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MUSC Hollings Cancer Center researchers are exploring the use of peptide carriers for the delivery of small RNA drugs as a novel treatment for cancer. The team's recent work, published online March 19 in the Molecular Therapy - Nucleic Acids journal, lays the foundation for developing a clinically relevant peptide carrier RNAi-based drug treatment strategy for human oral cancer.

According to the American Cancer Society, the estimated risk of developing oral cancer in the U.S. is 1 in 60 for men and 1 in 140 for women. Cancer therapies face multiple challenges, including off-target side effects and low efficacy. RNAi-based therapeutics have great potential to overcome these specific treatment challenges.

Andrew Jakymiw, Ph.D., who is also an associate professor in the Oral Health Sciences Department at MUSC, focuses on the study of RNA interference (RNAi)-based therapies for oral cancer. RNAi is a method of gene silencing that specifically targets, or tags, messenger RNA (mRNA) for degradation. mRNA contains the genetic code needed to make proteins. Small interfering RNA (siRNA) are the pieces of RNA that can bind to specific regions on mRNA that stop proteins from being made. Scientists are figuring out how to use this to target and silence disease-causing genes. Decades of research have shown that certain proteins are overexpressed in cancer and drive cancer cell growth. The goal of the RNAi drug treatment strategy is to "turn off" the proteins that promote cancer development.

Jakymiw said that although the principle is biologically sound, there are many technical challenges with siRNA delivery. "For example, rapid renal excretion, degradation by RNases, low intracellular uptake, endosomal entrapment and low release of the siRNA cargo from the delivery platform are all challenges that we must consider when modifying a peptide siRNA carrier," he said.

To harness the gene silencing capabilities of siRNA, scientists must get the siRNA into the appropriate cells. The siRNA must be attached to a larger molecule to protect it during delivery to the desired location. Peptide carriers are an attractive tool for delivering siRNA, because they are affordable and easy to modify.

In earlier studies, the Jakymiw laboratory found that the original peptide carrier they designed, called 599, could deliver the siRNA cargo into cancer cells and turn off a targeted cancer gene, which inhibited tumor growth in a mouse cancer model.

"We originally designed the 599 peptide so that it could help the siRNA cargo penetrate the cell and escape endosomes more easily. However, by looking at the three-dimensional arrangement of the amino acids in the 599 peptide, in particular their stereochemistry, we were able to make additional changes that beneficially affected the peptide carrier's capabilities," said Jakymiw.

Charles Holjencin, a dual D.M.D./Ph.D. student in the Jakymiw lab, used confocal fluorescence microscopy and observed that one of the modified 599 siRNA-loaded peptide carriers, called RD3AD, was arranged around the cancer cells in a clear pattern that he had not seen with the original 599 peptide carrier.

"Charles' keen observations through confocal work allowed us to identify an important intracellular delivery mechanism," said Jakymiw.

The modified RD3AD peptide carrier was delivering the siRNA drug by adhering to and potentially moving along cell surface protrusions, called filopodia. Entry into the cell via filopodia is a very efficient way for small biological complexes to enter cells; some viruses and bacteria also use this entry method. Since the siRNA-loaded RD3AD peptide carrier was able to enter cancer cells more efficiently, the research team saw improved gene silencing. This meant that the peptide carrier had heightened potential to deliver a cancer therapeutic, Jakymiw explained.

One of the next steps will be to test the RD3AD peptide in animal cancer models. Additionally, the researchers want to understand the mechanisms associated with this form of drug delivery more fully. For example, an unanswered question is what protein is the peptide carrier interacting with on filopodia? If this molecule is overexpressed in cancer, then this could be a valuable therapeutic target, especially for aggressive cancers, which typically have increased numbers of filopodia.

While cancer cells were the biological target for improving this drug delivery system, peptide carriers, such as RD3AD, have more applications than just in cancer therapies. In fact, peptides such as RD3AD could be used to deliver siRNA in any instance where gene silencing is desired for the treatment of a disease.

Now that the Jakymiw lab understands how to harness the specific amino acid stereochemical modifications in their peptide designs, the carrier's abilities are not limited to just siRNA. Other nucleic acid cargoes can be delivered by these peptide carriers, which opens future options for more targeted delivery of other forms of therapeutic molecules to treat challenging diseases.

"I look forward to collaborating with members of the Hollings Cancer Center in future studies related to how filopodia can be exploited for the enhancement of drug delivery, especially in the treatment of aggressive cancers," said Jakymiw.

According to researchers at the University of Illinois Chicago, the antibiotics used to treat common bacterial infections, like pneumonia and sinusitis, may also be used to treat human diseases, like cancer. Theoretically, at least.

As outlined in a new Nature Communications study, the UIC College of Pharmacy team has shown in laboratory experiments that eukaryotic ribosomes can be modified to respond to antibiotics in the same way that prokaryotic ribosomes do.

Fungi, plants, and animals -- like humans -- are eukaryotes; they are made up of cells that have a clearly defined nucleus. Bacteria, on the other hand, are prokaryotes. They are made up of cells, which do not have a nucleus and have a different structure, size and properties. The ribosomes of eukaryotic and procaryotic cells, which are responsible for the protein synthesis needed for cell growth and reproduction, are also different.

"Some antibiotics, used for treating bacterial infections, work in an interesting way. They bind to the ribosome of bacterial cells and very selectively inhibit protein synthesis. Some proteins are allowed to be made, but others are not," said Alexander Mankin, the Alexander Neyfakh Professor of Medicinal Chemistry and Pharmacognosy at the UIC College of Pharmacy and senior author of the study. "Without these proteins being made, bacteria die."

When people use antibiotics to treat an infection, the cells of the patient are not affected because the drugs are not designed to bind to the differently shaped ribosomes of eukaryotic cells.

"Because there are many human diseases caused by the expression of unwanted proteins -- this is common in many types of cancer or neurodegenerative diseases, for example -- we wanted to know if it would be possible to use an antibiotic to stop a human cell from making the unwanted proteins, and only the unwanted proteins," Mankin said.

To answer this question, Mankin and study first author Maxim Svetlov, research assistant professor with the department of pharmaceutical sciences, looked to yeast, a eukaryote with cells similar to human cells.

The research team, which included partners from Germany and Switzerland, performed a "cool trick," Mankin said. "We engineered the yeast ribosome to be more bacteria-like."

Mankin and Svetlov's team used biochemistry and fine genetics to change one nucleotide of more than 7,000 in yeast ribosomal RNA, which was enough to make a macrolide antibiotic -- a common class of antibiotics that works by binding to bacterial ribosomes -- act on the yeast ribosome. Using this yeast model, the researchers applied genomic profiling and high-resolution structural analysis to understand how every protein in the cell is synthesized and how the macrolide interacts with the yeast ribosome.

"Through this analysis, we understood that depending on a protein's specific genetic signature -- the presence of a 'good' or 'bad' sequence -- the macrolide can stop its production on the eukaryotic ribosome or not," Mankin said. "This showed us, conceptually, that antibiotics can be used to selectively inhibit protein synthesis in human cells and used to treat human disorders caused by 'bad' proteins."

The experiments of the UIC researchers provide a staging ground for further studies. "Now that we know the concepts work, we can look for antibiotics that are capable of binding in the unmodified eukaryotic ribosomes and optimize them to inhibit only those proteins that are bad for a human," Mankin said.

MISSOULA, Mont., May 24, 2021 -- Scientists from the Rocky Mountain Research Station collaborated to explore how research and management can confront increasing uncertainty due to climate change, invasive species, and land use conversion.

Wildland management and policy have long depended on the idea that ecosystems are fundamentally static, and periodic events like droughts are just temporary detours from a larger, stable equilibrium. However, ecosystems are currently changing at unprecedented rates. For example, bark beetle infestations, droughts, and severe wildfires have killed large numbers of trees across the western United States. In many cases, these changes may be irreversible.

In new research published in Frontiers in Forests and Global Change, Dr. Kevin McKelvey and colleagues from several Rocky Mountain Research Station science programs suggest ways for managers to respond. As ecosystems change in increasingly unpredictable ways, we will need more flexible and adaptive approaches to manage them. Rather than relying on knowledge of what ecosystems once looked like, we will need to learn and adjust to new conditions quickly. To achieve that goal, the authors recommend a more inclusive and collaborative governance model that would increase public and stakeholder participation, integrate research and management, and incorporate multiple forms of knowledge, including from indigenous communities. Such an approach, they argue, will encourage collaborative learning, increase trust in management, and allow for more efficient responses to change.

"Because all paths forward are fraught with uncertainties, limitations, and the likelihood that plans will fail due to unforeseen events, we need a much broader public not only involved in the decision process, but additionally to understand the limits both to knowledge and to achievable actions," said McKelvey.

The authors also explore priorities for research under this new model. For example, they note that rapidly changing ecosystems will increase our dependency on predictive modeling - and therefore will require better models. As a result, research should focus on collecting the types of data that support model development and validation.

Finally, the scientists offer a set of concrete recommendations to pivot toward accepting uncertainty – from conducting landscape-level assessments to focusing on retaining species that are resilient to disturbances.

“The implications for management and particularly for planning are profound,” said McKelvey. “We need to vastly accelerate the planning process to keep pace with rapidly changing landscapes. We need much more local flexibility to find out what works and what doesn’t. And we need to change the process for data collection and analyses – in many landscapes, 5-year-old data and analyses are already obsolete.”

A 23 year study being presented at the 23rd European Congress of Endocrinology (e-ECE 2021), on Monday 24 May 2021 at 14:40 CET (http://www.ece2021.org), has found that women who experience gestational diabetes (GDM) when they are pregnant, are more prone to developing type-1 and type-2 diabetes later in life. The long-term study suggests that autoantibody testing should be considered for women who experience GDM in order to have a better understanding of their prognosis.

Diabetes is a chronic disease that occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Globally, the number of people with diabetes rose from 108 million in 1980 to 422 million in 2014. Gestational diabetes is a form of diabetes women may experience during pregnancy and usually disappears after giving birth. However, 50% of women who experience GDM go on to develop type-2 diabetes later in life (published results from the same study), and 5.7% develop type-1 diabetes (even though it is often considered 'juvenile diabetes'). Due to the number of significant health issues diabetes can cause, this study is important as it allows healthcare professionals and women at risk of developing diabetes to be aware of their potential condition and adapt their lifestyle accordingly.1

Dr Kaisu Luiro of Helsinki University Hospital assessed 391 women who gave birth between 1984-1994 and experienced gestational diabetes during their pregnancy. A follow-up questionnaire assessing later onset of type-1 and type-2 diabetes was sent in 2012-2013. The mean follow-up time was 23 years, making this study the longest follow-up to date in relation to GDM studies. The study found that glutamic acid decarboxylase and islet cell autoantibodies present during pregnancy can reliably predict the development of type-1 diabetes later in life. The results were as follows:

* Single autoantibody positivity was detected in 12% of the cohort of women who experienced gestational diabetes and in 2.3% of the control cohort.

* In the cohort of women who experienced gestational diabetes, 2.6% tested positive for two autoantibodies and 2.3% for three autoantibodies, whereas only one subject in the control cohort had two autoantibodies detected.

"The strong relationship between women who have gestational diabetes and women who experience type-1 and type-2 diabetes later in life, suggests that women should now receive more extensive testing during pregnancy, in order to determine their level of risk. We also hope that healthcare professionals initiate conversations with their patients about the relationship between GDM and diabetes later in life. In the future, there are on-going developments for more accurate prediction models which hope to give a more specific suggestion as to who should be tested during pregnancy," Dr Luiro comments.

As diabetes is an increasingly prevalent health problem, this study is particularly important as it highlights women potentially at risk of developing type-1 or type-2 diabetes. This, and more specific prediction methods in the future, hopefully will provide an opportunity for healthcare professionals to inform and educate on the increased risk of developing diabetes in later life, and women with GDM to consider a healthy and balanced lifestyle in order to prevent or delay the onset.

SILVER SPRING, Md.-- Multi-factorial metabolic and inflammatory abnormalities in obesity, independently or in combination, seems to be the critical biological link of obesity, cancer and racial/gender health disparities. However, the specific cross-talk between these factors remain elusive. Because of the extraordinary relevance in understanding the relationship between obesity-associated inflammation and comorbidities with cancer development, progression and intervention, three new papers emphasizing different aspects of the obesity and cancer connection can be found in the latest online issue of Obesity, The Obesity Society's flagship journal.

"We highlighted in the review the contribution of alteration of metabolic factors such as lipids, insulin and leptin in obesity on the modulation of immunosuppressive and pro-oncogenic capabilities of myeloid cells, as key players in the chronic inflammation, which is a feature in obesity and cancer. Also, although the maintenance of a healthy weight is an essential principle to prevent cancer, obesity--within the context of a certain metabolic and inflammatory phenotype that remains to be defined--seems to be advantageous for the anti-cancer immunotherapy, a clinically and scientifically fascinating observation recently published," said Maria D. Sanchez-Pino, MSc., PhD, assistant professor of research at the Stanley S. Scott Cancer Center, member of the Department of Interdisciplinary Oncology and Department of Genetics at the LSU Health Sciences Center in New Orleans, and corresponding author of the paper titled "Obesity-associated Myeloid Immunosuppressive Cells, Key Players in Cancer Risk and Response to Immunotherapy". "Deciphering the molecular mechanisms by which obesity-associated metabolic factors activate or enhance the function of Myeloid-derived Suppressor Cells (MDSC) and immunosuppressive macrophages will allow us to identify biomarkers for prognosis and therapeutic responses, as well as, to discover potential targets for pharmacological therapies, and then, possibly disrupt the pathophysiologic inflammatory link between obesity and cancer."

Co-authors of Sanchez-Pino's paper include Justin Brown of the Louisiana State University (LSU) Pennington Biomedical Research Center in Baton Rouge, La., and member of the Stanley S. Scott Cancer Center of the LSU Health Science Center. Augusto Ochoa of the Stanley S. Scott Cancer Center from LSU Health Sciences Center, School of Medicine in New Orleans, and Linda Anne Gilmore of the University of Texas Southwestern Medical Center in Dallas, also contributed to the review.

Brown also described in his study titled "Obesity and Cancer Risk in White and Black Adults: A Prospective Cohort Study" that meaningful differences in the predictive associations of obesity and cancer risk are explained by race and sex. In his prospective cohort study of 18,296 Caucasian and African-American adults with cancer, the body mass index and waist circumference were not positively associated with cancer risk in Black men. However, among White men and White and Black women, a larger body mass index and waist circumference were associated with a higher risk of cancer.

Other authors of the study include Shengping Yang, Emily Mire, and Peter Katzmarzyk from the LSU Pennington Biomedical Research Center in Baton Rouge, and Xiacheng Wu, who is also part of the School of Public Health/Louisiana Tumor Registry, and Lucio Miele, Jovanny Zabaleta and Augusto Ochoa of the School of Medicine, LSU in New Orleans.

Brown also participated in the symposium titled "Hitting A Triple--Diabetes, Obesity, and the Emerging Links to Cancer Risk," during ObesityWeek® 2019 in Las Vegas. During the symposium, experts discussed the state-of-the-science and highlighted research gaps with the mechanistic link between diabetes, obesity and cancer. The researchers and clinicians settled that because the prevalence of obesity and diabetes increases, which in turn amplify the risk of malignances, clinical and public health interventions are urgently needed. Researchers explained that identifying how to disrupt the linkages among obesity, diabetes and cancer can transform the health and wellness of society; such a discovery would represent a "grand slam" for public health and medicine.

In everyday life, phase transitions usually have to do with temperature changes - for example, when an ice cube gets warmer and melts. But there are also different kinds of phase transitions, depending on other parameters such as magnetic field. In order to understand the quantum properties of materials, phase transitions are particularly interesting when they occur directly at the absolute zero point of temperature. These transitions are called "quantum phase transitions" or a "quantum critical points".

Such a quantum critical point has now been discovered by an Austrian-American research team in a novel material, and in an unusually pristine form. The properties of this material are now being further investigated. It is suspected that the material could be a so-called Weyl-Kondo semimetal, which is considered to have great potential for quantum technology due to special quantum states (so-called topological states). If this proves to be true, a key for the targeted development of topological quantum materials would have been found. The results were found in a cooperation between TU Wien, Johns Hopkins University, the National Institute of Standards and Technology (NIST) and Rice University and has now been published in the journal Science Advances.

Quantum criticality - simpler and clearer than ever before

"Usually quantum critical behaviour is studied in metals or insulators. But we have now looked at a semimetal," says Prof. Silke Bühler-Paschen from the Institute of Solid State Physics at TU Wien. The material is a compound of cerium, ruthenium and tin - with properties that lie between those of metals and semiconductors.

Usually, quantum criticality can only be created under very specific environmental conditions - a certain pressure or an electromagnetic field. "Surprisingly, however, our semimetal turned out to be quantum critical without any external influences at all," says Wesley Fuhrman, a PhD student in Prof. Collin Broholm's team at Johns Hopkins University, who made an important contribution to the result with neutron scattering measurements. "Normally you have to work hard to produce the appropriate laboratory conditions, but this semimetal provides the quantum criticality all by itself."

This surprising result is probably related to the fact that the behaviour of electrons in this material has some special features. "It is a highly correlated electron system. This means that the electrons interact strongly with each other, and that you cannot explain their behaviour by looking at the electrons individually," says Bühler-Paschen. "This electron interaction leads to the so-called Kondo effect. Here, a quantum spin in the material is shielded by electrons surrounding it, so that the spin no longer has any effect on the rest of the material.''

If there are only relatively few free electrons, as is the case in a semimetal, then the Kondo effect is unstable. This could be the reason for the quantum critical behavior of the material: the system fluctuates between a state with and a state without the Kondo effect, and this has the effect of a phase transition at zero temperature.

Quantum fluctuations could lead to Weyl particles

The main reason why the result is of such central importance is that it is suspected to be closely connected to the phenomenon of "Weyl fermions". In solids, Weyl fermions can appear in the form of quasiparticles - i.e. as collective excitations such as waves in a pond. According to theoretical predictions, such Weyl fermions should exist in this material," says theoretical physicist Qimiao Si of Rice University. Experimental proof, however, is yet to be found. "We suspect that the quantum criticality we observed favours the occurrence of such Weyl fermions," says Silke Bühler-Paschen. "Quantum critical fluctuations could therefore have a stabilising effect on Weyl fermions, in a similar way to quantum critical fluctuations in high-temperature superconductors holding superconducting Cooper pairs together. This is a very fundamental question that is the subject of a lot of research around the world, and we've discovered a hot new lead here."

It seems to us that certain quantum effects - namely quantum critical fluctuations, the Kondo effect and Weyl fermions - are tightly intertwined in the newly discovered material and, together, give rise to exotic Weyl-Kondo states. These are "topological" states of great stability that, unlike other quantum states, cannot be easily destroyed by external disturbances. This makes them particularly interesting for quantum computers.

To verify all this, further measurements under different external conditions are to be carried out. The team expects that a similar interplay of the various quantum effects should also be found in other materials. "This could lead to the establishment of a design concept with which such materials can be specifically improved, tailored and used for concrete applications," says Bühler-Paschen.

Press release - Abstract 1394: Alterations in clock genes expression in Eutopic and Ectopic Endometrial Tissue

New research suggests that night shift work is linked to menstrual irregularity and increased chance of developing endometriosis

According to a study being presented at the 23rd European Congress of Endocrinology (e-ECE 2021), on Sunday 23 May at 19:00 CET (http://www.ece2021.org), women working night shifts may be at a greater risk of menstrual irregularity and developing endometriosis. The research found a reduction in the expression of PER-2, CRY-1 and CLOCK genes along with an increase in REV-ERBb in ectopic compared to eutopic tissues. Prior to this research, there had been no previously published studies relating to the alterations in core clock-genes and the impact on women with endometriosis.

Endometriosis is a condition where tissue similar to the lining of the womb starts to grow in other places such as ovaries and fallopian tubes. Endometriosis affects roughly 10% (190 million) of reproductive age women and girls globally. The symptoms of endometriosis can vary - some women are badly affected, while others might not have any noticeable symptoms. In severe cases, it can be very painful and can cause infertility, miscarriages and ectopic pregnancies due to the probable effects of endometriosis on the pelvic cavity, ovaries, fallopian tubes, or uterus.2 Disruption of circadian rhythm in night shift workers has been associated with menstrual irregularity, as well as an increased chance of developing endometriosis and ovarian tumours.

Dr. Narjes Nasiri-Ansari, Dr. Aggeliki Karapanagioti, and a team of colleagues under the guidance and supervision of Professor Eva Kassi from the National and Kapodistrian University of Athens, Greece, investigated the expression of the core clock related genes in paired eutopic and ectopic endometrial tissues. The study looked at 27 patients with confirmed ovarian endometriosis. Eleven (11) paired samples were collected from ovarian cysts (ectopic endometrial tissues) and normal endometrium (eutopic tissues), while further eight (8) ectopic and eight (8) eutopic endometrial tissues were collected from 16 different patients with the same diagnosis.

"The clinical evidence that circadian rhythm disruptions can be associated with endometriosis, is now confirmed at tissue level, by the altered expression of local clock genes in ectopic endometrium. Understanding the causes and effects of endometriosis will improve our ability to detect, manage or even prevent the condition. These findings provide us with a better understanding of biological rhythm disturbances," commented Professor Eva Kassi.

The results from this study demonstrate an altered expression of CLOCK, CRY1, PER-2 and Rev-ERBb in normal endometrium tissues, as compared to ectopic endometrial tissues, indicating a disturbance of biological timing. However, the causal relationship of the altered expression pattern of these genes with the development of endometriosis needs further investigation.

Scientists are investigating whether rising global temperatures may lead to more stillbirths, saying further study is needed on the subject as climates change.

Researchers from The University of Queensland's School of Earth and Environmental Science and the Mater Research Institute reviewed 12 studies, finding extreme ambient temperature exposures throughout pregnancy appeared to increase risk of stillbirth, particularly late in pregnancy.

UQ PhD candidate Jessica Sexton said while this was very early research, it did show a possible link between stillbirth and high and low ambient temperature exposures during pregnancy.

"Overall, risk of stillbirth appears to increase when the ambient temperature is below 15 degrees Celcius and above 23.4 degrees Celsius, with the highest risk being above 29.4 degrees Celsius," Ms Sexton said.

"An estimated 17 to 19 per cent of stillbirths are potentially attributable to chronic exposure to extreme hot and cold temperatures during pregnancy.

"And, as the world's temperatures rise due to climate change, this link will potentially increase stillbirth likelihood globally.

"But these findings are from the very limited research currently available, so expectant mothers shouldn't be anxious - there's still plenty of follow-up research that needs to happen."

Environmental scientist Dr Scott Lieske said the findings suggested that as temperatures rise, women in the developing world would feel the effects..

"More than two million stillbirths occur every year around the world, with the most occurring in low resource settings," Dr Lieske said.

"Not only are these poorer countries already affected disproportionately by stillbirth, they're now going to be disproportionately affected by climate change as well.

"If the link apparent in this research bears out upon further scrutiny, the majority of new stillbirths will occur invariably in the nations already suffering the most."

Professor Vicki Flenady, Director of the Centre of Research Excellence in Stillbirth (Stillbirth CRE) at Mater Research, said the research highlighted the importance of research to reduce global stillbirth rates.

"Even in 2021, a stillbirth occurs somewhere in the world every 16 seconds," Professor Flenady said.

"Stillbirth has a traumatic long-lasting impact on women and their families, who often endure profound psychological suffering as well as stigma, even in high-income countries.

"Here in Australia, stillbirth is still a major public health problem.

"As outlined in my recent research, in 2015 Australia's late gestation stillbirth rate was over 30 per cent higher than that of the best-performing countries globally.

"Further work is needed to understand the role that temperature plays in keeping women and babies safe during pregnancy.

"To fully understand the effects of maternal exposure to ambient temperatures and stillbirth, future studies should focus on the biological mechanisms involved and contributing factors, in addition to improving measurement of ambient temperature exposure.

"In the meantime, we would encourage pregnant women to talk to their healthcare providers about staying safe during the cold days of winter and hot days of summer."

Tokyo, Japan - Researchers from Tokyo Metropolitan University have been quantifying how different batches of mesenchymal stem cells respond to the mechanical stiffness of their environments. They focused on how certain proteins were "localized" in cell nuclei and found key trends in how this changed with stiffness. Their findings explain inconsistencies between previous findings and may guide how scientists control the state of stem cells for research and medical treatments.

Mesenchymal stem cells (MSCs) are important "progenitor" cells that can transform into muscle, cartilage, bone or fat cells. In 2006, pioneering work by Engler and coworkers showed that they could control what cell type mesenchymal stem cells transformed (or "differentiated") into by simply placing them on surfaces with a different mechanical stiffness, or elastic modulus. Ever since, scientists have been trying to identify exactly how this occurs. The trouble is, despite the phenomenon being robust and reproducible, it turns out that they are very sensitive to the exact environment into which they are placed, even which batch they came from. The stakes are high: reliable control over MSC states would mean more research and even potential biomedical applications.

This search inspired a team led by Associate Professor Hiromi Miyoshi of Tokyo Metropolitan University to look at how different batches of MSCs respond to different environments. They focused on two proteins present in MSCs, the YAP protein, which helps cells respond to mechanical environments, and RUNX2, a key player in helping MSCs turn into osteoblasts which eventually become bone. They looked at how different MSC batches have different distributions of YAP and RUNX2 inside their cells. For their "stiff" environments, they chose a specially designed gelatin substrate which had significantly better reproducibility than popular collagen alternatives.

From the beginning, they found that their batches were quite distinct. In basic experiments looking at how they turned into bone-making or fat-making cells, they found that the batches produced very different levels of calcium and fat deposits. But when it came to their mechanoresponsive behavior, it turned out they were not as wildly distinct as initially thought. Firstly, the team found that the proportion of YAP found in the nuclei of cells (or "localization") turns out to vary in a consistent manner between batches, plateauing at the same stiffness. For RUNX2, though the localization varied differently, they still plateaued at a specific stiffness value (a different one to YAP). Even then, the trend in RUNX2 localization was linear up to the plateau.

With this kind of information, anyone could make a gel of a specific stiffness and actively control the level of YAP/RUNX2 in the nucleus of mesenchymal stem cells. By doing so, they could tune when and how their cells differentiate. The team hope this new level of control over cell fate will help accelerate research into MSCs and potentially lead to therapeutic applications.

One trait shared by all humans is that they don't remember specific life episodes that occurred before the age of 3 or 4. Many scientists have attributed this so-called "infantile amnesia" to a lack of development in the hippocampus, an area of the brain located in the temporal lobe that is crucial to encoding memory.

However, a new brain imaging study by Yale scientists shows that infants as young as three months are already enlisting the hippocampus to recognize and learn patterns. The findings were published May 21 in the journal Current Biology.

"A fundamental mystery about human nature is that we remember almost nothing from birth through early childhood, yet we learn so much critical information during that time -- our first language, how to walk, objects and foods, and social bonds," said Nick Turk-Browne, a professor of psychology at Yale and senior author of the paper.

For the new study, the Yale team used a new functional magnetic resonance imaging
(fMRI) technology to capture activity in the hippocampus in 17 babies, aged three months to two years old, as they were presented two sets of images on a screen. One set of images appeared as a structured sequence containing hidden patterns that could be learned. In the other, images appeared in a random order that offered no opportunity for learning. After the babies were shown these two sets of images several times, the hippocampus responded more strongly to the structured image set than to the random image set.

What might be happening, Turk-Browne said, is that as a baby gains experience in the world, their brain searches for general patterns that help them understand and predict the surrounding environment. This happens even though the brain is not equipped to permanently store each individual experience about a specific moment in space and time - the hallmark of episodic memory that is also lost in adult amnesia.

The strategy makes sense because learning general knowledge -- such as patterns of sounds that make up the words in a language -- may be more important to a baby than remembering specific details, such as a single incident in which a particular word was uttered.

The size of the hippocampus doubles in the first two years of life and eventually develops connections necessary to store episodic memories, Turk-Browne said.

"As these circuit changes occur, we eventually obtain the ability to store memories," he said. "But our research shows that even if we can't remember infant experiences later on in life, they are being recorded nevertheless in a way that allows us to learn from them."

Yale's Cameron Ellis is first author of the study, and this research was included in his recently completed and award-winning PhD dissertation.

Ionization energy is one of the most important physicochemical parameters. It is defined in terms of the amount of energy required to rip an electron from an atom. The dependence of the ionization energy on the atomic number determines the periodic law of chemical elements, which is assumed to be fundamentally constant. Based on the previously predicted effect of changing the electron mass, the research team showed that the ionization energy of atoms placed in photonic crystals with an ultrahigh refractive index can be significantly changed.

Photonic crystals are media with periodically changing electromagnetic properties. An example of a photonic crystal is a dense packing of dielectric microspheres, between which there is an empty space. The size of these voids is large enough to consider an electron or an atom placed there free from interaction with the material of the walls. Nevertheless, the environment of photonic crystals indirectly affects the properties of particles by modifying their own radiation field.

The fact is that according to the modern picture of the world, all particles participate in vacuum quantum fluctuations. In particular, an electron constantly creates and immediately destroys virtual photons. It turned out that photonic crystals are capable of influencing this interaction. Traditionally, this question has been studied only for electrons bound in an atom. An atom participating in such a process acquires a correction to its energy which is called the Lamb shift and is very small relative to the atomic energies themselves, even if the atom is placed in photonic crystals.

The reason why no one has considered the quantum fluctuations of a free electron in a photonic crystal is its mass in this state equals infinity. The fact is that due to the interaction with vacuum, the mass of a free electron must acquire a correction, which is called the electromagnetic mass. This correction is added to the "bare" mass of the electron and forms its factually observed mass.

However, calculations performed in the first half of the 20th century showed that the integrals in the formulas for the electromagnetic mass diverge. To get around this problem, physicists came up with a mass renormalization procedure, which consisted of ignoring the electromagnetic mass and replacing in all other formulas the "bare" mass of the particle by the observed mass. This paved the way to quantum electrodynamics, whose predictions under ordinary conditions are confirmed in experiments with high accuracy.

However, if photonic crystals affect the interaction with a vacuum, this should be reflected in the electromagnetic mass, and, as a consequence, in the actually observed electron mass. The researchers showed that in this case a final correction arises, which is equal to the difference between the electromagnetic masses of an electron in a photonic crystal and in a vacuum. Moreover, due to the anisotropy of the photonic crystal, the mass depends on the direction in which the electron is flying. This leads to the fact that an electron bound in an atom has new energy corrections, which depend on its state. It turned out that for very high refractive indices of the substance from which the photonic crystal is made, these corrections become comparable to the energies of transitions between levels, including the energies of ionization transitions.

In this work, they calculated corrections to the ionization energy of hydrogen and alkali atoms placed in the voids of a one-dimensional photonic crystal made of materials with an ultra-high refractive index. It turned out that the decrease in the ionization energy can reach 68 percent in the case of the cesium atom.

The predicted effect is of great importance for both fundamental and applied physics and chemistry. In particular, a method for manipulating the electromagnetic mass has been proposed for the first time. In addition, the effect will allow influencing the periodic law of chemical elements, and the very change in the ionization energy can be used to synthesize new chemical compounds and create drugs based on them.

In the future, the team plans to cooperate with large pharmaceutical centers and study the possibility of its use for the synthesis of new compounds. An experimental verification of the effect can be done by measuring the rate of a chemical reaction occurring in the gas phase between the walls of a one-dimensional photonic crystal. In addition, they want to calculate the correction to the ionization energy for other chemical elements.

Plant diseases don't stop at national borders and miles of oceans don't prevent their spread, either. That's why plant disease surveillance, improved detection systems, and global predictive disease modeling are necessary to mitigate future disease outbreaks and protect the global food supply, according to a team of researchers in a new commentary published in Proceedings of the National Academy of Sciences.

The idea is to "detect these plant disease outbreak sources early and stop the spread before it becomes a pandemic," says lead-author Jean Ristaino, William Neal Reynolds Distinguished Professor of Plant Pathology at North Carolina State University. Once an epidemic occurs it is difficult to control, Ristaino says, likening the effort to the one undertaken to stop the spread of COVID-19.

"We've seen how important information sharing, data analytics, and modelling have been in responding to the COVID-19 pandemic. These types of tools could also be leveraged to help build resilience to future plant disease outbreaks - from identifying risk in global crop trade networks to local citizen science monitoring," says co-author Graham MacDonald, Assistant Professor in the Department of Geography at McGill University.

While some diseases are already under some sort of global surveillance - such as wheat rust and late blight, an important pathogen that affects potatoes and caused the Irish famine - other crop diseases are not routinely monitored.

"There are a few existing surveillance networks, but they need to be connected and funded by intergovernmental agencies and expanded to global surveillance systems," says Ristaino. "We can improve disease monitoring using electronic sensors that can help rapidly detect and then track emerging plant pathogens."

Working together to protect crops

The researchers say the efforts from a wide range of scholars - so-called convergence science - are needed to prevent plant disease pandemics. That means economists, engineers, crop scientists, crop disease specialists, geneticists, geographers, data analysts, statisticians and others working together to protect crops, the farmers growing crops and the people fed by those crops.

Research is underway to model the risk of plant pathogen spread and help predict and then prevent outbreaks, they report in the paper. Modeling and forecasting disease spread can help mobilize mitigation strategies more precisely to stop pandemics.

Plant disease outbreaks are increasing

Global plant disease outbreaks are increasing in frequency and threaten the global food supply, the researchers say. Mean losses to major food crops such as wheat, rice and maize ranged from 21 percent to 30 percent due to plant pests and diseases, according to a paper published in 2019.

Take the case of bananas, specifically the Cavendish variety, which has no resistance to a specific pathogen called Fusarium odoratissimum Tropical race 4, which causes Panama disease. That pathogen spread rapidly from Asia to Africa, the Middle East and recently into South America, where it affects the main type of banana grown in the Americas for export.

Climate change exacerbating outbreaks

Climate change will likely exacerbate these outbreaks, the researchers say. In Africa, for example, climate change and drought in Saharan Africa affects the population and range of locusts, which devastate crops further south in sub-Saharan Africa. Climate data can help drive disease forecasting and spread models.

"More frequent rainfall can allow airborne plant pathogens to spread and fungal spores can move with hurricanes, which is how soybean rust came to North America from South America - via storms," says Ristaino, who also directs North Carolina State's faculty cluster on emerging plant disease and global food security. "There are also cases of early emergence, when pathogens emerge earlier in the growing season than usual due to warmer springs."

Further, the global nature of food trade is driving some plant disease pandemics. The emergence of new harmful plant pathogens adds other risks to the food supply, which is already strained by growing global demand for food.

"Globalization means that agriculture and food supplies are increasingly interconnected across national borders. Analyzing these crop trade networks combined with greater information sharing among countries can help to pinpoint risks from pests or diseases," says MacDonald.

The researchers say there is a need to link human global health and plant global health scientists to work together. Food security and livelihoods are linked to agriculture and human health is linked to the food we consume.

SINGAPORE, 21 May 2021 - Alzheimer's Disease is the most common form of dementia and is characterised by the build-up of amyloid plaques in the brain. Microglia, the immune sentinels of the brain, are not only responsible for eliminating foreign invaders, but also maintaining brain homeostasis by clearing toxic waste such as the amyloid plaques.

However, the role of microglia in Alzheimer's Disease and its relationship to amyloid plaque accumulation remain unclear. Now, a team of scientists from Duke-NUS Medical School and Monash University have found the gene expression signatures underlying microglia associated with amyloid plaque phagocytosis - i.e. the engulfing of deposits of the amyloid beta (Aβ) protein in the brain. The findings, reported in the journal Nature Communications, offer a new target for interventions that aim to address the underlying disease mechanism of this incurable disease.

To investigate the differences between healthy brains and those of patients with Alzheimer's Disease at the single cell resolution, the team of scientists at Duke-NUS and Monash embarked on an ambitious project to comprehensively study gene expression changes in specific human brain cell types that are associated with progression of Alzheimer's disease. From that study, which was published in Nature Neuroscience in 2019, the team have honed in on microglia.

"We sought to understand the molecular mechanisms and differences between microglia that were actively engulfing amyloid plaques in Alzheimer's disease and those that weren't," said Associate Professor Enrico Petretto from Duke-NUS's Cardiovascular and Metabolic Disorders Programme, a co-senior author of the study.

The team did this by using a stain, called methoxy-XO4, that specifically targets microglia that have engulfed amyloid plaques. They used the stain in preclinical models of Alzheimer's disease and then examined gene expression in the stained microglia. They investigated differences in gene expression underlying microglia's ability to ingest particles (e.g. amyloid plaque) and identified associated regulatory molecules.

"Understanding this mechanism is important because now we have several new targets to go after, and in the future, these targets may open a new front against this devastating disease," said Professor Jose M. Polo from the Monash Biomedicine Discovery Institute, a co-senior author of the study.

The studies revealed that for microglia that have not taken up amyloid, their gene expression patterns are most similar to aged microglia, which are known to be dysfunctional and a major player in Alzheimer's Disease pathogenesis. In addition, after microglia engulfed the amyloid plaques associated with Alzheimer's Disease, they develop a characteristic gene expression pattern or signature. This change in gene expression is induced, in part, by a gene called Hif1a. The changed gene expression increases the ability of microglia to take up proteins such as amyloid, while reducing Hif1a does the reverse, highlighting the importance of Hif1a in controlling this microglia function. This regulatory role of Hif1a might also apply to the microglia function of removing damaged synapses.

"It is possible that this process is initially protective," said Assoc Prof Petretto, "with the microglia effectively pruning damaged synapses located near plaques." The scientists suspect, however, that this pruning process later goes awry as the disease progresses.

The team also used computational models to predict the networks of molecules involved in microglia uptake of proteins and identified potential targets to study for drug development. The widely used immunosuppressant drug rapamycin, for example, was found to block the gene Hif1a from triggering microglia to engulf amyloid plaques.

"This relationship between Hif1a and cognitive decline in Alzheimer's disease is yet to be comprehensively uncovered," said PhD student Gabriel Chew, who is a co-first author of the paper. "Future work could focus on using gene editing tool CRISPR to test the impact of manipulating Hif1a on symptom severity and disease progression."

Most of commercial chemicals are produced using catalysts. Usually, these catalysts consist of tiny metal nanoparticles that are placed on an oxidic support. Similar to a cut diamond, whose surface consists of different facets oriented in different directions, a catalytic nanoparticle also possesses crystallographically different facets - and these facets can have different chemical properties.

Until now, these differences have often remained unconsidered in catalysis research because it is very difficult to simultaneously obtain information about the chemical reaction itself and about the surface structure of the catalyst. At TU Wien (Vienna), this has now been achieved by combining different microscopic methods: with the help of field electron microscopy and field ion microscopy, it became possible to visualize the oxidation of hydrogen on a single rhodium nanoparticle in real time at nanometer resolution. This revealed surprising effects that will have to be taken into account in the search for better catalysts in the future. The results have now been presented in the scientific journal Science.

The rhythm of chemical reactions

"In certain chemical reactions, a catalyst can periodically switch back and forth between an active and an inactive state," says Prof. Günter Rupprechter from the Institute of Materials Chemistry at TU Wien. "Self-sustaining chemical oscillations can occur between the two states - the chemist Gerhard Ertl received the Nobel Prize in Chemistry for this discovery in 2007."

This is also the case with rhodium nanoparticles, which are used as a catalyst for hydrogen oxidation - the basis of every fuel cell. Under certain conditions, the nanoparticles can oscillate between a state in which oxygen molecules dissociate on the surface of the particle and a state in which hydrogen is bound.

Incorporated oxygen changes the surface behaviour

"When a rhodium particle is exposed to an atmosphere of oxygen and hydrogen, the oxygen molecules are split into individual atoms at the rhodium surface. These oxygen atoms can then migrate below the uppermost rhodium layer and accumulate as the subsurface oxygen there," explains Prof. Yuri Suchorski, the first author of the study.

Through interaction with hydrogen, these stored oxygen atoms can then be brought out again and react with hydrogen atoms. Then, there is again room for more oxygen atoms inside the rhodium particle and the cycle starts again. "This feedback mechanism controls the frequency of the oscillations", says Yuri Suchorski.

Until now, it was thought that these chemical oscillations always took place synchronously in the same rhythm over the entire nanoparticle. After all, the chemical processes on the different facets of the nanoparticle surface are spatially coupled, as the hydrogen atoms can easily migrate from one facet to the adjacent facets.

However, the results of the research group of Prof. Günther Rupprechter and Prof. Yuri Suchorski show that things are actually much more complex: Under certain conditions, the spatial coupling is lifted and adjacent facets suddenly oscillate with significantly different frequencies - and in some regions of the nanoparticle, these oscillating "chemical waves" do not propagate at all.

"This can be explained on an atomic scale," says Yuri Suchorski. "Under the influence of oxygen, protruding rows of rhodium atoms can emerge from a smooth surface." These rows of atoms can then act as a kind of "wave breaker" and hamper the migration of hydrogen atoms from one facet to another - the facets become decoupled.

If this is the case, the individual facets can form oscillations of different frequences. "On different facets, the rhodium atoms are arranged differently on the surface," says Günther Rupprechter. "That's why the incorporation of oxygen under the differing facets of the rhodium particle also proceeds at different rates, and so oscillations with different frequencies result on crystallographically different facets."

A hemisphere tip as a nanoparticle model

The key to unravelling this complex chemical behaviour lays in using a fine rhodium tip as a model for a catalytic nanoparticle. An electric field is applied, and due to the quantum mechanical tunnelling effect, electrons can leave the tip. These electrons are accelerated in the electric field and hit a screen, where a projection image of the tip is then created with a resolution of around 2 nanometers.

In contrast to scanning microscopies, where the surface sites are scanned one after the other, such parallel imaging visualizes all surface atoms simultaneously - otherwise it would not be possible to monitor the synchronization and desynchronization of the oscillations.

The new insights into the interaction of individual facets of a nanoparticle can now lead to more effective catalysts and provide deep atomic insights into mechanisms of non-linear reaction kinetics, pattern formation and spatial coupling.

Atmospheric ozone, which can regulate the amount of incoming ultraviolet radiation on the Earth's surface, is important for the atmospheric environment and ecosystems. Tropospheric ozone, primarily originating from photochemical reactions, is the third most prominent greenhouse gas causing climate warming.

A research team led by Dr. Jinqiang Zhang from the Institute of Atmospheric Physics (IAP) of the Chinese Academy of Sciences tried to analyze vertical ozone distributions and explore the influence of deep stratospheric intrusions and wildfires on ozone variation in the northern Tibetan Plateau (TP) during the Asian summer monsoon period.

Their findings were published in Atmospheric Research.

Ozone variation over the TP can influence weather and climate change. Unfortunately, surface observation sites on the northern TP are sparse due to the special terrain and harsh climate.

Ozonesonde, developed by the Key Laboratory of Middle Atmosphere and Global Environment Observation at IAP, was released over the northern TP in 2016, 2019, and 2020.

The researchers found that the deep stratospheric intrusion contributed to the occurrence of large ozone partial pressure in the troposphere.

"We also found that the large wildfire smoke occurring around central and eastern Russia in July 2016 caused ozone pollution in the troposphere over the northern TP, via long-range transport processes," said Dr. Dan Li, the corresponding author of the study.

The researchers warn that due to global warming, wildfires will increase and more pollution can be transported across China via long range.