arts and Sciences. "The fact that this isn't true across species -- a long-standing paradox in evolutionary medicine and cancer biology -- indicates that evolution found a way to reduce cancer risk."

In the new study, "We explored how elephants and their living and extinct relatives evolved to be cancer-resistant," Lynch says. "We have past research looking at TP53, a well-known tumor suppressor. This time, we said, 'Let's just look at whether the entire elephant genome includes more copies of tumor suppressors than what you'd expect.' Is the trend general? Or is the trend specific to one gene? We found that it was general: Elephants have lots and lots and lots of extra copies of tumor suppressor genes, and they all contribute probably a little bit to cancer resistance."

Elephants do have enhanced cancer protections, compared with relatives

Though many elephant relatives harbor extra copies of tumor suppressor genes, the scientists found that elephant genomes possess some unique duplications that may contribute to tumor suppression through genes involved in DNA repair; resistance to oxidative stress; and cellular growth, aging and death.

"By determining how big, long-lived species evolved better ways to suppress cancer, we can learn something new about how evolution works and hopefully find ways to use that knowledge to inspire new cancer treatments," says Vazquez, PhD, a postdoctoral researcher at UC Berkeley who completed much of the project while earning his PhD at the University of Chicago.

A related mystery: How did giant sloths and ancient mega-armadillos get so big?

Elephants are a great case study for understanding the evolution of cancer protection because they belong to a group of mammals -- the Afrotherians -- that are mostly small-bodied.

The study searched for extra copies of tumor suppressor genes in the DNA of Asian, African savanna and African forest elephants, as well as in the genomes of a number of fellow Afrotherians, such as Cape golden moles, elephant shrews, rock hyraxes, manatees, extinct woolly mammoths, extinct mastodons and more. The team also studied certain species belonging to a group of mammals called Xenarthra that is closely related to Afrotherians, and found some extra copies of tumor suppressors in those animals' genomes as well.

Given the findings, Lynch wonders whether the duplication of tumor suppressors may have aided the evolution of other ancient large bodies within these groups.

"If you pick a weird mammal, there's a good chance that it will be in these groups, the Afrotherians and Xenarthrans: armadillos, aardvarks, sloths, anteaters, all of these weird mammals," Lynch says. "We found that within these groups of organisms, the ones we studied all seem to have extra copies of tumor suppressor genes. That may be why in the last Ice Age, there were giant sloths and ancient mega-armadillos. There's even an extinct species of manatee relative called the Steller's sea cow that was elephant-big. Extra copies of tumor suppressors may have helped all of these animals get really, really big."

Over the past 30 years, the use of soil fumigants and nematicides used to protect cole crops, such as broccoli and Brussel sprouts, against cyst nematode pathogens in coastal California fields has decreased dramatically. A survey of field samples in 2016 indicated the nematode population has also decreased, suggesting the existence of a natural cyst nematode controlling process in these fields.

Thanks to California's pesticide-use reporting program, nematologists have been able to follow the amounts of fumigants and nematicides used to control cyst nematodes over the past three decades.
"Application of these pesticides steadily declined until they were completely eliminated in 2014 while, for example, broccoli yields continued to increase each year," said Ole Becker, a scientist with the Department of Nematology at the University of California.

In a study of 152 fields, Borneman, Becker and colleagues detected cyst nematodes in about 38% of them. Only a few of these fields had enough nematodes to potentially damage the crops. This showed that growers had likely reduced their usage of nematicides because of a natural decline in the nematode populations.

To identify the cause of this natural decline, Borneman, Becker and colleagues used cyst nematodes as a bait and found that a diverse population of fungi were likely killing the nematodes. The most abundant genus was Hyalorbilia, which contains species previously described as effective parasites of cyst and root-knot nematodes.

"The results from our baiting analysis combined with advanced molecular tools gave us a detailed depiction of the possible nematode-parasitizing fungi in these soils, which then provided a plausible explanation for this dramatic decrease in pesticide use," said Borneman.

Their research demonstrates the usefulness of monitoring plant-parasitic nematode density before using nematicides and increases the awareness of beneficial fungi in crop protection. These fungi might be considered as possible biological control agents for nematodes.

Plastics are among the most successful materials of modern times. However, they also create a huge waste problem. Scientists from the University of Groningen (The Netherlands) and the East China University of Science and Technology (ECUST) in Shanghai produced different polymers from lipoic acid, a natural molecule. These polymers are easily depolymerized under mild conditions. Some 87 per cent of the monomers can be recovered in their pure form and re-used to make new polymers of virgin quality. The process is described in an article that was published in the journal Matter on 4 February.

A problem with recycling plastics is that it usually results in a lower-quality product. The best results are obtained by chemical recycling, in which the polymers are broken down into monomers. However, this depolymerization is often very difficult to achieve. At the Feringa Nobel Prize Scientist Joint Research Center, a collaboration between the University of Groningen and ECUST, scientists developed a polymer that can be created and fully depolymerized under mild conditions.

Self-healing

'We found a way to produce polymers from the natural molecule lipoic acid in a very controlled way,' explains Ben Feringa, Professor of Organic Chemistry at the University of Groningen. 'It is a beautiful molecule and a perfect building block that was created by nature.' The molecule has a ring structure that includes a sulphur-sulphur bond. When this bond is broken, the sulphur atoms can react with those of another monomer. 'This process was known before, but we managed to find a way to control it and to create long polymers.'

The molecule also has a carboxyl group, which readily reacts with metal ions. These can crosslink the polymers, which results in an elastic material. By dissolving the molecule in water with sodium hydroxide and then evaporating the water, a firmer polymer film is produced through ionic bonds. As the polymerization is achieved through reversible bonds, the material is also self-healing, explains Feringa: 'When it is cut, you can simply press the ends together and they will reconnect in a few minutes.'

Fully reversible
Most of the work in the Materials paper was carried out by Qi Zhang, first as a PhD student at ECUST in Shanghai and later as a postdoctoral researcher at the University of Groningen. 'Lipoic acid is a natural small molecule with an elegant structure,' he says. 'We didn't have to do any tedious re-designing of the monomer to achieve a fully reversible polymerization.' Simply exposing the polymers to sodium hydroxide dissolves the polymers into monomers. 'By adding a little acid, the monomers precipitate and can be recovered. The quality of these recycled monomers is identical to that of the original material.'

'Our experiments show what is possible with these monomers,' adds Feringa. 'We can even recycle the material into monomers several times, without loss of quality.' However, industrial applications of this new polymer are a long way off. Feringa: 'This is a proof of principle. We are conducting experiments now to create polymers with new functionalities and to better understand the polymerization and depolymerization processes.' Furthermore, although 87 per cent of the monomers can already be recovered, the scientists want to get as close to a hundred per cent as possible. 'Our experiments show that we can produce, in a controlled fashion, hard and soft, elastic polymers that can be fully depolymerized,' Feringa sums up. 'This molecule is really very promising.'

The work that was described in the Matter article was carried out at the Feringa Nobel Prize Scientist Joint Research Center. The Research Institute is led by 2016 Nobel laureate in Chemistry Ben Feringa and Professors Da-Hui Qu and He Tian. Feringa received an honorary professorship at ECUST in November 2016. The Feringa Nobel Prize Scientist Joint Research Center was officially opened in October 2017.

Simple Science Summary

Plastics are made of long molecules called polymers. These polymers are chains of smaller building blocks, the monomers. A problem with the recycling of plastics is that the polymers must be broken down into monomers. This depolymerization often reduces the quality of the monomers. Scientists from China and the Netherlands have now found a way to produce polymers (plastics) from a natural monomer called lipoic acid. These polymers can be broken down under mild conditions without a loss of quality. Some 87 per cent of the monomers can be recovered and then reused several times over. This shows that it is possible to create fully recyclable plastics.

Reference: Qi Zhang, Yuanxin Deng, Chen-Yu Shi, Ben L. Feringa, He Tian and Da-Hui Qu: Dual closed-loop chemical recycling of synthetic polymers by intrinsically reconfigurable poly(disulfides) Matter 4 February 2021.

Journal

Matter

DOI

10.1016/j.matt.2021.01.014

Scientists of Far Eastern Federal University (FEFU) have advanced the technology of high-speed sintering for optical ceramics (Nd3+:YAG), i.e. active elements generating laser emission in the near-infrared wavelength range (1.06 μm) for cutting the edge microelectronics and medicine. The researchers have managed to reduce significantly the initial nanopowders consolidation period (10 - 100 times) forming a nanostructure with ensured high optical transparency of the ceramic material. A related article appears in Optical Materials.

Diode-pumped microlasers based on Nd3+:YAG nanoceramics, due to their short lasing pulse duration, high peak power, and beam quality in combination with the elements' small size, are relevant for the ranging, telecommunications, space technology, industry, and medicine.

Introduced a new approach to the technology of high-speed synthesis, young FEFU scientists achieved the optical quality of experimental ceramic materials at the level of world developments and commercial analogs. For that, they had combined the stages of the solid-state synthesis of the Nd3+:YAG structure from the initial Nd2O3, Y2O3, and Al2O3 oxide nanopowders, and its spark plasma sintering (SPS).

"The affectation of the SPS-technology is ceramics contaminates with carbon-containing impurities from the graphite parts of the set-up during sintering. For example, on carbides basis, new chemical compounds can form in the glassy and/or crystalline state, gas impurities, etc. Unwanted inclusions can dramatically reduce the transparency of optical materials and lead to the degradation of their mechanical characteristics. Our main task was to minimize or completely eliminate the formation of such impurities", explains Anastasia Vornovskikh, junior researcher at the Advanced Ceramic Materials REC, Polytechnic Institute of Far Eastern Federal University.

Thanks to the SPS method, the total consolidation time for RE3+:YAG optical ceramics has been reduced by a factor of 10 - 100. Due to ultrafast sintering, the nanoscale of the grain structure of ceramics sustained provided their higher transparency in comparison with coarse-grained analogs. Their physical and mechanical properties as hardness, fracture toughness, plasticity, etc., significantly improved.

"In the context of the effect of carbon contamination, the team investigated all key sintering parameters such as heating rate, external pressure, temperature, and duration of sintering/post-annealing for transparency of Nd3+:YAG ceramics. We sew up a detailed sintering map to minimize the negative technological aspect. In general, in the case of suppressing carbon contaminations, the SPS technology acquires many advantages in comparison with conventional sintering technologies," says Denis Kosyanov, FEFU research team lead, director of the FEFU PI REC for Advanced Ceramic Materials Research.

According to scientist, the most challenging thing turned out to be to determine the boundary parameters of the process where begins the chemical interaction of graphite impurities with the sintered material. Most of the analytical methods failed to apply due to the ultra-low content of these impurities. Only through a modern high-precision method of X-ray photoelectron spectroscopy, that is being jointly developed by the teams from FEFU, the Institute of Chemistry (FEB RAS), and the Institute for Single Crystals (NAS of Ukraine), it became possible for the first time to record the initial stage of carbonization during SPS of optical materials, describe its nature and mechanism.

As a result, an experimental high-doped 4 at% Nd3+:YAG transparent ceramics was synthesized. Its residual porosity is less than 0.02 vol%, in-line optical transmittance is about 87% of the theoretical value, microhardness of 13.2 GPa with average grain size is near 740 nm. The developers 3 times increased the level of doping of the garnet structure with neodymium ions in comparison with permissible values for the growth technologies of commercial Nd3+:YAG single crystals, preserving the nano grained structure and high mechanical characteristics of the material.

The 2019-2020 flu season in the U.S. was unusual in a number of ways. Cases picked up in August rather than the more typical fall and early winter months, and it hit children particularly hard. It was also dominated early on by a Type B influenza virus instead of one of the much more common Type A viruses like H1N1 or H3N2.

A new study by researchers at the University of Georgia suggests that these dynamics were driven largely by a new, more transmissible strain encountering a population with very little existing immunity to it.

Their findings, just published in the Proceedings of the National Academy of Sciences, have implications for future vaccination and preparedness strategies.

"Influenza B viruses until now have been thought of as the junior partner in this endeavor, and what our paper demonstrates is that, in the 2019-2020 flu season, they were in fact the senior partner in the U.S. flu epidemic," said Pejman Rohani, Regents' and Georgia Athletic Association Professor in the Odum School of Ecology and College of Veterinary Medicine, the paper's senior author.

Rohani, lead author Rebecca Borchering, and their colleagues used a combinatioFINAn of mechanistic transmission models and likelihood-based statistical inference to test potential explanations for the 2019-2020 season's unusual dynamics.

"That's one way to see whether or not a proposed hypothesis fits in with the observed patterns," said Borchering, at the time of the study a postdoctoral associate working with Rohani. She is now at Penn State University.

One hypothesis involved within-host interactions between different viruses, in which the immune response to one virus prevents the other from gaining a foothold; studies have suggested that such interference may be possible even across virus types if the exposures happen within a short enough time. They created one model to test that assumption.

Another possibility was that the genetic mutations that distinguished the 2019-2020 virus strain--known as "B/Victoria subclade V1A.3"--had made it more easily transmissible, as the mutations occurred on two genes that are involved in triggering the immune response. The team built a second model to test that premise.

They then compared the results of both models to see which most closely resembled the pattern observed in the actual outbreak data.

"We arrived at the explanation that it really was increased transmissibility of this novel variant, and at the same time the fact that the susceptible population, the population of individuals naïve to this virus, was larger than you would expect, which led to the dynamics that we see," said Rohani.

One reason for the larger than usual number of people susceptible to the V1A.3 variant was that the previous year's flu season was almost entirely the result of Type A influenza viruses, rather than a mix of A and B. People who've been infected by a Type A virus generally gain some immunity to related Type A viruses, but not to Type B viruses, while those previously infected by a Type B virus are likewise somewhat protected from other Type B viruses but not from Type A.

"That's where age starts to come into it a bit," said Borchering. "In the paper, we mention younger individuals were more severely affected [in 2019-2020] and that's likely related to them having less time to be infected by other B viruses."

Rohani and Borchering said that their findings pointed to the need to learn more about Type B influenza viruses and incorporate that knowledge into vaccine development and timing strategies.

"Our study suggests it's important to keep an eye on the evolution of influenza B to avoid a vaccine mismatch in the same way they do with H3N2," Rohani said, explaining that vaccine updates are based on predictions about what's likeliest to be the next year's H3N2 variant.

"Anticipating the timing of influenza A and influenza B epidemics could improve vaccination schedules, so that individuals have protection throughout the influenza season."

Borchering said the team's findings also point to the need for enhanced surveillance for influenza beyond the winter months, and that hospitals may want to consider ensuring that they are prepared for an influx of flu patients earlier than usual.

Another factor to consider is how steps taken to curtail COVID-19 transmission may affect future flu seasons.

"Measures trying to restrict transmission of SARS-CoV-2 prevent transmission of other respiratory viruses too--it's not like you get to pick which virus you transmit," said Borchering. "It's unclear what exactly will happen, but there has been a very small influenza season this year. People aren't getting the exposures they would normally get during flu season. Fewer exposures lead to fewer infections, and thus fewer individuals acquiring immunity. This could lead to large influenza epidemics in the future, particularly when combined with relaxation of COVID-19 prevention measures, such as social distancing and mask wearing."