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New research led by Flinders University has found a link between beta-blockers and survival outcomes in some breast cancer patients.

Beta-blockers, commonly used to manage cardiovascular disease, were negatively associated with survival outcomes in patients with HER2 (Human Epidermal Growth Factor Receptor 2) positive advanced breast cancer, according to a new paper in the Frontiers In Oncology.

Using data collected from 2,777 patients in clinical trials, the study showed worse survival outcomes for patients with HER2 positive ABC group using concomitant beta-blocker, compared to patients not using a BB.

"The research highlights a group of breast cancer patients whose survival outcomes are profoundly poorer," says Professor of Clinical Pharmacology Michael Sorich, director of the Precision Medicine Group at Flinders University's College of Medicine and Public Health

"Given about 20% of breast cancer patients overexpress HER2 - and cardiovascular toxicities are a known complication anti-HER2 therapies - this study importantly identifies a subgroup of patients in which we recommend further investigation to find strategies to improve treatment outcomes."

The research concluded: "Future research should aim to gain a deeper understanding of the effects of beta-blockers on specific breast cancer subtypes, cancer types, and cancer treatments."

PHILADELPHIA-- Stopping the cannibalistic behavior of a well-studied enzyme could be the key to new drugs to fight age-related diseases, according to a new study published online in Nature Cell Biology. For the first time, researchers in the Perelman School of Medicine at the University of Pennsylvania show how the self-eating cellular process known as autophagy is causing the SIRT1 enzyme, long known to play a role in longevity, to degrade over time in cells and tissue in mice. Identifying an enzymatic target is an important step that may lead to new or modified existing therapeutics.

"Blocking this pathway could be another potential approach to restore the level of SIRT1 in patients to help treat or prevent age-related organ and immune system decline," said first author Lu Wang, PhD, a postdoctoral researcher in the lab of Shelly Berger, PhD, a professor of Cell and Developmental Biology in the Perelman School of Medicine and a professor of Biology in the School of Arts and Sciences at Penn. Berger also serves as senior author on the paper.

"The findings may be of most interest to the immune aging field, as autophagy's role in SIRT1 in immune cells is a concept that hasn't been shown before," Wang added. "Exploiting this mechanism presents us with a new possibility of restoring immune function."

Cells are like leaky faucets, dripping away levels of proteins and enzymes, such as SIRT1, as the body ages, which can lead to chronic diseases, organ decline, and weaker immune responses to infections. New ways to stop these leaks and replenish SIRT1 have been demonstrated, including by cardiovascular researchers at Penn Medicine, but this is the first study to show autophagy's role in that degradation during senescence--a natural process in which cells stop creating new cells--and aging.

SIRT1 is crucial for cell metabolism and immune responses, researchers have known, and has been shown to extend lifespan when overexpressed.

To determine the mechanism of SIRT1 loss during senescence, the researchers first ruled out it was driven by mRNA synthesis and stability, important factors in the control of gene expression, using RNA sequencing techniques on mouse cells. Instead, through further experiments, they found that "knocking out" the autophagic protein Atg7 in senescent cells left SIRT1 levels in place, indicating the autophagic pathway, and not proteasomes--the other recycling factory of the body--played a role in the loss of the enzyme. Immunofluorescence staining also showed that another autophagy protein, LC3, drives the loss of SIRT1 in senescent cells and tissue.

Treating mice with various drugs further supported autophagy's role. A proteasome inhibitor--which blocks the breakdown of proteins in the cell--failed to restore SIRT1 protein in senescent cells and tissue, while treatment with Lys05, an autophagy inhibitor, rescued the loss of SIRTI, supporting that the enzyme is degraded through lysosomes. Lysosomes are the "stomach" of cells that help break down larger waste materials.

To determine autophagy's role in SIRT1 in immune cells, the researchers treated human donor CD8 T cells with low-dose Lys05 and a proteasome inhibitor, and found that only Lys05 increased SIRT1 levels. The results, the authors said, indicate that SIRT1 is degraded at least in part through the autophagy-lysosome pathway during T cell aging in humans--a mechanism that could inform the reprograming of aged immune cells.

Next, the researchers will further explore the LC3 and SIRT1 interaction in preclinical studies and better characterize the signaling pathway to block it.

"Stabilizing SIRT1 protein level by interrupting this interaction could be a new direction for the design of anti-aging compounds," the authors said.

Shannon Meseck, a NOAA Fisheries research chemist and marathon runner, was initially interested in how ultra-runners can tolerate higher levels of carbon dioxide than non-athletes. A chance conversation with a medical doctor about ciliated cells in the human lung turned on a light bulb in her head. Could similarities between the function of these cells in humans and in blue mussels explain the mussels' response to increasing acidification in the ocean?

Blue mussels, one of the mollusks Meseck studies, are economically and environmentally important filter-feeding bivalves. Like other bivalves, they use their gills for feeding and respiration. Gill cilia--microscopic, hair-like structures--create and control the current that allows water and food to flow over the gills. The cilia also help capture and sort food particles.

Similar ciliated cells in the human lung have receptors that sense the environment, including carbon dioxide concentration. They signal responses that can include changes in cilia beat frequency. Ultra-runners' lungs are very efficient at this. They can tolerate higher levels of carbon dioxide in the body than non-athletes, and don't get "winded" as quickly or for as long.

What if, thought Meseck, the increased carbon dioxide characteristic of ocean acidification also inhibited shellfish cilia? Feeding and respiration would also be inhibited. This "what if" question led to a study conducted by the NOAA Northeast Fisheries Science Center's laboratory in Milford, Connecticut.

This study may be the first to show that shellfish gill cilia slow down with increasing dissolved carbon dioxide. The results confirm that elevated carbon dioxide concentration reduces feeding rates of blue mussels. Further, the researchers found evidence that slowing the cilia beat frequency--how often they twitch and move water--causes these decreased feeding rates. This is similar to what can happen in human lungs. These findings are important to understanding how ocean acidification affects shellfish and marine ecosystems. The study appeared in Ecological Indicators.

What Happens to Mussels When There's Too Much Carbon Dioxide?

Reduced feeding and filtration have important implications for energy and growth in blue mussels, as well as ecosystem level effects. "Bivalve filtration is an ecosystem service, and how ocean acidification may be affecting that must be better understood," said Meseck.

As atmospheric carbon dioxide concentration increases, the ocean is absorbing approximately 30 percent of it, making the water more acidic. In the Northeastern United States, dissolved carbon dioxide in seawater increased 2.5 percent from 2007 to 2015.

Researchers measured the feeding rates of mussels in low and high carbon dioxide conditions in a field experiment in Milford Harbor. They used a biodeposition method developed by other Milford researchers. For comparison, a similar experiment was conducted in the laboratory, exposing blue mussels to two different carbon dioxide concentrations using an experimental delivery system.

In both the field and laboratory experiments, the volume of water that the mussels filtered over time was lower at higher carbon dioxide levels and higher at lower levels. Mussels in the higher carbon dioxide conditions had significantly lower filtration rates and efficiency in selecting food particles.

The team used a high-speed digital video imaging system with software used in biomedical research to measure cilia beat frequency. They found beat frequency decreased as carbon dioxide concentration increased.

Laboratory Technician Melissa Krisak explained, "It is amazing how often you find great tools from the medical community to help answer questions about marine animals."

Working memory: it's how you make a mental shopping list without forgetting the milk, or memorize a number just long enough to write it down. But working memory is more than a prerequisite for a successful errand--the ability to briefly hold information in our minds lies at the heart of almost everything we do.

And, as a new study of forgetful mice shows, the brain processes behind this skill are more complex than commonly appreciated.

In a paper in Cell, the researchers present evidence that working memory isn't neatly confined to one brain area, but requires the synchronous activity of at least two. The findings challenge long-held assumptions that working memory is the job of just one part of the brain and help scientists pinpoint its genetic and mechanistic basis.

"There were in fact hints from earlier research that multiple brain structures are somehow involved in working memory," says Priya Rajasethupathy, neuroscientist at Rockefeller University. "Our new findings give us more-tangible insights into what these areas are and how they are contributing."

Ingredients of good memory

Pioneering studies in the 70s and 80s traced the neural underpinnings of working memory to the brain's prefrontal cortex. There, neurons appear to preserve information by collectively firing for seconds to minutes, much longer than the millisecond norm for individual neurons. But this mechanism alone doesn't explain the more complicated aspects of working memory--including, for example, how we can hold more than one item in mind, or face distractors and still remember the thing that we care about.

"It became increasingly clear that persistent activity in the prefrontal cortex, while important, can't be the whole story," says Rajasethupathy, Jonathan M. Nelson Family Assistant Professor.

To further investigate this, Rajasethupathy's team partnered with Praveen Sethupathy and his lab at Cornell University to explore how working memory functions among a special population of genetically diverse mice. "Unlike standard lab mice, these mice have a level of genetic diversity mirroring that of human populations," Sethupathy says, "This means some may be great at working memory tasks, and some not so much, and we can study what in their brain's physiology gives rise to that variability."

Mice can't recite a shopping list to show off their memory skills. But when put in a maze, they prefer to explore a new arm of the maze on every visit. How successfully a mouse finds new territory inside the maze is therefore a measure of its working memory.

As expected, the scientists saw broad variations in the mice's performance, and a subsequent genetic analysis highlighted one place in the genome that could explain a considerable portion--17 percent--of that variability.

There, the researchers found one gene with striking effects on the animals' working memory. By boosting its expression, they could turn a mouse from one who used to perform at chance level to one who gets it right 80 percent of the time--or create more forgetful mice by hampering the gene's expression.

From genes to brain circuits

The team then investigated how this gene, which also exists in other mammals and humans, affects a mouse's brain and behavior.

The gene encodes Gpr12, an "orphan receptor," so-called because it's unclear what molecule in the brain activates it. To their surprise, the researchers found these receptors are not in the prefrontal cortex, the presumed seat of working memory, but in neurons much farther away in the brain's thalamus.

High-performing mice had about 2.5 times more of these receptors in their thalamus than low-performing mice. Brain activity recordings revealed that these receptors help establish synchronous activity between the thalamus and the prefrontal cortex during working memory tasks.

This synchrony appears to be essential for maintaining memory, the researchers found: The higher it was, the more likely the mouse was to make an accurate "left or right" choice when it found itself at a fork in the maze, showing it had remembered the information obtained in a previous visit.

"We demonstrate that mice that perform better, have more of these receptors and are therefore able to establish more synchrony," Rajasethupathy said.

The findings expand classical models by revealing the crucial role of the dialogue between the prefrontal cortex and thalamus, suggesting new ways for researchers to think about working memory. Rajasethupathy and her colleagues plan to continue investigating the details of the role played by Gpr12 receptors--work which may lead to potential therapeutic targets for treating deficits in working memory.

"It's rare to find a single gene with a strong influence on a complex cognitive function like working memory," she says. "But it happened to be true in this case, and it led us to unexpected mechanisms involved in working memory."

Skoltech researchers have proposed a fast and accurate numerical method of addressing the problem plaguing electroencephalography (EEG) studies that monitor the brain's electrical activity -- having to laboriously locate the source of EEG signal in the brain due to the low spatial resolution of this method. The new approach may help improve both medical and research applications of EEG. The paper was published in IEEE Transactions on Biomedical Engineering.

Suppose you want to study the properties and activity of a human brain without cracking open the brain owner's skull (invasive research methods have their applications too, but those are understandably limited). You could put the brain, with its owner, into an MRI machine, and that's how most of those trendy studies in the news are done. MRI can offer great spatial resolution in that you could locate brain activations quite accurately. But it is exasperatingly slow, capturing processes that take minutes when a human brain's typical reaction times are in the span of tens and hundreds of milliseconds. Then there's MEG, magnetoencephalography, which is very accurate and more attuned to the quick thinking of humans but requires extremely expensive equipment that needs to be cooled down with liquid helium and operated in a magnetically shielded room.

EEG, electroencephalography, however, is much simpler and easier to set up and use, and it provides a very good temporal resolution; that is why it is so widely used in healthcare and research. There's just one catch, explains Mikhail Malovichko, a coauthor of the study: even a small active area of the cortex generates electrical potential on a large portion of the surface of the head, so an accurate localization of small active patches of the brain is a challenging mathematical task, the so-called inverse EEG problem.

To solve this problem, researchers normally use MRI scans to build a model of the subject's head, place some candidate electric dipoles, essentially best guesses for where the signals might be coming from, and have a computer tinker with the model until its output fits the actual signal measured on the head. For this, the machine has to first solve many complementary forward problems: figure out what kinds of electrical activity these candidate dipoles would generate.

"This approach is universal. The preliminary solution of forward problems reduces the inverse EEG problem to a small system of linear equations, which is of the same type regardless of the position of candidate dipoles and the numerical method used to solve the forward problem. But if one needs to consider each subject's anatomical features, then the forward problem has to be solved by the finite element method, a very resource-intensive numerical procedure," says Nikolay Koshev, another coauthor of the study.

That takes quite a lot of time, so Malovichko and his colleagues from the Skoltech Center for Data-Intensive Science and Engineering (CDISE) have proposed to approach this challenge in a different way. Their solution for the inverse EEG problem directly "backpropagates" measured signals from the skin inside the head down to the cortex. This requires reframing the whole task as a Cauchy problem, a type of mathematical problem that is known to be unstable for EEG: that means even slight deviations in the input, for instance, from unavoidable measurement errors, can significantly skew the result. Yet recent research has brought new approaches to tackling these unstable problems efficiently, and the scientists used them in their research.

"In essence, instead of treating each candidate electric dipole separately and having to solve the forward problem first for each of them, the algorithm now has to solve just one inverse problem, which is, however, of a rather peculiar kind. This helps speed up the processing of EEG data and increases accuracy for source localization; in addition, the algorithm explicitly incorporates the information on how the brain surface is shaped," Mikhail Malovichko says.

"We believe our approach will open the door for a new generation of fast and accurate algorithms for the inverse EEG problem," he concludes.

The power of the sun, wind and sea may soon combine to produce clean-burning hydrogen fuel, according to a team of Penn State researchers. The team integrated water purification technology into a new proof-of-concept design for a sea water electrolyzer, which uses an electric current to split apart the hydrogen and oxygen in water molecules.

This new method for "sea water splitting" could make it easier to turn wind and solar energy into a storable and portable fuel, according to Bruce Logan, Kappe Professor of Environmental Engineering and Evan Pugh University Professor.

"Hydrogen is a great fuel, but you have to make it," Logan said. "The only sustainable way to do that is to use renewable energy and produce it from water. You also need to use water that people do not want to use for other things, and that would be sea water. So, the holy grail of producing hydrogen would be to combine the sea water and the wind and solar energy found in coastal and offshore environments."

Despite the abundance of sea water, it is not commonly used for water splitting. Unless the water is desalinated prior to entering the electrolyzer -- an expensive extra step -- the chloride ions in sea water turn into toxic chlorine gas, which degrades the equipment and seeps into the environment.

To prevent this, the researchers inserted a thin, semipermeable membrane, originally developed for purifying water in the reverse osmosis (RO) treatment process. The RO membrane replaced the ion-exchange membrane commonly used in electrolyzers.

"The idea behind RO is that you put a really high pressure on the water and push it through the membrane and keep the chloride ions behind," Logan said.

In an electrolyzer, sea water would no longer be pushed through the RO membrane, but contained by it. A membrane is used to help separate the reactions that occur near two submerged electrodes -- a positively charged anode and a negatively charged cathode -- connected by an external power source. When the power is turned on, water molecules start splitting at the anode, releasing tiny hydrogen ions called protons and creating oxygen gas. The protons then pass through the membrane and combine with electrons at the cathode to form hydrogen gas.

With the RO membrane inserted, seawater is kept on the cathode side, and the chloride ions are too big to pass through the membrane and reach the anode, averting the production of chlorine gas.

But in water splitting, Logan noted, other salts are intentionally dissolved in the water to help made it conductive. The ion-exchange membrane, which filters ions by electrical charge, allows salt ions to pass through. The RO membrane does not.

"RO membranes inhibit salt motion, but the only way you generate current in a circuit is because charged ions in the water move between two electrodes," Logan said.

With the movement from the bigger ions restricted by the RO membrane, the researchers needed to see if there were enough tiny protons moving through the pores to keep a high electrical current.

"Basically, we had to show that what looked like a dirt road could be an interstate," Logan said. "We had to prove that we could get a high amount of current through two electrodes when there was a membrane between them that would not allow salt ions to move back and forth."

Through a series of experiments recently published in Energy & Environmental Science, the researchers tested two commercially available RO membranes and two cation-exchange membranes, a type of ion-exchange membrane that allows the movement of all positively charged ions in the system.

Each were tested for membrane resistance to ion movement, the amount of energy needed to complete reactions, hydrogen and oxygen gas production, interaction with chloride ions and membrane deterioration.

Logan explained that while one RO membrane turned out to be a "dirt road," the other performed well in comparison to the cation-exchange membranes. The researchers are still investigating why there was such a difference between the two RO membranes.

"The idea can work," he said. "We do not know exactly why these two membranes have been functioning so differently, but that is something we are going to figure out."

Recently, the researchers received a $300,000 grant from the National Science Foundation (NSF) to continue investigating sea water electrolysis. Logan hopes their research will play a critical role in reducing carbon dioxide emissions around the world.

"The world is looking for renewable hydrogen," he said. "For example, Saudi Arabia has planned to build a $5 billion hydrogen facility that is going to use sea water. Right now, they have to desalinate the water. Maybe they can use this method instead."

A previously banned insecticide, which was approved for agricultural use last year in the United States, is harmful for bees and other beneficial insects that are crucial for agriculture, and a second pesticide in widespread use also harms these insects. That is according to a new analysis from researchers at The University of Texas at Austin.

As the agricultural industry turns to new types of pesticides to protect crops, the biologists behind the recent large-scale meta-analysis warn that two of these -- flupyradifurone (sold under the brand name Sivanto®) and the recently approved pesticide sulfoxaflor (sold under the name Transform® WG) -- have harmful effects similar to a class of pesticides known as neonicotinoids, several of which were recently banned in the European Union and Canada. Neonicotinoid pesticides have been shown to be detrimental to honeybees and other beneficial insects.

Postdoctoral researcher Harry Siviter and Felicity Muth, assistant professor of integrative biology, reviewed 19 studies from the past five years on sulfoxaflor and flupyradifurone for the analysis, which appears today in the journal Proceedings of the Royal Society B.

"This research found that exposure to both of these insecticides at field-realistic levels significantly increased insect mortality and impaired insect health," Siviter said.

In 2016, the Environmental Protection Agency banned the use of sulfoxaflor on crops that attract bees, such as cotton. In 2019, the agency approved its use in most circumstances, but it retained restrictions on applying the insecticide to blooming plants that may attract bees. The second insecticide involved in the study, flupyradifurone, is currently approved for agricultural use by the EPA without these restrictions.

"It is clear that these insecticides are harmful to bees," Muth said. She noted that regulators made decisions before scientists had completed all of the research included in the meta-analysis.

In addition to harming honeybees, the insecticides also showed signs of harming other beneficial insects, such as wild bumblebees and lacewings, according to the research.

"We have around 4,000 species of native bees in North America, and they are crucial to our ecosystems," Muth said. "They are the ones we need to be worried about. We need to assess the effects of insecticides on these native bees as part of the regulatory review process."

In addition to increasing mortality in bees, the insecticides had some less than lethal effects, such as reducing reproductive ability and making pollinators less efficient foragers.

"So much of the regulatory process is focused on looking at toxicity, meaning how much of the insecticide you need to kill an insect," Siviter said. "And what research has found over the last decade is that these insecticides can have a lot of sub-lethal effects on pollinators, influencing things like foraging ability or a bee's ability to reproduce. These effects need to be considered in the regulatory process as well, because that can affect survival."

As the globe warms, the atmosphere is becoming more unstable, but the oceans are becoming more stable, according to an international team of climate scientists, who say that the increase in stability is greater than predicted and a stable ocean will absorb less carbon and be less productive.

Stable conditions in the atmosphere favor fair weather. However, when the ocean is stable, the layers of the ocean do not mix. Cooler, oxygenated water from beneath does not rise up and deliver oxygen and nutrients to waters near the surface, and warm surface water does not absorb carbon dioxide and bury it at depth.

"The same process, global warming, is both making the atmosphere less stable and the oceans more stable," said Michael Mann, distinguished professor of atmospheric sciences and director of the Earth System Science Center at Penn State. "Water near the ocean's surface is warming faster than the water below. That makes the oceans become more stable."

Just as hot air rises, as is seen in the formation of towering clouds, hot water rises as well because it is less dense than cold water. If the hottest water is on top, vertical mixing in the oceans slows. Also, melting ice from various glaciers introduces fresh water into the upper layers of the oceans. Fresh water is less dense than salt water and so it tends to remain on the surface as well. Both elevated temperature and salinity cause greater ocean stratification and less ocean mixing.

"The ability of the oceans to bury heat from the atmosphere and mitigate global warming is made more difficult when the ocean becomes more stratified and there is less mixing," said Mann. "Less downward mixing of warming waters means the ocean surface warms even faster, leading, for example, to more powerful hurricanes. Global climate models underestimate these trends."

Mann and his team are not the first to investigate the impact of a warming climate on ocean stratification, but they are looking at the problem in a different way. The team has gone deeper into the ocean than previous research and they have a more sophisticated method of dealing with gaps in the data. They report their results today (Sept. 29) in Nature Climate Change.

"Other researchers filled in gaps in the data with long-term averages," said Mann. "That tends to suppress any trends that are present. We used an ocean model to fill in the gaps, allowing the physics of the model to determine the most likely values of the missing data points."

According to Mann, this is a more dynamic approach.

"Using the more sophisticated physics-based method, we find that ocean stability is increasing faster than we thought before and faster than models predict, with worrying potential consequences," he said.

New research has identified a mechanism by which low levels of insecticides such as, the neonicotinoid Imidacloprid, could harm the nervous, metabolic and immune system of insects, including those that are not pests, such as our leading pollinators, bees.

A study published today in the Proceedings of the National Academy of Sciences USA, led by researchers at the University of Melbourne and Baylor College of Medicine, shows that low doses of Imidacloprid trigger neurodegeneration and disrupt vital body-wide functions, including energy production, vision, movement and the immune system, in the vinegar fly, Drosophila melanogaster.

With insect populations declining around the world and intense use of insecticides suspected to play a role, the findings provide important evidence that even small doses of insecticides reduce the capacity of insects to survive, even those that are not pests.

"Our research was conducted on one insecticide, but there is evidence that other insecticides cause oxidative stress, so they may have similar impacts," Professor Philip Batterham, from the School of BioSciences and Bio21 Institute, at the University of Melbourne, said.

"Our findings emphasize the importance of better understanding the mechanisms of action of insecticides, in particular on beneficial insects. Without further research we do not know if other insecticides are any safer."

Imidacloprid, has been banned from agricultural use by the European Union because of concerns about impacts on honeybees, but remains one of the top selling insecticides in the world. Attacking the central nervous systems of the insects, it increases the transmission of stimuli in the insect nervous system, activating receptors resulting in the insect's paralysis and eventual death.

The researchers arrived at the findings by studying the effects of Imidacloprid in vinegar fly larvae. In the field, the insecticide is generally used at concentrations of up to 2,800 parts per million (ppm). In the lab, researchers tested lower doses, identifying that the very small dose 2.5 ppm was enough to reduce the movement of fly larvae by 50 percent after just two hours of exposure.

"That's an indication of the impact of the insecticide on the function of the brain," said Dr Felipe Martelli, whose PhD work conducted at the University of Melbourne and the Baylor College of Medicine in the laboratory of Professor Hugo Bellen led to the current research paper.

"From there, the accumulation of massive amounts of reactive oxygen species (ROS) or free radicals inside the brain triggers a cascade of damaging events that spread to many other tissues."

Researchers also tested the insecticide on adult flies, finding that flies exposed to very low doses (4 ppm) over 25 days became blind and developed movement problems that affected their ability to climb, symptomatic of neurodegeneration in other parts of the brain.

"Although many studies have shown that low doses of insecticides can affect insect behaviour, they have not uncovered how insecticides trigger changes at the cellular and molecular levels," Dr Martelli, now a research fellow in the School of Biological Sciences at Monash University, said.

Osaka, Japan - Human cells need to work like well-oiled machines to keep our bodies running as they should. Waste products such as misfolded proteins, damaged cellular components, and carbohydrates get in the way and must be quickly disposed of. Dealing with this cellular "trash" are spherical, membrane-bound organelles called lysosomes filled with a mixture of potent enzymes. In a process called autophagy, waste products are contained within a double-membraned vesicle, called an autophagosome, that fuses with a lysosome. The lysosomal enzymes then get to work breaking down the waste into components that can be recycled.

The problem with lysosomes is that if they are ruptured, their contents can leak out and cause serious damage to the cell. Calcium oxalate crystal-induced kidney injury, which is linked to the progression of chronic kidney disease, is actually the result of lysosomal damage caused by the crystals. It is not surprising then that cells have several pathways to repair or quickly eliminate damaged lysosomes. Yet the exact steps in these pathways and how they interact during the lysosomal damage response are not entirely clear.

In a study published in Nature Cell Biology, a team of researchers led by Osaka University have finally unraveled the interactions among the lysosomal damage response pathways and determined how they prevent oxalate-induced kidney injury.

"A protein called TFEB turns on genes necessary for autophagy and the production of new lysosomes in response to lysosomal damage," explains lead author Shuhei Nakamura. "By inhibiting TFEB function in HeLa cells and then inducing lysosome damage, we confirmed that TFEB is activated upon lysosomal damage and is necessary for the removal of damaged lysosomes."

Attachment of lipids to a protein called LC3 is an essential step in the formation of the autophagosome. To their surprise, the researchers also found that lipidated LC3 was necessary for the activation of TFEB during the lysosomal damage response, but there was no clear link between the systems.

"Calcium is a known activator of TFEB," says senior author Tamotsu Yoshimori. "To identify how the TFEB and LC3 systems overlapped, we investigated lysosomal calcium channel TRPML1. We found that lipidated LC3 was recruited by lysosomes in response to damage, and that the lipidated protein interacted with TRPML1, causing increased calcium efflux from the lysosome, which activated TFEB."

The physiological importance of this interaction was then confirmed using a mouse model of oxalate crystal-induced kidney damage. Mice lacking TFEB had more severe kidney damage compared with control animals. Understanding how these pathways interact is the first step in preventing lysosomal damage-associated diseases.

New research has confirmed long-suspected links between sleep apnea and Alzheimer's disease, finding identical signs of brain damage in both conditions.

While the cause of Alzheimer's disease remains a mystery, amyloid plaques that are toxic to brain cells are known indicators of the disease.

The new research showed these plaques start in the same place and spread in the same way in the brains of people with obstructive sleep apnea, as in those with Alzheimer's.

The clinical study by Australian and Icelandic researchers, led by RMIT University, is published in the journal Sleep.

Lead investigator Professor Stephen Robinson said scientists have known the two diseases are related, but what drives the connection is still unclear.

"We know that if you have sleep apnea in mid-life, you're more likely to develop Alzheimer's when you're older, and if you have Alzheimer's you are more likely to have sleep apnea than other people your age," he said.

"The connection is there but untangling the causes and biological mechanisms remains a huge challenge.

"Our study is the first to find Alzheimer's-like amyloid plaques in the brains of people with clinically-verified obstructive sleep apnea.

"It's an important advance in our understanding of the links between these conditions and opens up new directions for researchers striving to develop therapies for treating, and hopefully preventing, Alzheimer's disease."

Significantly, the severity of sleep apnea was linked with a corresponding build-up of amyloid plaques.

The study found that treatment with continuous positive airway pressure (CPAP) - the standard approach for moderate to severe sleep apnea - made no difference to the amount of plaques found in the brain.

Brain damage connection

Obstructive sleep apnea (OSA) is a serious condition that occurs when a person's breathing is repeatedly interrupted during sleep.

OSA is increasingly common, affecting more than 936 million people worldwide and up to 30% of elderly people.

Alzheimer's is the most common form of dementia, affecting up to 70% of all people with dementia, with age the biggest risk factor for developing the disease.

The new study investigated the extent of Alzheimer's-like indicators in autopsy tissue from the hippocampus of 34 people and the brainstems of 24 people with OSA.

The researchers looked for both amyloid plaques and neurofibrillary tangles, another known indicator of Alzheimer's disease.

The hippocampus is the part of the brain associated with memory.

In Alzheimer's disease, plaques and tangles first appear in a nearby cortical area and then move into the hippocampus, before spreading to the rest of the cortex.

While the study found both plaques and tangles in the brains of people with sleep apnea, the plaques showed a stronger association with severe sleep apnea.

"In cases of mild sleep apnea, we could only find plaques and tangles in the cortical area near the hippocampus, precisely where they are first found in Alzheimer's disease," said Robinson, a researcher in RMIT's School of Health and Biomedical Sciences and Austin Health's Institute for Breathing and Sleep (IBAS).

The subjects of the research showed no clinical symptoms of dementia before they died, suggesting they may have been in an early pre-dementia stage.

"While some people may have had mild cognitive impairment or undiagnosed dementia, none had symptoms that were strong enough for an official diagnosis, even though some had a density of plaques and tangles that were sufficiently high to qualify as Alzheimer's disease," Robinson said.

"The next stage for our research will be to continue analysing these samples to get a full understanding of the neuropathology, including signs of inflammation and changes to the blood vessels that supply nutrients to the brain.

"The sample size for this study was limited, so we would also like to work towards establishing a clinical study with a larger cohort."

Landslides have long-term effects on tundra vegetation, a new study shows. Conducting the study in North West Siberia, the researchers found that tundra vegetation regenerated rapidly after a major landslide event in 1989. Two decades later, differences in the vegetation of the landslide area and the areas surrounding it have evened out, but even after 30 years, the vegetation of the landslide area is nowhere close to the vegetation of the surrounding areas.

Several studies have reported changes in the Normalized Difference Vegetation Index (NDVI) in Arctic regions. So far, remote sensing data that is used to calculate the NDVI hasn't been able to discern, in detail, landscape level factors that have an effect on, e.g., greening.

"Landslides caused by the thawing of permafrost will become increasingly common in North West Siberia and elsewhere in the Arctic, too. These are caused by climate change and they also have an effect on vegetation. However, the exact effect of landslides on NDVI is difficult to discern from low-resolution satellite data," Professor Timo Kumpula from the University of Eastern Finland says.

The researchers point out that permafrost thawing also has implications for all construction. Indeed, the Bovanenkovo gas field, one of Russia's largest gas fields in the Arctic, is located in the study site. Permafrost thawing can cause structural collapses and put infrastructure at risk. This, in turn, could lead to various types of environmental damage.

VHR satellite data sheds detailed light on regional changes in vegetation

Published in Environmental Research Letters, the study was conducted in collaboration between the University of Eastern Finland, Northern Arizona University and the University of Lapland. In addition to data from the Landsat satellite, the researchers used very high resolution (VHR) satellite data from the QuickBird-2 and WorldView-2 and 3 satellites to analyse post-landslide changes in vegetation. The study site on the Yamal Peninsula covers 35 square kilometres.

"VHR satellite images allow us to see very small changes in the land cover, such as temporary degradation of vegetation or new landslides that can be very small, even less than 0.1 hectares in size. We can also see sites where existing permafrost thawing expands," Researcher Mariana Verdonen from the University of Eastern Finland says.

CO2 electroreduction reaction driven by renewable electricity is an effective way to reduce the concentration of CO2 in the atmosphere and alleviate environmental problems such as global warming. It can convert CO2 into valuable products (such as CO, HCOOH, CH4) to realize effective carbon cycle. At present, the reported highly efficient electrocatalysts for electrocatalytic CO2 reduction reaction (CO2RR) are mainly concentrated on nanomaterials. Among them, N-doped or N-heterocyclic nanostructured electrocatalysts have made important progress in reduction product conversion and Faraday efficiency. However, due to the lack of accurate and clear structural information and other influencing factors (including defects and impurities), it is still difficult to determine the activity of N sites in these electrocatalysts.

In this case, the crystal electrocatalysts with clear crystal structure have great advantages in solving the above problems, because their accurate structure information can provide a visual research platform for identifying catalytic active sites and studying reaction mechanism. Metalloporphyrin complexes applied in CO2RR have many advantages. Among them, the rigid ring with conjugated π - electron system of metalloporphyrin is favorable to the rapid electron migration. More importantly, their clear molecular structure information and structural tunability are very helpful for studying reaction mechanisms and rationally optimizing catalytic performance.

Based on this, establishing a reasonable crystal model system to accurately identify the activity of catalytic sites in electrocatalysis is very important for the development of electrocatalytic CO2RR.

In a new research paper published in National Science Review (NSR), the research group of professor Ya-Qian Lan of Nanjing Normal University, for the first time, established a crystal supramolecular coordination compound model system (including Ni-TPYP, Ni-TPYP-1 and Ni-TPP, as shown in Figure 1) to identify structurally the catalytic activity of pyridine N for electrocatalytic CO2RR. This work is of great significance for understanding the catalytic activity and reaction mechanism of N-doped or N-heterocyclic nanostructured electrocatalysts in electrocatalytic CO2RR.

Experimental and theoretical calculations show that the rate determining step (RDS) of electrocatalytic CO2RR in this system is the formation of *COOH. In this step, the energy required for Ni active site (denoted as Ni1) in Ni-TPYP and Ni active site (denoted as Ni2) in Ni-TPP are almost the same (1.60 eV and 1.59 eV) and both are higher than that of active pyridine N (denoted as N, 0.97 eV) in Ni-TPYP, indicating that N site has higher CO2 electroreduction activity than Ni2 and Ni1 sites, that is, active pyridine N is a more suitable catalytic active site.

Researchers in the group of Jeroen den Hertog, in collaboration with researchers in Leiden, have found that a compound inhibits a group of proteins called BMP receptors. This compound, called cercosporamide, was previously only known to inhibit a different group of proteins. When overactive, BMP receptors can induce several diseases. Studying compounds that may counteract this overactivity may lead to more treatment options in the future. Their results were published in the scientific journal Disease Models & Mechanisms.

Fungi

We constantly need new therapeutic compounds for use in the clinic for various reasons, including our increasing age, corresponding illnesses and resistance to existing drugs. Fungi are an excellent, but underexplored source of these kinds of compounds. Researcher Jelmer Hoeksma explains: "Every year new compounds produced by fungi are identified, but so far we have only investigated a very small subset of all existing fungi. This suggests that many more biologically active compounds remain to be discovered."

Together with the Westerdijk Fungal Biodiversity Institute, home to the largest collection of live fungi in the world, the researchers set up a large library of filtrates derived from more than ten thousand different fungi. A filtrate contains all the products that the fungus excretes. To search for therapeutic compounds, the researchers investigate the effects of fungal products present in this large library on zebrafish embryos. This enables them to study effects on the whole body during development.

Cercosporamide

Using this approach, the researchers identified a compound, called cercosporamide, that had an effect in zebrafish. This effect is known for a certain type of molecules that inhibit a group of proteins called BMP receptors. When these BMP receptors are overactive, they can induce several diseases, such as Fibrodysplasia ossificans progressiva. In people that suffer from this disease, muscle tissue is progressively replaced with bone tissue, leading to a severe loss of mobility over time. Therefore, finding new compounds that may counteract overactive BMP receptors may provide new options for treatment of such diseases.

Although the compound cercosporamide had been identified before, its effect on BMP receptors was unknown until now. The researchers discovered this additional effect because they tested the effects of compounds on whole zebrafish embryos. Additional tests in both zebrafish and human cells confirmed the results.

Surprisingly, the molecules of cercosporamide have a completely different structure compared to other common BMP receptor inhibitors. So, even if cercosporamide itself turns out unusable as therapeutic drug, there may be a completely different class of structurally related chemicals that may have BMP receptor inhibiting effects.

More compounds

Currently, the researchers are looking for other bioactive compounds. Hoeksma: "For now, we are continuing to look for (new) compounds and understand their effects. Thus far, we only investigated a small subset of all these fungal products - we have only scratched the surface."

While the majority of snakes would normally swallow their prey whole, the Small-banded Kukri Snake seems to have evolved a particularly macabre feeding habit that has never before been witnessed in a serpent.

During a survey on the relatively small-bodied Asian kukri snakes in Thailand, a Danish-Thai research team, led by Henrik Bringsøe, documented three occasions where a snake uses its enlarged posterior maxillary teeth to cut open the abdomen of a large poisonous toad, then inserts its entire head and pull out the organs one by one, while the prey is still alive. The discovery is published in the open-access, peer-reviewed journal Herpetozoa.

In those gory attacks, the toads struggled vigorously to escape and avoid being eviscerated alive, but, on all occasions, this was in vain. The assaults could last for up to a few hours, depending on the organs the snake would pull out first.

The toads observed belong to the quite common species called Asian Black-spotted Toad (Duttaphrynus melanostictus), which is known to secrete a potent toxin from their prominent parotid glands, located on the neck. Could it be that the snakes have adopted this sophisticated and gruesome approach to avoid being poisoned?

In a fourth, and equally important, case, an adult kukri snake attacked a somewhat smaller individual of the same toad species. This time around, the snake swallowed the entire toad. Why, the researchers still remain to understand. One hypothesis is that smaller toads are less toxic than adults. On the other hand, the kukri snakes might be indeed resistant to the Asian Black-spotted toad's poison, yet the large size of adult toads could be what have prevented swallowing the whole victim in the three afore-mentioned cases.

"At present, we cannot answer any of these questions, but we will continue to observe and report on these fascinating snakes in the hope that we will uncover further interesting aspects of their biology," says Bringsøe.

"Perhaps you'd be pleased to know that kukri snakes are, thankfully, harmless to humans. However, I wouldn't recommend being bitten by one of those. The thing is that they can inflict large wounds that bleed for hours, because of the anticoagulant agent these snakes inject into the victim's bloodstream. Their teeth are designed to inflict lacerations rather than punctures, so your finger would feel as if cut apart! This secretion, produced by two glands, called Duvernoy's glands and located behind the eyes of the snakes, are likely beneficial while the snakes spend hours extracting toad organs," he explains in conclusion.