Earth

Receptor location plays a key role in their function

image: Beta1- and beta2-adrenergic receptors in heart muscle cells: In the left cell, beta1 receptors are labeled -- they are found both on the cell surface (yellow) and in the T-tubules (green). In the right cell, the beta2-receptors are labeled -- they appear only in the T-tubules (green), but not on the cell surface (which is therefore not visible in the image).

Image: 
Marc Bathe-Peters & Horst-Holger Boltz

In the heart there are two different subtypes of beta-adrenergic receptors - beta1 and beta2 - which are activated by the stress hormones adrenaline and noradrenaline. They both trigger the strongest stimulation of the heart rate and pumping capacity that we know of. The two subtypes are highly similar biochemically, but differ substantially in terms of their functional and therapeutic relevance.

Both receptor types can stimulate the heart in the short term, yet when the beta1 receptor is activated over a prolonged period of time, it has a range of effects that are not seen with beta2. Beta1 can elicit a number of persistent changes and is endowed with the ability to initiate - oftentimes detrimental - growth of the heart muscle cells by activating various genes.

Recent studies by researchers at the Universities of Würzburg and Erlangen, the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) in Berlin, and the ISAR Bioscience Institute in Munich-Planegg have now shed light on the mechanisms behind these different effects. The research teams have published the results of their work in the current issue of the journal Proceedings of the National Academy of Sciences of the USA.

Special ligands and new microscopy methods

"Using a fluorescent ligand synthesized at the University of Erlangen and novel highly sensitive microscopy methods, we were able to show for the first time where these receptors are located on heart muscle cells," explains Professor Martin Lohse of the Institute of Pharmacology and Toxicology at the Julius Maximilians University of Würzburg (JMU). He is co-lead author of the study along with Dr. Paolo Annibale, who is acting head of the MDC's Receptor Signaling Lab. "The endogenous receptors are expressed at relatively low levels," explains Annibale. "To detect their movement, it was necessary to use a form of spectroscopy based on the analysis of the signal's minute fluorescence fluctuations."

This revealed that beta1 receptors are found on the entire surface of heart muscle cells, while beta2 receptors are exclusively found in specific structures in these cells called T-tubules. Through invaginations of the cell surface, these tubules create a pipe-like network that runs through the entire interior of heart muscle cells. "One of the research focuses of our team at the MDC is the relationship between receptor function and subcellular localization," adds Annibale. "So the biophysical environment of T-tubules, which have curved membranes, is of particular interest to us."

Not all heart muscle cells have beta1 receptors

"The specific cellular location of beta2 receptors explains why they have a much narrower range of functionality than beta1 receptors and why they are limited to direct and short-term stimulation of the heart," explains Lohse. Such stimulation is mediated by signals that are locally restricted to the cell membrane. In contrast, gene activation and cell growth stimulation occur via more far-reaching signals that can only be triggered at the cell surface, where only beta1 receptors are located.

Another surprising finding of the study is that not all heart muscle cells have these receptors. "There are apparently different types or states of heart muscle cells, so not all cells respond to adrenaline," Lohse said. Until now, it was assumed that heart muscle cells in the large chambers were all the same.

New target for heart failure therapy

It has been known for many years that in chronic heart failure, too much adrenaline and noradrenaline circulate in the bloodstream and stimulate the heart to such an extent that it causes changes in the heart and its cells to grow. This initially compensates for heart failure, but in the long run the excessive growth damages the heart. Therefore, based in part on earlier findings by the Würzburg team, blocking beta receptors has become the accepted therapy for chronic heart failure.

The new findings now show why beta1 receptors play a much greater role in producing these adverse effects than beta2 receptors. Beta1 receptors are localized on the entire cell surface, enabling them to have a more diverse impact than beta2 receptors. The new knowledge about the differential localization and distinct functional effects of beta1 and beta2 receptors in the heart could possibly be exploited to develop better therapies for chronic heart failure. These would selectively inhibit the harmful effects of beta receptors (such as heart muscle cell growth), while at the same time activating the beneficial effects (such as stimulation of heart function).

Credit: 
University of Würzburg

Plants use a blend of external influences to evolve defense mechanisms

image: An image of Arabidopsis thaliana (A. thaliana) -- a type of cress.

Image: 
Public domain

Plants evolve specialised defence chemicals through the combined effects of genes, geography, demography and environmental conditions, a study published today in eLife reports.

The findings reveal a pattern in the types of defence chemicals plants produce across Europe, and describe some of the evolutionary processes that create them.

As plants are immobile organisms, they rely on producing defence chemicals called specialised metabolites for survival. Specialised metabolites have extensive variation in their structure, such as the number of carbon molecules and the other chemical groups that attach to those carbon molecules. Each plant under each environment has a unique profile of specialised metabolites as a result of genetic variation that has developed over years by different evolutionary processes and events.

"We already know that environmental pressures such as the type of herbivores that prey on plants influences the specialised metabolites plants produce," explains first author Ella Katz, Postdoctoral Researcher at the Department of Plant Sciences, University of California, Davis, US. "We wanted to understand how the intersection of environmental pressure, demography and genomic complexity gives rise to the pattern of metabolic variation across a plant species."

To do this, the team measured the variation in specialised metabolites across a population of almost 800 seed samples of the plant species Arabidopsis thaliana (A. thaliana) - a type of cress - taken from across Europe.

They looked at three locations in the plant genome known to influence A. thaliana's survival fitness as well as across the entire genome to find genes linked to metabolite production. They then grouped each gene into classes representing types of specialised metabolite, called chemotypes. This allowed them to see which chemotypes were most prevalent in different regions of Europe and reveal specific geographic patterns. For example, in central Europe and parts of Northern Europe, such as Germany and Poland, there was large variability in the chemotypes. But in southern Europe, including the Iberian Peninsula, Italy and the Balkan, there were two predominant chemotypes that were clearly geographically separated.

Next, they looked at whether these geographical differences in chemotypes were linked to weather and landscape conditions. They assigned each gene an environmental value based on its location - such as distance to the coast, rainfall in the wettest and driest months, and temperature of the warmest and coldest months. They also assigned the genes to Northern or Southern locations, based on their position relative to the Pyrenees, Alps or Carpathian mountain ranges. Using the most commonly found chemotypes, they showed that the environmental conditions had different relationships to the chemotypes that shift by geographical area. This suggests that the relationship between environmental conditions and specialised metabolites varies across different regions in Europe - so, even if wetter weather was linked to a certain chemotype in Southern Europe, this was not the same in Northern Europe.

Finally, they looked at how these genes evolved over time. Gene traits can evolve either independently within a species, called convergent evolution, or by parallel evolution, where species respond to similar external challenges in a similar way. They found that gene evolution at the three most common genome locations was shaped by a blend of events reminiscent of either parallel or convergent evolution. Moreover, the presence of variation at each of the three locations also plays a role in further shaping the evolution of the other genes. This is most likely because the effects of different specialised metabolites may work with or against each other to help the plant survive.

"Our work provides a new perspective on the complexity of the forces and mechanisms that shape the generation and distribution of specialised metabolites and affect the plant's ability to survive in a changing environment," concludes senior author Daniel Kliebenstein, Professor at the Department of Plant Sciences, University of California, Davis, and the DynaMo Center of Excellence, University of Copenhagen, Denmark. "Using a larger plant population from other locations around the world will enable us to deepen our understanding of the evolutionary mechanisms that determine the variation in a population."

Credit: 
eLife

Yale Cancer Center study reveals new pathway for brain tumor therapy

New Haven, Conn. --In a new study led by Yale Cancer Center, researchers show the nucleoside transporter ENT2 may offer an unexpected path to circumventing the blood-brain barrier (BBB) and enabling targeted treatment of brain tumors with a cell-penetrating anti-DNA autoantibody. The study was published today online in the Journal of Clinical Investigation Insight.

"These findings are very encouraging as the BBB prevents most antibodies from penetrating the central nervous system and limits conventional antibody-based approaches to brain tumors," said James E. Hansen, MD, associate professor of therapeutic radiology, radiation oncology chief of the Yale Gamma Knife Center at Smilow Cancer Hospital, and corresponding author of the study.

Deoxymab-1 (DX1) is an unusual cell-penetrating autoantibody that localizes into live cell nuclei, inhibits DNA repair, and is synthetically lethal to cancer cells with defects in the DNA damage response (DDR). Researchers have now found that the transporter ENT2 facilitates brain endothelial cell penetration and BBB transport by DX1. In efficacy studies in mice models, DX1 crossed the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases.

"Our data demonstrate the ability of DX1 to cross the BBB and suppress brain tumors in multiple models, and we are particularly impressed that DX1 was able to yield these results as a single agent in these difficult to treat tumor models," said Jiangbing Zhou, associate professor of neurosurgery at Yale School of Medicine and co-corresponding author of the study.

"We believe that the ENT2-linked mechanism that transports DX1 across the BBB and into tumors has potential to contribute to multiple new strategies in brain tumor therapy," added Hansen. "In addition to establishing proof of concept for single agent use of DX1 in brain tumor models, we also now recognize the potential for DX1 to target linked cargo molecules to brain tumors or to be useful as a platform for designing additional brain tumor targeting antibodies, including DX1-based bispecific antibodies."

Credit: 
Yale University

Teens experienced helplessness when exposed to secondhand racism

This past year has been transformational in terms of not only a global pandemic but a sustained focus on racism and systemic injustice. There has been a widespread circulation of images and videos in the news and online. Just like adults, adolescents are exposed to these images with important consequences for their emotional health and coping. However, few studies have sought to understand the influence of racism experienced online.

According to a qualitative study published in JAMA Network Open adolescents expressed feelings of helplessness when exposed to secondhand racism online. Specifically, adolescents described helplessness stemming from the pervasiveness of racism in our society. This was illustrated by quotes, such as "[racist events are] just another day in the life" referring to racism as a constant force and unmovable by saying, "there's nothing I can do." However, many adolescents emphasized activism as a way to cope with the vicarious racism they experience. One adolescent stated, "Yeah, and then sometimes my response is it's something I can do something about, like right now..." Further, participation in activism may help mitigate negative feelings.

Lead study author, Dr. Nia Heard-Garris, MD, MSc is a pediatrician and physician-investigator at the Ann & Robert H. Lurie Children's Hospital of Chicago and an Assistant Professor of Pediatrics at Northwestern University Feinberg School of Medicine. The study team conducted 4 focus groups of 18 adolescents across the Chicagoland area between November 2018-April 2019. Dr. Heard-Garris noted that teens felt that adults underestimated how much they witness discrimination around them. One adolescent said, "It's funny because a lot of people think that teenagers are not socially aware, but I think the friends I keep around me, once we start talking about something, it goes on and on and on and on..."

It is important to note that this study, that took place prior to the wave of racialized violence of Black Americans publicized in the summer of 2020, however, it emphasizes the need to study how adolescents respond to witnessing these events. Dr. Nia Heard-Garris states, "Investigating adolescents' exposure and response to racism online proves critical because of the negative changes in emotional state and potential adverse physical and mental health across the life course." The researchers of this study also highlight that "this study aligns with previous studies that demonstrate social cohesion or connectedness can buffer the negative influence racism has on health generally, and the benefits of activism may be because adolescents can connect to a larger social network to draw support and participate in collective action."

Credit: 
Ann & Robert H. Lurie Children's Hospital of Chicago

Soaking up the sun: Artificial photosynthesis promises clean, sustainable source of energy

image: Yulia Pushkar, a Purdue biophysicist, is working to decipher photosynthesis to unlock the possibilities of artificial photosynthesis as a reliable, clean energy source.

Image: 
Purdue Univeristy/Rebecca McElhoe

Humans can do lots of things that plants can't do. We can walk around, we can talk, we can hear and see and touch. But plants have one major advantage over humans: They can make energy directly from the sun.

That process of turning sunlight directly into usable energy - called photosynthesis - may soon be a feat humans are able to mimic to harness the sun's energy for clean, storable, efficient fuel. If so, it could open a whole new frontier of clean energy. Enough energy hits the earth in the form of sunlight in one hour to meet all human civilization's energy needs for an entire year.

Yulia Puskhar, a biophysicist and professor of physics in Purdue's College of Science, may have a way to harness that energy by mimicking plants.

Wind power and solar power, harnessed by photovoltaic cells, are the two major forms of clean energy available. Adding a third -- synthetic photosynthesis -- would dramatically change the renewable energy landscape. The ability to store the energy easily, without requiring bulky batteries, would dramatically improve humans' ability to power society cleanly and efficiently.

Both wind turbines and photovoltaics have downside in terms of environmental effects and complicating factors. Pushkar hopes that artificial photosynthesis might be able to bypass those pitfalls.

"We and other researchers around the world are working incredibly hard to try to come up with accessible energy," Pushkar said. "Energy that is clean and sustainable that we can create with nontoxic, easily available elements. Our artificial photosynthesis is the way forward."

Photosynthesis is a complex dance of processes whereby plants convert the sun's radiance and water molecules into usable energy in the form of glucose. To do this, they use a pigment, usually the famous chlorophyll, as well as proteins, enzymes and metals.

The closest process to artificial photosynthesis humans have today is photovoltaic technology, where a solar cell converts the sun's energy into electricity. That process is famously inefficient, able to capture only about 20% of the sun's energy. Photosynthesis, on the other hand, is radically more efficient; it is capable of storing 60% of the sun's energy as chemical energy in associated biomolecules.

The efficiency of simple photovoltaic cells - solar panels - is limited by semiconductors' ability to absorb light energy and by the cell's ability to produce power. That limit is something scientists could surpass with synthetic photosynthesis.

"With artificial photosynthesis, there are not fundamental physical limitations," Pushkar said. "You can very easily imagine a system that is 60% efficient because we already have a precedent in natural photosynthesis. And if we get very ambitious, we could even envision a system of up to 80% efficiency.

"Photosynthesis is massively efficient when it comes to splitting water, a first step of artificial photosynthesis. Photosystems II proteins in plants do this a thousand times a second. Blink, and it's done."

Pushkar's group is mimicking the process by building her own artificial leaf analog that collects light and splits water molecules to generate hydrogen. Hydrogen can be used as a fuel by itself via fuel cells or be added to other fuels such as natural gas, or built into fuel cells to power everything from vehicles to houses to small electronic devices, laboratories and hospitals. Her most recent discovery, an insight into the way water molecules split during photosynthesis, was recently published in the journal Chem Catalysis: Cell Press.

Scientists in Pushkar's lab experiment with natural photosystem II proteins and synthetic catalysts combinations in attempts to understand what works best - and why. She also puts a priority on using compounds and chemicals that are readily abundant on Earth, easily accessible and nontoxic to the planet.

Progress in artificial photosynthesis is complicated, though, by the fact that photosynthesis is so multifaceted, a fact bemoaned by biochemistry students everywhere.

"The reaction is very complex," Pushkar said. "The chemistry of splitting water molecules is extremely intricate and difficult."

Scientists have been working on artificial photosynthesis since the 1970s. That's a long time, but not when you remember that photosynthesis took millions of years to evolve. Not only that, but scientists believe that, unlike flight, communication or intelligence, photosynthesis has evolved only once - about 3 billion years ago, only about 1.5 billion years into Earth's existence.

Pushkar posits that within the next 10-15 years, enough progress will have been made that commercial artificial photosynthesis systems may begin to come online. Her research is funded by the National Science Foundation.

Credit: 
Purdue University

Scientists explain the crucial role of motor proteins in cell division

video: Spindle elongation depends on the joint activity of the motor EG5/kinesin-5 and the microtubule crosslinker PRC1. Without them, elongation is completely blocked, which is visible from this movie with chromosomes stained by SiR-DNA and color-coded for depth.

Image: 
Toli? Lab

Proper chromosome segregation into two future daughter cells requires the mitotic spindle to elongate in anaphase. However, although some candidate proteins are implicated in this process, the molecular mechanism that drives spindle elongation in human cells has been unknown, until now! Researchers at the Croatian Ruđer Bošković Institute (RBI) have discovered the exact molecular mechanism of bridging microtubules sliding and its role in proper distribution of genetic material during cell division. These latest results were published in the scientific journal Developmental Cell (IF: 10.092).

Cell division is a fundamental process required for stable transmission of genetic information from a parent cell to two daughter cells. Sister chromatids segregate into future daughter cells during anaphase by kinetochore fibre shortening (anaphase A) and spindle elongation (anaphase B).

Moreover, the importance of spindle elongation in human cells is evident from the fact that in addition to being the main driver of chromosome movement, it promotes correct segregation of lagging chromosomes, and its defects correlate with cancer.

Since this is one of the key steps in cell division, which occurs in almost all organisms, the molecular mechanism that drives spindle elongation has been in the spotlight of intensive research for many decades now. Although there has been some important breakthrough made in the last twenty years, that shed light on the molecular mechanisms behind the elongation process, the researchers did not manage to identify the exact proteins involved in the self-elongation of the spindle in human cells.

However, the team of molecular biologist at the Croatian Ruđer Bošković Institute - Dr Kruno Vukušić, doctoral students Ivana Ponjavić, Patrik Risteski and Dr Renata Buđa, led by Prof Iva Tolić, discovered that two mechanistically distinct sliding modules, one based on a self-sustained kinesin and the other on a crosslinker-assisted kinesin motor, power the mechanism of spindle elongation in human cells.

"We hope these results will encourage new research into the role of spindle elongation in the final steps of cell division, when the cell completes the division between the newly formed daughter cells. I believe these results are just the first step on a path of elucidating the complex control mechanisms acting behind these motor proteins, that operate under strict control of many other factors in the cell. Moreover, the principle of co-operation between these motor proteins, that we have described, could help other scientists in determining molecular mechanisms in other crucial cell processes," said Professor Iva Tolić, research leader.

What molecular mechanisms are responsible for spindle elongation?

The mitotic spindle is crucial to the process of cell division. It is a dynamic and complex cellular structure made of microtubules and associated proteins. In addition to providing structural support within cells, among many other roles, these microtubules provide tracks for motor proteins, which transport chromosomes with our genetic material and position them in the centre of the mitotic spindle. They are assisted by special motor and microtubule-binding proteins.

After all the chromosomes have been successfully connected to the microtubules on either side of the mitotic spindle, the bond between sister chromatids, that make up the chromosome, breaks down and the chromatids begin their journey at the two distant halves of the mitotic spindle. At the same time, the mitotic spindle begins to elongate to further contribute to the physical removal of chromatids, which is the final goal of any division process.

"We wanted to understand which motor proteins are responsible for elongation of the mitotic spindle in anaphase, so we developed a set of tools to remove individual proteins and groups of proteins at a specific time, just before the spindle elongation. We also used various other methods, some of which we adapted for the first time to the study of the mitotic spindle, which allowed us to study the organization of microtubules in the central part of the mitotic spindle. We used methods that enable very rapid monitoring of dynamic changes in bridging microtubules, structure we have previously shown to be crucial for proper chromosome segregation in human cells." explains Dr. Kruno Vukušić, postdoctoral fellow in the Tolić Lab, who is one of the first authors on this paper together with his colleague Ivana Ponjavić.

The key role of motor proteins KIF11 and KIF4A

"By applying the approach of simultaneous silencing of the function of multiple motor proteins, we wanted to discover a potential network of independent motor protein systems involved in the process of the mitotic spindle elongation. By using this approach, we observed that after simultaneous removal of the activity of KIF11 protein and KIF4A protein, spindle elongation does not occur at all, unlike their individual perturbations, which means that combined work of these proteins is crucial for elongation. This is the first case of stopping the elongation of the mitotic spindle by removal of specific motor proteins in human cells. In addition, we have seen that the KIF4A protein depends on the PRC1 protein to localize bridging fibres, so the same effect can be obtained by silencing the PRC1 protein combined with inhibition of the KIF11 motor protein." says Patrik Risteski, a doctoral student and one of the authors of the paper.

Further experiments demonstrated that independent motor proteins KIF11 and KIF4A participate specifically in the sliding of bridging microtubules, which then push the poles of the mitotic spindle from each other. This confirms that their role in the sliding of antiparallel microtubule bundles also occurs in anaphase cells, since the same has been shown in previous works only in vitro.

"These results have led us to conclude that anaphase B is a process driven by independent motor protein systems that have quite different mechanisms of action and probably different control mechanisms. This means that the cell ensures by the use of independent modules very high success of this process, which is not surprising, since it is one of the riskiest processes for the fate of future daughter cells that arise as a result of the division of the mother cell.

This work has shown that the consequences of unsuccessful elongation of the mitotic spindle are devastating for the division of human cells and the properly balanced inheritance of genetic material." concludes Professor Iva Tolić.

Credit: 
Ruđer Bošković Institute

PSMA-targeted radiotracer pinpoints metastatic prostate cancer across anatomic regions

image: Case example: A 54-year-old man with a history of RP+LND and a subsequent PSA of 1.25 ng/mL had no evidence of disease by baseline imaging. Piflufolastat F 18 (18F-DCFPyL)- PET/CT accurately detected biochemically recurrent prostate cancer with the PSMA PET/CT scan identifying positive left (left panel) and right peri-rectal lymph nodes (right panel).

Image: 
Images courtesy of Lantheus Holdings, Inc., Billerica, MA.

Reston, VA (Embargoed until 3:00 p.m. EDT, Tuesday, June 15, 2021)--A phase III clinical trial has validated the effectiveness of the prostate-specific membrane antigen (PSMA)-targeted radiotracer 18F-DCFPyL in detecting and localizing recurrent prostate cancer. Approved by the U.S. Food and Drug Administration last month, the radiotracer identified metastatic lesions with high positive predictive values regardless of anatomic region, adding to the evidence that PSMA-targeted radiotracers are the most sensitive and accurate agents for imaging prostate cancer. This study was presented at the Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2021 Annual Meeting.

Prostate cancer patients have high levels of PSMA expression, which makes PSMA an effective target for imaging the disease. In previous studies, the novel positron emission tomography (PET) imaging agent 18F-DCFPyL was found to bind selectively with high affinity to PSMA. To demonstrate the diagnostic performance of 18F-DCFPyL for regulatory approval, a prospective, multicenter study was conducted in 14 sites across the United States and Canada.

The study sought to determine the positive predictive value (the probability that patients with a positive screening test actually have the disease) and detection rate of 18F-DCFPyL PET/computed tomography (CT) by anatomic region, specifically the prostate/prostate bed, pelvic lymph nodes, and regions outside the pelvis. Study participants included men who had rising prostate-specific antigen (PSA) levels after local therapy as well as negative or equivocal conventional imaging results.

Patients were imaged with 18F-DCFPyL PET/CT, then imaged again after 60 days to verify suspected lesions using a composite "standard of truth," which consisted of histopathology, correlative imaging findings and PSA response. Comparing findings between the 18F-DCFPyL imaging and the "standard of truth," the positive predictive value and detection rate were measured.

18F-DCFPyL-PET/CT was found to successfully detect and pinpoint metastatic lesions with high positive predictive value, regardless of their location in the body, in men with biochemically recurrent prostate cancer who had negative or equivocal baseline imaging. Higher positive predictive values were observed in extra-pelvic lymph nodes and bone compared to soft tissue regions.

With the recent approval of 18F-DCFPyL (now referred to as piflufolastat F-18) by the FDA, the impact of this research may be realized in the very near future. As these agents become more widely available, patients with newly diagnosed, recurrent, and metastatic prostate cancer may have new therapeutic approaches available to them. The results of the study will be presented at the SNMMI meeting by Steven Rowe, MD, PhD, associate professor of radiology and radiological science at Johns Hopkins University in Baltimore, Maryland.

Abstract 123. "A Phase 3 study of 18F-DCFPyL-PET/CT in Patients with Biochemically Recurrent Prostate Cancer (CONDOR): An Analysis of Disease Detection Rate and Positive Predictive Value (PPV) by Anatomic Region," Steven Rowe and Michael Gorin, Johns Hopkins, Baltimore, Maryland; Lawrence Saperstein, Yale School of Medicine, New Haven, Connecticut; Frederic Pouliot, Departement de Chirurgie, Division d'Urologie, University of Quebec, Quebec, Canada; David Josephson, Tower Urology, Cedars Sinai Medical Center, Los Angeles, California; Peter Carroll, UCSF, San Francisco, California; Jeffrey Wong, City of Hope, Sierra Madre, California; Austin Pantel, University of Pennsylvania Health System, Philadelphia, Pennsylvania; Morand Piert, University of Michigan, Ann Arbor, Michigan; Kenneth Gage, Diagnostic Imaging and Interventional Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; Steve Cho, University of Wisconsin-Madison, Madison, Wisconsin; Andrei Iagaru, Stanford University, Stanford, California; Janet Pollard, University of Iowa Hospital, Iowa City, Iowa; Vivien Wong, Jessica Jensen and Nancy Stambler, Progenics Pharmaceuticals, Inc., New York, New York; Michael Morris, Memorial Sloan-Kettering Cancer Center, New York, New York; and Barry Siegel, Washington University School of Medicine, St. Louis, Missouri.

Credit: 
Society of Nuclear Medicine and Molecular Imaging

The long view

What will the Earth be like for our children and grandchildren, as temperatures continue to rise? We can be fairly certain of some things: Some regions will become inhospitable, as heat drives their inhabitants away or causes massive declines and changes in their ecosystems. Many other physical, chemical and biological processes will also be affected by rising temperatures that threaten critical ecosystem services such as food production, biodiversity and energy security.

But what these changes will be and exactly how they impact the Earth -- and ultimately us humans -- are still difficult to predict. Many of them are so gradual and happen over such a long timescale that they wouldn't be noticeable until they accelerate past the point of no return. Other events, meanwhile, are so rare and unpredictable that it would be impossible to prepare for them by ordinary means. Yet others have such wide-ranging effects that experts from several disciplines would be needed to unravel the mystery.

Fortunately, the National Science Foundation has developed a network of 28 sites representing diverse ecosystems where more than 2,000 multidisciplinary scientists work to get a grasp on the situation, and the changes to come. UC Santa Barbara is home to two of these Long Term Ecological Research (LTER) Network sites: Santa Barbara Coastal (SBC), focused on local kelp forests, and Moorea Coral Reef (MCR), focused on coral reefs in French Polynesia.

"Long term research is really critical for developing predictive models," said Marty Downs, who directs the LTER Network Office, housed at the National Center for Ecological Analysis & Synthesis at UC Santa Barbara. "Models need really good information on the mechanisms that underlie those dynamic relationships. LTER sites have not only the observations of the natural systems but also deliberate experiments that tease out the interacting effects of different drivers."

The value of long-term ecological research is brought to the fore in a newly published special issue of the online journal Ecosphere, in which the importance of LTER research is highlighted in the effort to understand mechanisms that aren't easily addressed by short-term studies, such as time lags, cascading effects, resilience, connectivity and ecosystem state change.

Connectivity: Santa Barbara Coastal LTER

Just off the coast of Santa Barbara, giants sway gently beneath the waves, and with them, communities of animals find food and shelter.

"Giant kelp is a foundation species that supports the entire kelp forest community," said project lead investigator Robert Miller. Both on the floor and in the canopy, a diverse array of creatures, including urchins, sea cucumbers, brittle stars, fish and crustaceans rely on Macrocystis pyrifera to rear their young, feed and hide. On the ocean's surface, kelp forests are a source of food for marine mammals and seabirds, and on the shore, kelp wrack nourishes sandy beach organisms.

Unlike many other foundation species, however, giant kelp plants live only a few years, and their populations fluctuate greatly.

"This enables ecologists to examine how such changes in a foundation species affect the associated community," Miller said. "Studies like this might take centuries or longer in, say, a hemlock forest."

Thanks to rapid growth, giant kelp can recover quickly from disturbance by periodic winter storms, and maintain a relatively stable habitat for animals. Wind, waves and current serve to disperse kelp spores between reefs to recolonize them, and send kelp wrack to shore where multitudes of beach critters eat it and live in it. Ocean circulation and upwelling also provide plankton that kelp forest filter feeders depend on for food.

How could a changing climate affect giant kelp's ability to replenish itself and maintain its community? Thanks to years of data from experiments monitoring this rather ephemeral foundation species and the habitat it creates, researchers at the SBC LTER found, to their surprise, that the frequency of disturbance had more impact on the biodiversity of a kelp forest than did the severity of the disturbance. If, as predicted, climate change brings more storms and marine heat waves, kelps' ability to create that essential canopy could be suppressed, leading to a less productive environment overall -- a blow not just to animals that live there but also to visiting seabirds and the sandy beach community, and to the humans who rely on food produced in and supported by the kelp forest.

"An improved understanding of how kelp is affected by the environment, and how it affects the kelp forest community as a whole, informs strategies to conserve and restore these economically and ecologically valuable ecosystems," Miller said. "Long term research," say the Ecosphere article authors, "is vital to understanding how short-lived foundation species and the ecosystems they support react to environmental change, including future climate change."

Corals are at the front lines of climate change, as rising water temperatures, increasing ocean acidification and other stressors continue to take their toll on coral reefs, which provide food, shelter and spawning ground for more than a quarter of all marine animal species.

"Coral reefs are one of the most diverse and productive of the world's ecosystems, supporting vast biodiversity and providing ecosystem services of enormous value," said Russell Schmitt, the principal investigator at the Moorea Coral Reef (MCR) LTER. The millennia-old structures dominate their habitats, but changes to temperature and ocean water chemistry, in addition to the physical pounding from storms and destructive fishing practices, have resulted in widespread death of coral.

"When coral is lost from a tropical reef as a result of these disturbances, it can be replaced by seaweeds, which can negatively impact biodiversity and ecosystem services," Schmitt said. Under normal circumstances, the disturbances pass and corals once again assert their dominance. However, under the constant onslaught of stress, "many seaweed-dominated reefs are remaining in that state, failing to transition back to their coral communities."

The coral reef community at Moorea isn't giving up without a fight. Case in point: From 2007 to 2010, the reefs experienced a series of setbacks -- from an outbreak of coral-eating crown-of-thorns seastar to damage wrought by Cyclone Oli -- that gave the researchers reason to expect the dominance to shift to seaweed in relatively short order. Instead, what they found was a rapid recovery brought about by grazing fish herbivores, which suppressed the seaweed and kept space unoccupied, and vigorous repopulation of coral from nearby reefs. Coral cover on the fore reef on the north shore of Moorea came back from 2% just after Cyclone Oli to 55% in 2015.

Yet the ability of corals to endure and recover from the longer term stress brought on by global warming is still not well understood. What processes allow coral reefs to withstand environmental perturbations and restore corals in the face of a changing climate and an increasing human footprint? How will a warmer and more acidic future due to ever increasing levels of carbon dioxide in the atmosphere alter resilience, community composition and ecosystem functioning in the coming decades?

"Answering these questions requires long-term studies because reefs must be studied as they undergo cycles of disturbances and recovery as temperatures continue to rise, which takes years to decades," said MCR co-principal investigator Sally Holbrook. "Understanding the factors that affect reef resilience is critical for development of management strategies for tropical reefs, which benefits the local communities in Moorea who depend on the reefs for fishing, tourism, recreational and cultural values."

Holbrook added, "Our work illustrates the ecological processes and feedbacks that either must be strengthened to keep a coral reef in a desirable state, or to break if the goal is to restore a degraded reef back to coral."

Credit: 
University of California - Santa Barbara

At underwater site, research team finds 9,000-year-old stone artifacts

image: Ashley Lemke, UT Arlington

Image: 
UT Arlington

An underwater archaeologist from The University of Texas at Arlington is part of a research team studying 9,000-year-old stone tool artifacts discovered in Lake Huron that originated from an obsidian quarry more than 2,000 miles away in central Oregon.

The obsidian flakes from the underwater archaeological site represent the oldest and farthest east confirmed specimens of western obsidian ever found in the continental United States.

"In this case, these tiny obsidian artifacts reveal social connections across North America 9,000 years ago," said Ashley Lemke, assistant professor of sociology and anthropology at UT Arlington. "The artifacts found below the Great Lakes come from a geological source in Oregon, 4,000 kilometers away---making it one of the longest distances recorded for obsidian artifacts anywhere in the world."

The unique study was a multi-faceted pursuit with divers in the water and researchers in the laboratory from UTA, the University of Michigan, Lake Superior National Marine Conservation Area, the University of Missouri Research Reactor Center, the Northwest Research Obsidian Studies Laboratory and the University of Georgia. Their combined work, "Central Oregon obsidian from a submerged early Holocene archaeological site beneath Lake Huron," was published last month in the journal PLOS One.

Because the site was underwater and undisturbed, researchers systematically and scientifically recovered the obsidian, a form of volcanic glass that was used and traded widely throughout much of human history as a prized material for making sharp tools.

"These are very small pieces that have very large stories to tell," Lemke said. "Obsidian from the far western United States is rarely found in the east."

Lemke is a leader and innovator in the field, serving as the chair of the Advisory Council on Underwater Archaeology, an international group dedicated to underwater archaeology and the preservation of underwater cultural resources. She is an expert on submerged ancient sites in the Americas and has researched other areas such as the Gulf of Mexico and Atlantic Ocean.

The find in Lake Huron is part of a broader study to understand the social and economic organization of caribou hunters at the end of the last ice age. Water levels were much lower then; scientists have found, for example, ancient sites like stone walls and hunting blinds that are now 100 feet underwater.

"This particular find is really exciting because it shows how important underwater archaeology is," Lemke said. "The preservation of ancient underwater sites is unparalleled on land, and these places have given us a great opportunity to learn more about past peoples."

Credit: 
University of Texas at Arlington

Enormous flock of declining shorebird discovered in South Carolina

image: Whimbrel are large, striking shorebirds known for their downcurved bills, which are ideally adapted to plucking fiddler crabs from muddy burrows.

Image: 
Matt Aeberhard/Cornell Lab of Ornithology

CHARLESTON, S.C. (June 15, 2021) - It's not every day that someone discovers a new-to-science bird migration spectacle. It's even more unexpected that such an encounter - in this case, tens of thousands of shorebirds gathering during their annual journey north - would be just a stone's throw from a metropolitan area. But two years ago, that's exactly what happened in coastal South Carolina.

In May 2019, South Carolina Department of Natural Resources (SCDNR) biologist Felicia Sanders and a team of researchers confirmed that approximately 20,000 whimbrel were roosting at night on a small island during their spring migration. The team documented similar numbers again in 2020. This single flock includes nearly half of the declining shorebird's estimated eastern population: a staggering spectacle hiding in plain sight. The findings were recently published in the peer-reviewed scientific journal Wader Study.

Sanders has devoted her career to protecting South Carolina's coastal birds. After decades exploring the coast, few are more familiar with the way shorebirds and seabirds use the state's salt marshes, tidal creeks and barrier islands. But when Sanders pursued a hunch about the large numbers of whimbrel she saw congregating at Deveaux Bank - a small island just 20 miles south of Charleston - she could barely believe what she'd found.

"A lot of people were skeptical, but after tallying results from coordinated surveys by fellow ornithologists and video documentation, we are certain of the magnitude of the flock," said Sanders. "Finding so many whimbrel here gives me hope that we can turn the tide for this and other declining shorebird species."

Whimbrel are large, striking shorebirds known for their downcurved bills, which are ideally adapted to plucking fiddler crabs from muddy burrows. Like many shorebirds, they migrate incredible distances across the western hemisphere each year, facing threats including habitat loss and overhunting along the way. In the last 25 years, whimbrel declined by two-thirds across the Atlantic Flyway, the eastern portion of their population. The discovery of a roost of this size - the largest known for the species - is of critical importance to successfully protecting this rare shorebird.

After spending the winter on the coasts of South America, whimbrel fly thousands of miles north to nest and raise young across subarctic regions of Canada and Alaska. They typically make just one stop along the way. For many of these birds, that stop is in South Carolina, where they rest and feed on rich coastal nutrients that will fuel their breeding season.

At high tides and at night, when feeding habitat and other safe resting sites are inundated, whimbrel flock together for safety. They seek large, isolated offshore refuges like Deveaux Bank, where disturbances from people and predators are minimal. But relatively few such places remain along the Atlantic coast.

"Having such a globally important phenomenon occur right here in our own backyards, that's really something to be proud of," said Sanders. "And I think it's really important to understand that biologists aren't the only ones that care about these birds. Local communities take ownership of places near their homes. It really does take a village to protect places as important as Deveaux."

Riley Bradham, mayor and lifelong resident of nearby Rockville, agrees. "It's a special place," said Bradham, who has been visiting Deveaux for his entire life and working for years with SCDNR to protect birds on the sensitive island. "We all love it, but it's one of the last special places."

In early 2019, Sanders' discovery inspired a collaboration between the South Carolina Department of Natural Resources, the University of South Carolina, the Cornell Lab of Ornithology and the conservation nonprofit Manomet to census and film this nocturnal roost during peak migration in April and May. For optimal visibility, the shorebird biologists, along with videographers specializing in filming sensitive wildlife, converged on Deveaux on full moon nights as flocks of whimbrel arrived during and after twilight.

"We worked to visually document what Felicia and the team have uncovered here, because this truly unique spectacle underscores the value of the wild spaces still left intact on our southeastern coasts," said Andy Johnson, who led a team from the Cornell Lab's Center for Conservation Media to film the whimbrel roost.

A shorebird roost of this magnitude offers a glimpse of the abundance that was once widespread across the Atlantic coast and now stands as a testament to South Carolina's commitment to coastal habitat conservation.

"There's only one place in the world, one place on Earth where 20,000 whimbrel land on an ephemeral island of really insignificant size," says Chris Crolley, naturalist, guide, and CEO of Charleston-based Coastal Expeditions. "That's Deveaux Bank. Right off the coast of South Carolina. It's just phenomenal, isn't it? It's nothing less than that."

Credit: 
South Carolina Department of Natural Resources

A 'pump' gene's surprising role in early brain formation

image: In polymicrogyria, the cortex of the brain has many irregular, small folds (gyria) and disorganization of its layers, caused by mutations in one of several genes. Many affected children have severe developmental delay, intellectual disabilities, and epilepsy,

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Richard Smith/Sebastian Stankiewicz, Boston Children's Hospital

In polymicrogyria, the cortex of the brain has many irregular, small folds (gyria) and disorganization of its layers. Many affected children have severe developmental delay, intellectual disabilities, and epilepsy, and many need to use a wheelchair. Mutations in several different genes can cause this "overfolding of the brain" condition.

Studying four patients with polymicrogyria, Richard Smith, PhD, identified mutations in a gene that caused him to do a double-take. His curiosity drove him to investigate the role of this gene, called ATP1A3, in the developing brain.

"ATP1A3 is critical to many cell biological processes," says Smith, an investigator the Division of Genetics and Genomics at Boston Children's Hospital. "It's one of the most important genes we have in our brains."

Bio-electricity and brain development

ATP1A3 encodes a protein that makes up part of a cellular pump. It moves sodium and potassium ions across the cell membrane, allowing our cells to maintain differing concentrations of charged ions on either side, similar to a battery. This difference enables electrical currents to flow into or out of cells, driving action potentials in neurons and other essential cell functions.

"For me it was very compelling to understand how these pump proteins, and the flow of ions, contribute to core mechanisms in brain development," says Smith, an electrophysiologist by training. "We got a lot of great biological insights by studying these four patients."

A spatial and temporal 'atlas' of ATP1A3

When and where in the typical developing brain is ATP1A3 turned on? To answer this question, Smith, with senior investigator Christopher Walsh, MD, PhD and colleagues at multiple other sites, obtained donated human tissues from several hospital tissue banks and the NIH NeuroBiobank. The investigators analyzed samples from two times in early brain development: at around 20 weeks' gestation, when the fetal cortex, initially smooth, starts to fold, and in infants soon after birth.

Using single-cell RNA sequencing (DropSeq) in collaboration with Marta Florio, PhD, at Harvard Medical School, they looked for expression (turning on) of ATP1A3 in about 125,000 individual neurons from 11 areas of the prenatal cortex. They also profiled about 52,000 neurons from the infants, sampling four areas of the cortex.

Overall, ATP1A3 expression levels were highest in the prefrontal cortex at both time points, and highest in the most active, frequently-firing neurons in the cortex. In the fetal cortex, ATP1A3 expression was particularly high in the subplate, a layer that disappears later in development. Electrical activity in the subplate is thought to be a hub of signaling driving synapse formation, neuron migration, and other brain developmental processes.

"In the infants, we found increased expression of the gene in interneurons, which are inhibitory," says Smith. "We think that ATP1A3 mutations may disrupt the balance of excitation and inhibition in the brain, which could contribute to epilepsy in other ATP1A3-related conditions."

Lessons for other ATP1A3-related diseases?

The work, published in PNAS, underscores how research in rare diseases can yield fundamental insights in biology -- in this case, how the brain develops its contours and organizational pattern. It provides a map for future studies of how mutations in ATP1A3 cause the brain to form abnormally.

"When we first published this as a preprint, we had a lot of people reach out to us with patients with overlapping phenotypes, so it is very exciting to better understand this disease," says Smith.

The findings may also inform scientists' understanding of other known ATP1A3-related disorders. While the patients with polymicrogyria had severe mutations causing loss of function of the gene, milder mutations cause a spectrum of later-onset neurologic diseases including alternating hemiplegia of childhood, which causes bouts of temporary paralysis; a movement disorder known as rapid onset dystonia parkinsonism; and childhood-onset schizophrenia. These later-onset disorders may be more amenable to therapeutic intervention.

"Polymicrogyria is at the extreme end of severity, but we think that ATP1A3-related disorders in the "middle" of this spectrum could have early pathogenic roots that could possibly be treated before they become more severe," says Smith.

He adds that if newborn DNA sequencing becomes common, it could offer a window of opportunity for treating ATP1A3 related disorders before they manifest clinically.

As for polymicrogyria, "a structural malformation is trickier to reverse, but infant brains are amazingly plastic and capable of reorganizing," says Smith. "So if you could lessen the epilepsy-related damage from the earliest point, you might be able to improve quality of life."

Credit: 
Boston Children's Hospital

UM research: Rocky mountain forests now burning more than any point in past 2,000 years

image: Philip Higuera, a University of Montana professor of fire ecology (right), and his team examine a lake-sediment core from Chickaree Lake in Colorado's Rocky Mountain National Park. The core is used to reconstruct fire and vegetation history over thousands of years.

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Photo by Grace Carter

MISSOULA - Following 2020's extreme fire season, high-elevation forests in the central Rocky Mountains now are burning more than at any point in the past 2,000 years, according to a new University of Montana study set to publish in the Proceedings of the National Academy of Sciences.

Researchers from UM and the University of Wyoming analyzed a unique network of fire-history records to understand how 21st-century fire activity compares to wildfires in the past. The findings highlight that burning in recent decades in high-elevation forests of northern Colorado and southern Wyoming is unprecedented over the past several millennia.

As fire paleoecologists - scientists who study historical ecosystems - the team uses charcoal found in lake sediments to piece together the fire history of forests across the Rocky Mountains. The idea, said lead author and UM professor Philip Higuera, is that understanding the past is key to understanding changes we see today and how forests may change in the future.

When 2020's massive fire season hit, it's ferocity startled Higuera and his co-authors - UM doctoral candidate Kyra Wolf and UW Professor Bryan Shuman. Last year, wildfires in Colorado burned through October, unusually late in the year. By November, the 2020 wildfires alone were responsible for 72% of the total area burned in high-elevation forests since 1984 in their study region, and Colorado had seen three of its largest fires on record.

"As the 2020 fire season unfolded, we realized we already had a well-defined understanding of the fire history of many of the places burning, based on over 20 lake-sediment records our teams had collected over the past 15 years," said Higuera, professor of fire ecology in the W.A. Franke College of Forestry and Conservation. "When the smoke settled, we thought 'Wow, we may have witnessed something truly unprecedented here.' So we combined the existing records for the first time and compared them to recent fire activity. To our surprise, 2020 indeed pushed fire activity outside the range of variability these forests have experienced over at least the past two millennia."

The authors found that since 2000, wildfires are burning nearly twice as much area on average compared to the last 2,000 years. Whereas a high-elevation forest historically burned once every 230 years on average, in the 21st-century that has now shrunk to around 120 years. That's more fire activity than occurred during the "Medieval Climate Anomaly," a period around 1,200 years ago when temperatures spiked higher than they were during the 20th century.

While human activity and past fire suppression are important contributing factors to wildfires across the West, the work highlights increasingly warm, dry conditions as an overarching cause of increased burning in these high-elevation forests.

"It isn't unexpected to have more fire as temperatures rise," said co-author Wolf, who is studying fire history in the northern Rocky Mountains in UM's Systems Ecology program. "Our records show that fire tracked past variations in climate just as it does today. What's striking is that temperatures, and correspondingly fire, are now exceeding the range that these forests have coped with for thousands of years - largely as result of human-caused climate change."

For decades, scientists have predicted that climate warming would increase wildfire activity in high-elevation forests beyond the range historically experienced, Higuera said.
"It's sobering to see that it's clearly happening, and early in the 21st century - not in 2050, not in 2075, but by 2020," he said.

Overall, the study is another indication that extreme fire seasons like 2020 - or like 2017 in Montana - will become increasingly common as summers continue to become warmer and drier than in past centuries.

Higuera and colleagues have previously highlighted ways communities and managers can respond to increasing fire activity, but he hopes this paper helps illustrate the significant impacts of human-caused climate change on wildfire, forests and the human communities that live among them.

"It may sound dire," Higuera said, "but it's critical to remember that we have ample opportunities to limit or reverse climate warming while still working to adapt to the increasing fire activity expected in upcoming decades."

Credit: 
The University of Montana

New theranostic approach joins radiopharmaceuticals and nanoparticles to kill cancer cells

image: Semiconducting polymer nanoparticles amplify and harness Cerenkov luminescence for cancer theranostics.

Image: 
Image created by ZT Rosenkrans, et al. University of Wisconsin-Madison, Madison, WI.

Reston, VA (Embargoed until 12:30 p.m. EDT, Monday, June 14, 2021) - Researchers have successfully developed a novel cancer treatment approach that utilizes Cerenkov radiation energy to target and destroy cancer cells more effectively. The approach uses light from decaying radiopharmaceuticals, known as Cerenkov luminescence, as an energy source to activate semiconducting polymer nanoparticles that kill cancer cells. This research was presented at the Society of Nuclear Medicine and Molecular Imaging's 2021 Virtual Annual Meeting.

Over the past several decades, many studies have been conducted on photodynamic therapy, which uses an external light source to activate nanomaterials for cancer therapy. This therapy, however, is limited by the ability of external light to penetrate tissues. As Cerenkov luminescence is spontaneously produced from certain radiopharmaceuticals as they decay in the body, it has recently been proposed as an internal energy source for cancer therapy.

While Cerenkov luminescence is advantageous because it is a light source produced inside of the body, the light source is generally very weak. "The good news is that the light source can be amplified with semiconducting polymers, which greatly increases its potential to target and destroy cancer cells," said Zachary Rosenkrans, graduate research assistant at University of Wisconsin-Madison in Madison, Wisconsin. "In our study we aimed to determine how to best utilize radiopharmaceuticals and nanoparticles to create the ideal cancer theranostics nanosystem."

Researchers found that semiconducting polymer nanoparticles optimized with photosensitizers dramatically intensified Cerenkov luminescence to kill cancer cells. Positron emission tomography and optical imaging studies also clearly visualized tumor uptake of these optimized semiconducting polymer nanoparticles. This approach was found to have excellent potential as a cancer theranostics nanosystem without any tissue penetration limits.

"This work is an important step toward translating nanomaterials that are activated by light, using radiopharmaceuticals as an activation source. The basic concept, using semiconducting polymers to harness and amplify light produced from radiopharmaceuticals, is also very exciting and could have many interesting applications in the future," Rosenkrans noted.

Abstract 71. "Semiconducting polymers enhance Cerenkov radiation energy transfer for multimodal cancer theranostics," Zachary Rosenkrans, Dalong NI, Kaelyn Becker, Eduardo Aluicio-Sarduy, Jonathan Engle, and Weibo Cai, University of Wisconsin-Madison, Madison, Wisconsin.

Credit: 
Society of Nuclear Medicine and Molecular Imaging

New PET tracer detects hallmark of Alzheimer's disease years before symptoms emerge

image: Tau accumulation over one year measured in composite A) mesial temporal ROI; and B) temporoparietal ROI in cognitively unimpaired participants (blue) and cognitively impaired participants (red). The CI group included participants with clinical mild cognitive impairment and dementia. Higher rates of tau accumulation were observed in participants on the AD continuum (CU Aβ+ve and CI Aβ+ve). Participants with the highest baseline tau and rates of tau accumulation were younger and more likely to be CI Aβ+ve.

Image: 
Image created by N Krishnadas et al. Florey Department of Neurosciences & Mental Health, The University of Melbourne; Department of Molecular Imaging & Therapy, Austin Hospital, Melbourne.

Reston, VA (Embargoed until 7:30 p.m. EDT, Monday, June 14, 2021)--A novel positron emission tomography (PET) radiotracer has been shown to effectively measure increases in brain tau--a distinguishing characteristic of Alzheimer's disease--before any symptoms of the disease are observed. With the potential to measure increases in tau over a long period of time, this tracer offers an important tool to assess the effectiveness of Alzheimer's disease treatments in clinical trials. This research was presented at the Society of Nuclear Medicine and Molecular Imaging 2021 Annual Meeting.

Tau is a protein commonly found in healthy brain neurons. In people with certain brain disorders, like Alzheimer's disease, chemical changes cause tau proteins to accumulate in various parts of the brain. As such, tau is valuable as a biomarker for measuring disease progression.

In the study, researchers sought to detect patterns and rates of tau accumulation in both a cognitively normal aging population and in those with Alzheimer's disease. PET imaging with the novel radiotracer 18F-MK6240 was performed on all participants at baseline and after 12 months. After each scan, uptake of the radiotracer was measured in multiple areas of the brain.

Increases in tau were measured in both participant groups and longitudinal tau imaging was effective in discriminating between the two cohorts. The uptake of 18F-MK6240 was higher at baseline and after one year in participants who were on the Alzheimer's disease continuum in comparison to the cognitively normal aging participants.

"The effectiveness of the 18F-MK6240 tracer is important for drug trials that aim to measure whether or not treatments to remove tau from the brain are actually working," said Christopher Rowe, BMBS, FRACP, MD, FAANMS, director of molecular imaging research at Austin Health and director of the Australian Dementia Network in Melbourne, Australia. "Use of the radiotracer will allow researchers to select people at different stages of Alzheimer's disease for clinical trials, which ultimately may speed the development of effective treatments for the disease."

Abstract 105. "18F-MK6240 longitudinal tau PET in ageing and Alzheimer's disease," Natasha Krishnadas, Florey Department of Neurosciences & Mental Health, The University of Melbourne, Parkville, Victoria, Australia, and Department of Molecular Imaging & Therapy, Austin Hospital, Heidelberg, Victoria, Australia; Vincent Dore, CSIRO Biomedical Imaging Health & Biosecurity Flagship, Parkville, Victoria, Australia, and Department of Molecular Imaging & Therapy, Austin Hospital, Heidelberg, Victoria, Australia; Rachel Mulligan, Regan Tyrrell, Svetlana Bozinovski, Kun Huang, Fiona Lamb and Victor Villemagne, Department of Molecular Imaging & Therapy, Austin Hospital, Heidelberg, Victoria, Australia; Samantha Burnham, CSIRO Biomedical Imaging Health & Biosecurity Flagship, Parkville, Victoria, Australia; and Christopher Rowe, Department of Molecular Imaging & Therapy, Austin Hospital, Heidelberg, Victoria, Australia, Australian Dementia Network (ADNeT), Victoria, Australia, and Florey Department of Neurosciences & Mental Health, The University of Melbourne, Parkville, Victoria, Australia.

Credit: 
Society of Nuclear Medicine and Molecular Imaging

Biodiversity 'hotspots' imperiled along California's streams

image: This image shows the riparian community woodlands along the lower Tuolumne River near Merced, California. The dry grassland in the background indicates the semi-arid conditions and drought environment.

Image: 
John Stella, ESF

A study of woodland ecosystems that provide habitat for rare and endangered species along streams and rivers throughout California reveals that some of these ecologically important areas are inadvertently benefitting from water that humans are diverting for their own needs. Though it seems a short-term boon to these ecosystems, the artificial supply creates an unintended dependence on its bounty, threatens the long-term survival of natural communities and spotlights the need for changes in the way water is managed across the state.

"We need to be more intentional in incorporating ecosystem water needs when we manage water--both for aquatic organisms and species on land," said Melissa Rohde, the lead author of a study published June 14, 2021 in the Proceedings of the National Academy of Sciences (PNAS). "These forest ecosystems are in a precarious state because we have disrupted the natural hydrologic processes that these plant species rely upon to support and sustain key life processes."

In California's seasonally dry Mediterranean climate, plants and animals are adapted to rely on precipitation and soil moisture recharge during the rainy winter and spring seasons for reproduction and growth during the typically dry summers. Once soil moisture is exhausted, tree species often found in stream corridors such as willows, cottonwoods and oaks, typically use groundwater from deeper depths. However, as Rohde, who led the study as a Ph.D. candidate at the State University of New York College of Environmental Science and Forestry (ESF) and scientist with The Nature Conservancy of California, and her colleagues discovered, the story was more complicated.

By analyzing five years of vegetation greenness data from satellite imagery, the researchers found that in some cases, these ecosystems were affected by "subsidies of water" delivered via human regulation of rivers, agricultural canals and discharges from wastewater treatment plants. That discovery, Rohde said, was a "mind bender." Altered streamside woodlands in the most arid regions of the state stayed greener longer into the dry season and were less responsive to changes in groundwater levels than natural ecosystems.

Many of the most-altered stream ecosystems are in California's Central Valley, the state's agricultural hub, which produces a third of the produce for the United States. Since the Gold Rush in the 1850s, the massive human settlement that followed led to clearing of 95 percent of the natural floodplain woodlands across the region. These isolated and restricted riparian -- or streamside -- forests, now provide important habitat for threatened and endangered species..

As water is rerouted from rivers into canals to accommodate urbanization and the multibillion-dollar agricultural industry, it creates an artificially stable environment for riparian woodland ecosystems and a "live fast, die young" phenomenon favoring fast-growing trees that peak and then decline within a few decades. But other key ecosystem functions, such as the regeneration of new forest stands and their development over time, are being compromised by the extensive alterations to streamflow and to river channels, which are fixed in place and no longer create new floodplain areas where young trees can establish.

"We call these forests the 'living dead' because the forest floor is devoid of saplings and younger trees that can replace the mature trees when they die," Rohde said. This has repercussions related to habitat for endangered species, biodiversity, carbon sequestration and climate change.

Rohde said, "California is one of the most biodiverse regions in the world, containing more species than the rest of the United States and Canada combined. In the midst of the sixth mass extinction, the long-term sustainability of California's river ecosystems and the preservation of the rare and endemic species that live within them now rely on the deliberate, coordinated management of resource and government agencies." She and TNC will use the insights from the study to provide scientific guidance to California natural resource agencies for sustainably managing groundwater-dependent ecosystems throughout the state.

The research team conducted the PNAS study using publicly available online data and Google Earth Engine, an open-source tool for analyzing data from satellites and other global spatial datasets. "Our methods and findings open up a whole new world of interdisciplinary research possibilities and ways that water practitioners can consider ecosystem water needs to achieve sustainable water management," Rohde said.

John Stella, an ESF professor and Rohde's Ph.D. advisor, is the principal investigator on the National Science Foundation grant that funded the study. He said, "This work is groundbreaking because Melissa was able to combine several big datasets in an innovative way to understand how climate and water management interact to put these sensitive ecosystems at risk. Her findings are important for sustainably managing groundwater, not only throughout California, but in water-limited regions worldwide. By creatively harnessing and integrating these large environmental datasets, we can now answer resource management questions at a scale that was previously impossible."

Credit: 
SUNY College of Environmental Science and Forestry