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NEW YORK CITY, June 2, 2021 -- New research from Memorial Sloan Kettering Cancer Center (MSK) medical oncologist Dean Bajorin, MD, and colleagues found that patients who received nivolumab (Opdivo®) after bladder cancer surgery reduced their overall risk for high-grade bladder cancer recurrence. This research was published in the New England Journal of Medicine.

In this phase III randomized study, Dr. Bajorin and a team of investigators evaluated 709 patients who were at high risk for recurrence of urothelial cancer after removal of their bladder, ureter, or kidney for high-grade cancer. To evaluate for benefit, patients were randomized to receive either nivolumab or a placebo every two weeks for one year. Patients and physicians were blinded to the treatment. Both safety and quality of life were evaluated.

Dr. Bajorin and investigators found that in high-risk patients, nivolumab reduced recurrence after surgery compared to patients who received the placebo. The current standard of care following surgery that removes the bladder or kidney and ureter has been observation without adjuvant therapy -- even in patients at high risk of recurrence and death. This is because no chemotherapy or immunotherapy has previously been shown to be of benefit. Participants who received nivolumab had disease-free survival of 21 months compared with 10.9 months in people receiving the placebo.

"We are very encouraged by the data and the results of the study," said Dr. Bajorin, first and corresponding author of the study. "Despite available therapies for advanced metastatic bladder cancer, new options are needed to improve long-term disease control and patient survival. These findings have the potential to change the standard of care for bladder cancer."

Urothelial cancers are tumors that start in the lining of the urine-collecting system that transports urine from the kidneys to the outside of our bodies. These cancers are often referred to as "bladder cancer" because most of them start in the bladder.

Dr. Bajorin and colleagues concluded that the survival data is not yet mature and will need additional research and follow-up. The primary endpoints of disease-free survival in the study population and disease free-survival in the subset of patients with PD-L1-positive tumors were met, and these findings are highly statistically significant and clinically relevant for a population of patients with a clear unmet medical need.

"The trial demonstrates that novel therapies can be identified as having patient benefit when the studies are conducted in a very rigorous fashion. We are hoping this treatment will get approval for all patients at high risk of recurrence after the US Food and Drug Administration has done a detailed review of all the data," said Dr. Bajorin.

Making Pioneering Advances for Bladder Cancer Patients

Cancer immunotherapy was born at MSK a little over a century ago. Since then, physician-scientists across MSK have led the effort to develop immune-based treatments for different types of cancer. MSK has been at the epicenter of discoveries in the field, and the institution's work is bringing exciting new treatment options to people around the world. MSK physicians have extensive experience using immunotherapy to treat people with melanoma, kidney cancer, lung cancer, and other cancers as well as handling immune-related side effects.

Without treatment, bladder cancer can be an aggressive disease. In 2021, it is estimated that there will be nearly 17,000 deaths due to bladder cancer in the United States -- and numbers are expected to rise significantly in the next decade.

"As physicians, we consistently strive to provide our patients with the most effective therapies and give those with advanced disease more options," said Dr. Bajorin.

SAN FRANCISCO, CA (June 3, 2021) -- Since arriving to the northern Atlantic Ocean less than 30 years ago, lionfish have quickly become one of the most widespread and voracious invasive species, negatively impacting marine ecosystems--particularly coral reefs--from the northeast coast of the United States to the Caribbean Islands. In a new study, an international research team including the California Academy of Sciences presents four new records of lionfish off the coast of Brazil, confirming the invasion of the predatory fish into the South Atlantic for the first time. Their findings, published today in Biological Invasions, discuss how the lionfish may have arrived in the region, and hold important insights on how Brazil's diving and fishing communities can help manage the invasion before it potentially devastates local ecosystems.

"For a while it was uncertain whether or not lionfish would extend into the South Atlantic," says Academy Curator of Ichthyology and study co-author Luiz Rocha. "Now that we know they are here, it is imperative that we uncover how they arrived and work with local communities to keep the population under control. If left unchecked, lionfish could have a huge impact on local species, particularly those that exist solely in the reefs surrounding Brazil's oceanic islands."

Sporting maroon stripes and more than a dozen venomous spines, lionfish have long been a staple in the hobbyist aquarium trade. Like other popular aquarium fish, however, they are sometimes irresponsibly released into the wild. Indeed, it is likely that the invasion of lionfish in the Atlantic Ocean began that way.

Once they enter new waters, lionfish can quickly disrupt local ecosystems and disperse to other locations. Due to their broad diet, lack of natural predators, unique hunting style, and year-round reproduction of buoyant eggs that can travel long distances on ocean currents, lionfish have expanded faster than any other invasive marine species.

Despite those traits, lionfish have been noticeably absent in the South Atlantic--a phenomenon that the researchers attribute to the northerly flowing currents at the oceanic boundary between Brazilian and Caribbean waters. But in 2015, a local diver photographed a lionfish swimming off the southern coast of Brazil and alerted the researchers, who 11 months later found and collected the specimen confirming the species' expansion into Brazil.

After that initial discovery, the researchers--with help from local fisherman and divers--were able to track down three additional lionfish in Brazil's waters: two from deep coral reefs known as mesophotic reefs and one from reefs surrounding the Fernando de Noronha Archipelago around 200 miles off the country's northeastern coast.

Though all of the incidents are troubling, the researchers say that the Fernando de Noronha record is of particular concern. "The arrival of lionfish to Brazil's oceanic islands is especially worrying," says marine biologist and study co-author Clara Buck. "These unique ecosystems have a high number of endemic species found nowhere else on Earth making them much more sensitive to adverse impacts."

To curb the invasion before it accelerates, it is crucial to know how the lionfish are arriving in the region in the first place. In their study, the researchers propose that the lionfish found in the mesophotic reefs may have arrived in a stepping-stone fashion, utilizing deeper reefs under the Amazon plume to slowly push southwards from the Caribbean.

In contrast, they suggest that the individual found at Fernando de Noronha arrived by more conventional means, traveling along the currents between the islands and the Caribbean as a larva. Since the archipelago is distant from the mainland, lionfish larva can subvert the oceanic boundary that exists closer to the coastline.

Finally, while the lionfish off the southern coast was too far away from the Caribbean to have arrived there by dispersal or mesophotic reef hopping, the researchers were able to confirm through a DNA analysis that it originated from the Caribbean population, suggesting it may have been removed from the Caribbean and introduced to Brazilian waters through the aquarium trade.

Regardless of how they arrived, now that the lionfish are there the researchers urge the Brazilian government and local communities to stem the invasion. While efforts elsewhere in the Atlantic have shown that full eradication of the lionfish is unlikely, the researchers say that keeping population numbers low could buy precious time for local species to adapt to the voracious fish and ultimately avoid predation.

From spearing the lionfish they come across to alerting researchers of emerging populations, local fishermen and divers--like those who assisted with this study--will play a critical role in managing the invasion, and protecting the coral reefs and local species that sustain their livelihoods.

Despite the challenges they face, Rocha is optimistic they can succeed. "Brazil, and Fernando de Noronha in particular, have robust local diving and fishing communities," he says. "If we put the right tools in their hands, it is absolutely possible to keep the invasion under control."

EDITORIAL NOTE: Due to a copyediting error, the original version of the following summary incorrectly cited the number 20 in both the title and first sentence of the text. The correct number – which is now reflected below – is 240. We apologize for the error.

In a six-month study of more than 1,000 Americans, R. Kelly Garrett and Robert Bond found that U.S. conservatives were less able to distinguish truth from falsehoods in 240 viral political news stories that appeared online between January and July 2019. Differences in the political orientation of these stories may help explain this observation, the researchers note, writing that "we find that high-profile true political claims tend to promote issues and candidates favored by liberals, while falsehoods tend to be better for conservatives." Two-thirds (65%) of the high-profile true stories were characterized as benefiting the political left, compared with only 10% that were described as benefiting the political right. Among high-profile false stories, 45.8% were perceived to benefit the political right while 23.3% benefited the left. While there has been a widespread perception that U.S. conservatives are likely to believe in false political news, most research in this area has focused on a narrow set of "hot-button" issues such as climate change and weapons of mass destruction in Iraq. Garrett and Bond sought to assess this idea systematically by measuring responses to a richer dataset of political information. They used a social media monitoring service to identify 10 true and 10 false viral political stories and asked the people in their study about their beliefs about those stories in 12 waves over the course of six months. The researchers then assigned 5 Democrats and 5 Republicans recruited through Amazon's Mechanical Turk service to evaluate the political slant of these belief statements. The study found that conservatives' propensity to hold misperceptions is partially explained by the political implications of widely shared news; socially-engaging, truthful claims tended to favor the left, while engaging falsehoods disproportionately favored the right. "In such an environment, the belief accuracy of liberals and conservatives would be expected to diverge even if ideological bias is symmetrical," the authors say. "Collectively, these results underscore the importance of policies designed to ensure that news shared in the political information environment is reliable and factually accurate," Garrett and Bond conclude. They note several limitations of their study, including - as with studies before theirs - the inability to provide definitive evidence as to whether bias is ideologically asymmetrical.

Experts at the Alfred Wegener Institute have, for the first time, experimentally measured the release of iron from the fecal pellets of krill and salps under natural conditions and tested its bioavailability using a natural community of microalgae in the Southern Ocean. In comparison to the fecal pellets of krill, Antarctic phytoplankton can more easily take up the micronutrient iron from those produced by salps. Observations made over the past 20 years show that, as a result of climate change, Antarctic krill are increasingly being supplanted by salps in the Southern Ocean. In the future, salps could more effectively stimulate the fixation of the greenhouse gas carbon dioxide in Antarctic microalgae than krill, as the team of researchers report in the journal Current Biology.

In many parts of the Southern Ocean, iron is the primary limiting resource for the growth of phytoplankton. Accordingly, the amount of available iron has a major impact on how much CO2 the microalgae can fix and, in turn, how much biomass is available at the base of the food web. Studies clearly show that, as climate change progresses, Antarctic krill, the key species in the Southern Ocean, will increasingly be supplanted by salps.

"We investigated what a dominance shift from krill to salps would mean for primary production," explains Dr Scarlett Trimborn from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI). As head of the AWI research group EcoTrace, during an expedition with the Research Vessel Polarstern she and her colleagues conducted experiments with natural phytoplankton populations in the Southern Ocean near Elephant Island. As a source of iron, the researchers offered the microalgae communities fecal pellets from krill and salps, since a dominance shift between the two species would mean higher feces production by salps in the future.

"We were surprised to find that, compared to krill, the fecal pellet material from salps released more iron per microgram of carbon. In addition, we determined that the iron released by the salps' fecal pellets was more bioavailable for phytoplankton than the iron from krill pellets," reports Sebastian Böckmann from the EcoTrace group and first author of the study. The phytoplankton communities were able to take up as much as five times more iron from the salps' fecal pellets than from the krill feces. This improved uptake could be due to ligands, which enhance the iron's bioavailability for the algae. This aspect could result in significantly increased CO2 fixation among the phytoplankton.

The Southern Ocean is extremely important for the future of our climate, as its vast expanses of water can potentially absorb or release large quantities of CO2 from or into the atmosphere. In some regions, e.g. surrounding the Antarctic Peninsula, climate change is affecting the sea-ice cover. When the ocean is ice-free, more sunlight penetrates the upper water layers, providing an energy source for photosynthesis. That being said, the availability of the resource iron is what chiefly determines CO2 uptake in microalgae. "Although we know from which sources iron is transported into the Southern Ocean, it's still completely unclear how much of the iron the microalgae can take up, especially with regard to its release through recycling on the part of grazers like salps and krill. Our study makes an important contribution to modelling biogeochemical cycles in the Southern Ocean of tomorrow," Trimborn summarises.

A facial expression or the sound of a voice can say a lot about a person's emotional state; and how much they reveal depends on the intensity of the feeling. But is it really true that the stronger an emotion, the more intelligible it is? An international research team comprised of scientists from the Max Planck Institute for Empirical Aesthetics, New York University, and the Max Planck NYU Center for Language, Music, and Emotion (CLaME) has now discovered a paradoxical relationship between the intensity of emotional expressions and how they are perceived.

Emotions vary in their intensity. A person being attacked by a house cat may well feel fear; but certainly their fear would be even greater if a lion or tiger were attacking them. So our emotions differ in terms of degrees of strength. But how does this affect our ability to infer meaning from how an emotion is expressed? Research on emotion has so far assumed that emotion expressions become more distinct as their intensity increases. But there is little empirical evidence to support this intuitive-sounding idea.

A team of researchers from Frankfurt am Main and New York have now systematically investigated the role of emotional intensity for the first time. They collected a multitude of nonverbal vocalizations, including screams, laughter, sighs, groans, etc. These sounds all expressed different positive and negative emotions ranging from minimal to maximal emotional intensity. They then examined how listeners perceived these sounds differently depending on the emotional intensity they expressed.

The team came to a surprising conclusion: at first, as the intensity of the emotions increased, participants' ability to judge them also improved, attaining a kind of 'sweet spot' in perceiving moderate to strong emotions. When the emotions became maximally intense, however, their legibility decreased quite drastically. Lead author Natalie Holz of the Max Planck Institute for Empirical Aesthetics explains:

"Counterintuitively, we found that maximally intense emotions are not the easiest to infer meaning from. In fact, they are the most ambiguous of all."

And the paradox? For extremely intense emotions, neither their individual categories, such as surprise and triumph, nor valence, such as pleasantness and unpleasantness, could be distinguished reliably; nor could they be classified as being more positive or negative. Nevertheless, both the intensity itself and the state of arousal were perceived consistently and clearly. Holz suggests a reason for this:

"At peak intensity, the most vital job might be to detect big events and to assess relevance. A more fine-grained evaluation of affective meaning may be secondary."

The research team's article, just published in the journal Scientific Reports, makes clear that emotional intensity is a dominant factor in the perception of emotion, but in a far more complex way than previously thought. This poses a challenge to prevailing theories of emotion. The study of emotional intensity, and of peak emotions in particular, can enrich our understanding of affective experience and how we communicate emotion.

Researchers from Bochum and Osnabrück have gained new insights into the structure of the Ras protein, which acts as a molecular switch for cell growth and is involved in the development of cancer. With the help of fluorescence markings, they have demonstrated that the protein is deposited in a pair at the cell membrane, and with the very structure that they predicted in theory back in 2012. The team from the Bochum Center for Protein Diagnostics (PRODI) hopes that these findings will open up a new approach for the development of cancer medications. The researchers from Ruhr-Universität Bochum (RUB) and Osnabrück University published the results in the Journal of Chemical Science in May 2021.

In an activated state, the Ras protein is bound to the molecule guanosine triphosphate, GTP for short. Ras separates one of the phosphate groups from the GTP molecule, thus switching off cell growth. Malfunctions of the Ras protein can cause it to remain in an active state or switch off with a significant delay. This causes uncontrolled cell growth and, as a result, cancer. Almost all attempts to find an active ingredient that docks to individual Ras proteins have so far failed.

Stronger in a pair

Other studies have since shown that the clustering of Ras as a pair causes the signal for cell growth to be transmitted considerably better. "If we could find a way to disrupt the formation of a pair of malfunctioning Ras proteins using an active ingredient, their signal for cell growth would be significantly weakened," says Professor Klaus Gerwert, Founding Director of PRODI. "As a result, the knowledge of the Ras pair structure offers a new starting point for active ingredients to combat cancer." Bioinformatic methods could help in the search for potential active ingredients. "However, the precise structure of the interface between the two Ras proteins needs to be known for this," explains Dr. Till Rudack, lead author of the current study.

Many different contradictory pair models

In 2012, the Bochum group led by Klaus Gerwert identified a structure for the Ras pair at the cell membrane using a specially developed combination of computer-aided and experimental methods. With biomolecular simulations, the group also predicted an initial model of the interface between the two proteins. However, the precise structure of the interface was the subject of controversial debate in the following years and many other contradictory structure models were predicted. "In order to dispel the controversy, experimental data are required to unequivocally validate the model," says Associate Professor Dr. Carsten Kötting, Project Group Leader at PRODI. These data were provided by the researchers in their current work.

They used the FRET method, short for fluorescence resonance energy transfer, which acts as a kind of molecular yardstick and is used to measure distances between proteins. To do this, two proteins are marked with two different dyes. If they are very close together, energy is transferred from one dye to the other. The distance between the proteins is determined based on the ratio of transferred energy. In order to ascertain the orientation of the two Ras proteins in the pair in relation to each other, the researchers had to measure the distances at different points. "We applied an innovative method to incorporate amino acids into the Ras protein, which are not found naturally in the protein but can attach to the dyes," explains Carsten Kötting.

Exchange of amino acids destroys the pair

The researchers thus measured a total of four different distances. They then examined with which of the pair models these distances correlated. Their analysis included all of the previously published pair models as well as a further 100 potential models that they predicted by computational methods. However, only one arrangement of the pair matched all four experimentally determined distances. "This arrangement corresponds to the structure we predicted back in 2012," summarises Till Rudack.

In further experiments, the researchers exchanged two of the most important amino acids at the point of contact between the two Ras proteins. The result: a pair was no longer formed. "The fact that the formation of a pair could be prevented by exchanging amino acids makes me optimistic that we can use the contact point of the Ras pair as a point of attack for active ingredients in the future," says Klaus Gerwert.

A team of researchers led by diabetes specialists and biomedical engineers at Washington University School of Medicine in St. Louis and Cornell University has demonstrated that, using a miniscule device, they can implant insulin-secreting cells into diabetic mice. Once implanted, the cells secrete insulin in response to blood sugar, reversing diabetes without requiring drugs to suppress the immune system.

The findings are published June 2 in the journal Science Translational Medicine.

"We can take a person's skin or fat cells, make them into stem cells and then grow those stem cells into insulin-secreting cells," said Jeffrey R. Millman, PhD, an associate professor of medicine at Washington University and one of the study's co-senior investigators. "The problem is that in people with Type 1 diabetes, the immune system attacks those insulin-secreting cells and destroys them. To deliver those cells as a therapy, we need devices to house cells that secrete insulin in response to blood sugar, while also protecting those cells from the immune response."

In previous research, Millman, also an associate professor of biomedical engineering, developed and honed a method to make induced pluripotent stem cells, and to then grow those stem cells into insulin-secreting beta cells. Millman previously used those beta cells to reverse diabetes in mice, but it was not clear how the insulin-secreting cells might safely be implanted into people with diabetes.

"The device, which is about the width of a few strands of hair, is micro-porous -- with openings too small for other cells to squeeze into -- so the insulin-secreting cells consequently can't be destroyed by immune cells, which are larger than the openings," said Millman. "One of challenges in this scenario is to protect the cells inside of the implant without starving them. They still need nutrients and oxygen from the blood to stay alive. With this device, we seem to have made something in what you might call a Goldilocks zone, where the cells could feel just right inside the device and remain healthy and functional, releasing insulin in response to blood sugar levels."

Millman's laboratory worked with researchers in the lab of Minglin Ma, PhD, an associate professor of biomedical engineering at Cornell. Ma has been working to develop biomaterials that can help implant beta cells safely into animals and, eventually, people with Type 1 diabetes.

Several implants have been tried in recent years, with varying levels of success. For this study, Ma, the study's other co-senior investigator, and his colleagues developed what they call a nanofiber-integrated cell encapsulation (NICE) device. They filled the implants with insulin-secreting beta cells that had been manufactured from stem cells and then implanted the devices into the abdomens of mice with diabetes.

"The combined structural, mechanical and chemical properties of the device we used kept other cells in the mice from completely isolating the implant and, essentially, choking it off and making it ineffective," Ma said. "The implants floated freely inside the animals, and when we removed them after about six months, the insulin-secreting cells inside the implants still were functioning. And importantly, it is a very robust and safe device."

The cells in the implants continued to secrete insulin and control blood sugar in the mice for up to 200 days. And those cells continued to function despite the fact that the mice were not treated with anything to suppress their immune systems.

"We'd rather not have to suppress someone's immune system with drugs, because that would make the patient vulnerable to infections," Millman said. "The device we used in these experiments protected the implanted cells from the mice's immune systems, and we believe similar devices could work the same way in people with insulin-dependent diabetes."

Millman and Ma are reluctant to predict how long it might be before such a strategy could be employed clinically, but they plan to continue working toward that goal.

Peer reviewed
Experimental study / Meta-analysis
Animals / Human data

Protein disguise could be new target for cancer immunotherapy

Researchers at the Francis Crick Institute have identified a protein that helps tumours evade the immune system and, in certain types of cancers, is linked to a poorer chance of survival. The protein could become a target for future cancer treatments.

A crucial part of the immune system's response to cancer is a group of white blood cells, called CD8+ T-cells, which kill tumour cells. Before they launch their anti-tumour response, these cells must be told who to attack by another immune cell, called a dendritic cell.

In their study, published in Cell today (2 June), the scientists identified a protein that is present in blood plasma and is also secreted by cancer cells, secreted gelsolin, which interferes with this relay process by blocking a receptor inside dendritic cells. With no instruction passed to the T-cells, the tumours avoid their killer response.

The team analysed clinical data and samples from cancer patients with 10 different types of the disease and found that individuals with liver, head and neck and stomach cancers, who have lower levels of this protein in their tumours had higher chances of survival.*

They also found that blocking the action of this protein in mice with cancer increased their response to treatments including checkpoint inhibitors, a major immunotherapy.

Caetano Reis e Sousa, author and group leader of the Immunobiology Laboratory at the Crick, says: "The interaction between tumour cells, the surrounding environment and the immune system is a complex picture. And although immunotherapies have revolutionised the way certain cancers are treated, there's still a lot to understand about who is most likely to benefit.

"It's exciting to find a previously unknown mechanism for how our body recognises and tackles tumours. This opens new avenues for developing drugs that increase the number of patients with different types of cancer who might benefit from innovative immunotherapies."

This work builds on the team's research into dendritic cell biology. These cells absorb debris from dead cancer cells and hold them internally in pockets called phagosomes. Binding to a protein on the debris, F-actin, triggers these pockets to burst, releasing the debris into the cell where they can be processed and moved to the surface to signal the presence of a tumour to nearby T-cells.

When the researchers examined the activity of secreted gelsolin, they found the protein outcompetes a key dendritic cell receptor, blocking its ability to bind to F-actin and therefore the ability of the dendritic cells to initiate a T-cell response.

"Dendritic cells play a vital role in the immune system and our body's response to cancer," says Evangelos Giampazolias, author and postdoc in the Immunobiology Laboratory at the Crick. "Understanding this process in more detail will enable us to identify how cancers are able to hide and how we might remove their disguise."

Oliver Schulz, author and research scientist in the of the Immunobiology Laboratory at the Crick says, "While secreted gelsolin circulates in healthy blood plasma, some cancer cells secrete really high levels of it - so these tumours are launching an anti-immune defence which helps them avoid killer T-cells.

"Reducing levels of this protein will help alleviate the competition for binding to F-actin and allow dendritic cells to communicate their vital message."

The researchers will continue this work, trying to develop a potential therapy that targets the secreted gelsolin in the tumour without affecting the activity of this protein in other parts of the body.

Amsterdam, June 2, 2021 - On the eve of the 50th anniversary of the 1972 Stockholm conference that created the United Nations Environmental Programme, it is clear that the global environmental situation has only deteriorated. In "Our Earth Matters: Pathways to a Better Common Environmental Future," an extended special issue of Environmental Policy and Law (EPL), leading scholars from more than five continents call for an honest introspection of what has been attained over the last 50 years relating to regulatory processes and laws and explore future trajectories with new ideas and frameworks for environmental governance in the 21st century.

"Our objective is to fire the imaginations of scholars and decision-makers to re-examine current approaches and to explore the future, with new tools, ideas, ecological frameworks, and new international environmental institutions," explains Guest Editor Bharat H. Desai, PhD, LLM, Professor of International Law and Jawaharlal Nehru Chair in International Environmental Law, Centre for International Legal Studies, School of International Studies, Jawaharlal Nehru University, New Delhi, India.

Contributors to the first section of the special issue review some of the structural problems of environmental law in the Anthropocene era, an era of significant human impact on the environment, and predict what frameworks and solutions will be necessary in the future. "Nations are not acting as if they are governing in the Anthropocene epoch, not yet," warns Nicholas A. Robinson, JD, Pace University School of Law, New York; Executive Governor, International Council of Environmental Law. "More than just air pollution and the loss of natural resources, future policies must cope with threats from cyber wars, nuclear war, genetic mutations, and artificial intelligence. International law will have to be more ambitious, taking advantage of cutting-edge science."

The next section explores international law-making processes, outlining current shortcomings and proposing possible frameworks for the future. Observing that current approaches seek to minimize economic impact at the expense of environmental protection, Jorge E. Viñuales, PhD, LLM, University of Cambridge, notes that, "The scale and urgency of the unfolding environmental crisis has made the critique of this hierarchy (economy over environmental protection) more powerful."

Since the 1960s, the United Nations General Assembly has been the central enterprise for the protection of the global environment. The special issue suggests that it is high time the UN system recalibrates itself for the vagaries of scientific assessments and the political realities of the future. A new environmental charter is proposed to rejuvenate the founding values of the international system and restore faith in international environmental governance.

The third section, focusing on problematic situations, highlights how State sovereignty is a major stumbling block for effective environmental conservation and sustainable development. The modern international law movement makes States responsible for adapting regulations and securing compliance. Existing multilateral treaties may serve as an organizational principle for planetary management of natural resources. Writing about the direct and indirect impacts of armed conflicts on the natural environment, Peter Maurer, PhD, President of the International Committee of the Red Cross (ICRC) Geneva, writes that States can integrate legal protections for the environment into their armed forces' doctrines, and humanitarians must commit resources and expertise to help those coping with the environmental consequences of conflict.

"We all have our part to play as we face this existential threat," Dr. Maurer states. "Perhaps the biggest challenge ahead is the shift in in mindset and mechanics needed from States, humanitarian organizations, and those engaged in hostilities."

Other contributions address sector-specific environmental problems including climate skepticism; transnational environmental crimes; soil protection and global food security; the impending global water crisis; ocean biodiversity, and a call for new approaches.

In a concluding section, contributors look to the future at international environmental governance structures and reforms that will be necessary to meet current and future challenges. It has become clear that the changes in attitudes and social structures called for at the 1972 United Nations Conference on the Human Environment have not taken place and that now time is even more limited to make necessary, far-reaching changes.

Contributor Anna Sundström, MA, Secretary General, Olof Palme International Centre, Stockholm, comments, "Together, we face humanity's greatest challenge. Together we must fix it. The need for international action remains even more acute."

International governance is proposed to deal with the practical challenges of repairing environmental conflict. Contributions suggest reviving the United Nations Trusteeship Council, dormant since 1994, with a mandate for the environment and the global commons and turning the United Nations Environment Programme into a specialized agency to elevate its status and equip it with the necessary competence and financial stability. International and national courts and tribunals could become the new "environmental sentinels," and a specialized International Environmental Court could serve as a global watchdog.

"The 50th Anniversary of the 1972 Stockholm Conference next year calls for honest introspection on what we have attained during the past 50 years," says Dr. Desai. "This special issue is a modest effort to challenge the connoisseurs of international law and diplomacy to look ahead at this time of perplexity in the 21st century."

On World Environment Day, June 5, 2021, an exclusive free online event featuring a panel of high-profile experts will explore the issues raised in "Our Earth Matters," discussing pertinent questions about how we might move ahead to forge pathways to a better environmental future.

Aging published "Cdkn1a transcript variant 2 is a marker of aging and cellular senescence" which reported that cellular senescence is a cell fate response characterized by a permanent cell cycle arrest driven primarily the by cell cycle inhibitor and tumor suppressor proteins p16Ink4a and p21Cip1/Waf1. In mice, the p21Cip1/Waf1 encoding locus, Cdkn1a, is known to generate two transcripts that produce identical proteins, but one of these transcript variants is poorly characterized.

The authors show that the Cdkn1a transcript variant 2, but not the better-studied variant 1, is selectively elevated during natural aging across multiple mouse tissues.

Importantly, mouse cells induced to senescence in culture by genotoxic stress upregulated both transcripts, but with different temporal dynamics: variant 1 responded nearly immediately to genotoxic stress, whereas variant 2 increased much more slowly as cells acquired senescent characteristics.

Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1. Variant 2 levels were also more sensitive to the senolytic drug ABT-263 in naturally aged mice.

Upon treating mice systemically with doxorubicin, which induces widespread cellular senescence in vivo, variant 2 increased to a larger extent than variant 1.

Thus, variant 2 is a novel and more sensitive marker than variant 1 or total p21Cip1/Waf1 protein for assessing the senescent cell burden and clearance in mice.

Dr. Judith Campisi from The Buck Institute for Research on Aging as well as The University of California said, "The stringent cell growth arrest associated with cellular senescence is determined, among other mechanisms, by activities of cyclin-dependent kinase inhibitor proteins p16Ink4a and p21Cip1/Waf1, encoded by the Cdkn2a and Cdkn1a loci, respectively."

The increased expression of these proteins is a major hallmark of senescence in most cells, and therefore have become markers of senescence both in culture and in vivo.

Consistent with the fact that senescent cells increase with age in many mouse and human tissues, Cdkn2a mRNA levels also increase with age in these tissues.

To date, possible changes in the expression of Cdkn1a transcript-specific variants during age or cellular senescence have not been explored.

The authors also analyze expression levels in a cell culture model of mouse cells subjected to genotoxic stress-induced senescence to evaluate their relative utility as senescence markers both in culture and in vivo.

The Campisi Research Team concluded in their Aging Research Output that it remains unexplored the possibility that the different transcript variants are preferentially associated with one or other cell fate.

Human cells also express several Cdkn1a transcript variants.

Among the ten human transcript variants currently annotated, at least one shares translational regulatory mechanisms with the murine p21var2.

Interestingly, even though murine variant 2 and human variant 4 do not appear to share sequence homology, the translational regulation in both transcripts is driven by the integrated stress response and results in cell cycle arrest.

The potential relevance of this mechanism for cellular senescence in humans remains unknown, and the functions and interrelations of the different Cdkn1a transcript variants have not been studied in depth.

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DOI - https://doi.org/10.18632/aging.203110

Full Text - https://www.aging-us.com/article/203110/text

Correspondence to: Judith Campisi email: jcampisi@buckinstitute.org

Keywords: p21, p53, mouse dermal fibroblast, ionizing radiation, doxorubicin

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.

To learn more about Aging-US, please visit http://www.Aging-US.com or connect with @AgingJrnl

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DOI

10.18632/aging.203110

Researchers from Carnegie Mellon University's Computational Biology Department in the School of Computer Science have developed a new process that could reinvigorate the search for natural product drugs to treat cancers, viral infections and other ailments.

The machine learning algorithms developed by the Metabolomics and Metagenomics Lab match the signals of a microbe's metabolites with its genomic signals and identify which likely correspond to a natural product. Knowing that, researchers are better equipped to isolate the natural product to begin developing it for a possible drug.

"Natural products are still one of the most successful paths for drug discovery," said Bahar Behsaz, a project scientist in the lab and lead author of a paper about the process. "And we think we're able to take it further with an algorithm like ours. Our computational model is orders of magnitude faster and more sensitive."

In a single study, the team was able to scan the metabolomics and genomic data for about 200 strains of microbes. The algorithm not only identified the hundreds of natural product drugs the researchers expected to find, but it also discovered four novel natural products that appear promising for future drug development. The team's work was published recently in Nature Communications.

The paper, "Integrating Genomics and Metabolomics for Scalable Non-Ribosomal Peptide Discovery," outlines the team's development of NRPminer, an artificial intelligence tool to aid in discovering non-ribosomal peptides (NRPs). NRPs are an important type of natural product and are used to make many antibiotics, anticancer drugs and other clinically used medications. They are, however, difficult to detect and even more difficult to identify as potentially useful.

"What is unique about our approach is that our technology is very sensitive. It can detect molecules with nanograms of abundance," said Hosein Mohimani, an assistant professor and head of the lab. "We can discover things that are hidden under the grass."

Most of the antibiotic, antifungal and many antitumor medications discovered and widely used have come from natural products.

Penicillin is among the most used and well-known drugs derived from natural products. It was, in part, discovered by luck, as are many of the drugs made from natural products. But replicating that luck is difficult in the laboratory and at scale. Trying to uncover natural products is also time and labor intensive, often taking years and millions of dollars. Major pharmaceutical companies have mostly abandoned the search for new natural products in the past decades.

By applying machine learning algorithms to the study of genomics, however, researchers have created new opportunities to identify and isolate natural products that could be beneficial.

"Our hope is that we can push this forward and discover other natural drug candidates and then develop those into a phase that would be attractive to pharmaceutical companies," Mohimani said. "Bahar Behsaz and I are expanding our discovery methods to different classes of natural products at a scale suitable for commercialization."

The team is already investigating the four new natural products discovered during their study. The products are being analyzed by a team led by Helga Bode, head of the Institute for Molecular Bioscience at Goethe University in Germany, and two have been found to have potential antimalarial properties.

Icebergs crumbling into the sea may be what first come to mind when imagining the most dramatic effects of global warming.

But new University of Arizona-led research, published in Geophysical Research Letters, suggests that more record-breaking temperatures will actually occur in the tropics, where there is a large and rapidly growing population.

"People recognize that polar warming is much faster than the mid-latitudes and tropics; that's a fact," said lead study author Xubin Zeng, director of the UArizona Climate Dynamics and Hydrometeorology Center and a professor of atmospheric sciences. "The second fact is that the warming over land is greater than over ocean. The question now is: Where do we see more extreme heat events? Over polar regions or the tropics? Over land or ocean? That's the question we answer."

Zeng and his collaborators analyzed temperature data from the last 60 years in two different ways: by looking at raw temperature trends and normalized temperature trends. Raw temperature is the actual temperature measured outside, whereas normalized temperature is raw temperature divided by the year-to-year variations.

Raw temperature data over the polar region reveals a huge range in temperature. Over the tropics, where it's warm and humid, raw temperature data reveals smaller temperature fluctuations. But when temperature is normalized - or divided- by the temperature fluctuations over the same period, the data shows that the tropics have greater normalized warming and are actually experiencing more record-breaking heat events.

This new perspective allowed Zeng and his team describe the threat to these areas in a new way.

"We realized that very few researchers have addressed the relationship between warming and extreme hot events between different regions, but when you do, the answer is unexpected," said Zeng, who is also the Agnes N. Haury Endowed Chair in Environment in the Department of Hydrology and Atmospheric Sciences.

Mitigating Harm

It is generally understood that warming trends would increase the occurrence of extreme events in a given region. For instance, Arctic amplification, which is the scientific way of saying there's a larger temperature increase at the poles, has been emphasized in all five Intergovernmental Panel on Climate Change, or IPCC, reports. But it can overshadow what's happening in regions like the tropics, around the equator, where less dramatic swings in temperature are the norm.

"Temperature trends in the tropics don't need to be as large to break records and affect the environment, ecosystem and human well-being," Zeng and his study co-authors write.

The study authors also identified two surprising "hot spots" for the occurrence of extreme events: over the Northern Hemisphere's ocean and over the Southern Hemisphere's tropical land.

This is important because marine heat waves are not well understood but would likely have large impacts on marine ecosystems.

"These regions we've identified should receive more attention due to their significant impacts on ecosystem and environment. People know tropical forests are important, but here we're saying they're even more important because suddenly we realized there are going to be more extreme events and weather over the Amazon rainforest," Zeng said.

Species can navigate change - if the change is gradual - via adaptation, but extreme events occur too quickly and often.

Zeng also publishes annual hurricane forecasts for the North Atlantic. He said ocean warming not only leads to more intense hurricanes, but ocean temperatures also affect climate and weather in other ways.

"For example, when we talk about the current drought over the western United States, it's linked to the ocean surface temperature," he said. "Earth system models for IPCC reports should not only use raw temperature data, but also normalized temperature data to understand the impacts of global warming on the occurrence of extreme heat events."

WASHINGTON--A new study finds people who consume two servings of fruit per day have 36 percent lower odds of developing type 2 diabetes than those who consume less than half a serving. The research was published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.

Diabetes is a disease where people have too much sugar in their bloodstream, and it is a huge public health burden. Approximately 463 million adults worldwide were living with diabetes in 2019, and by 2045 this number is expected to rise to 700 million. An estimated 374 million people are at increased risk of developing type 2 diabetes, the most common form of the disease. A healthy diet and lifestyle can play a major role in lowering a person's diabetes risk.

"We found people who consumed around 2 servings of fruit per day had a 36 percent lower risk of developing type 2 diabetes over the next five years than those who consumed less than half a serving of fruit per day," said study author Nicola Bondonno, Ph.D., of Edith Cowan University's Institute for Nutrition Research in Perth, Australia. "We did not see the same patterns for fruit juice. These findings indicate that a healthy diet and lifestyle which includes the consumption of whole fruits is a great strategy to lower your diabetes risk."

The researchers studied data from 7,675 participants from the Baker Heart and Diabetes Institute's Australian Diabetes, Obesity and Lifestyle Study who provided information on their fruit and fruit juice intake through a food frequency questionnaire. They found participants who ate more whole fruits had 36 percent lower odds of having diabetes at five years. The researchers found an association between fruit intake and markers of insulin sensitivity, meaning that people who consumed more fruit had to produce less insulin to lower their blood glucose levels.

"This is important because high levels of circulating insulin (hyperinsulinemia) can damage blood vessels and are related not only to diabetes, but also to high blood pressure, obesity and heart disease," Bondonno said.

Researchers at the University of Eastern Finland have uncovered potential mechanisms by which microRNAs (miRNA) drive atherogenesis in a cell-type-specific manner. Published in the Arteriosclerosis, Thrombosis, and Vascular Biology journal, the study provides novel insight into the miRNA profiles of the main cell types involved in atherosclerosis.

Atherosclerosis is the underlying cause of most cardiovascular diseases and one of the leading causes of mortality in the world. During atherosclerosis, arteries become progressively narrow and thick due to the formation of plaques containing cholesterol deposits, calcium and cells, among other components. Although the role and contribution to atherosclerosis of endothelial cells, smooth muscle cells and macrophages - the main cell types associated with disease progression in the vascular wall - has been previously described, the molecular mechanisms leading to gene expression changes during atherosclerosis in these cell types remain unknown. In particular, the cell-type specific expression and regulation of miRNAs in the disease context has remained unexplored. MiRNAs represent one class of small non-coding RNAs that regulate the protein production by binding to messenger RNAs of protein encoding genes and this way affect cell function and disease progression.

In this study, by integrating different next generation sequencing techniques, the researchers have provided a deeper understanding of the miRNA changes in primary human endothelial cells, smooth muscle cells and macrophages under various pro-atherogenic stimuli, and discovered that the precursor forms of the miRNA (primary miRNAs) were highly expressed in a cell-type specific manner, suggesting distinct regulatory mechanisms on transcriptional level. In contrast, the large majority of mature miRNAs were common to all cell types and dominated by 2-5 abundant miRNA species. Moreover, the researchers uncovered microRNA-messenger RNA networks through which miRNAs could drive cell-type-specific responses. Given that miRNAs play an essential role in maintaining tissue homeostasis and can be dysregulated in pathological states, miRNA therapeutics that manipulate cellular miRNA levels are essential and have already entered clinical trials. Thus, these results are fundamental for the atherosclerosis research community and could serve as the basis for future development of cell-targeted therapeutics.

Eating at least two serves of fruit daily has been linked with 36 percent lower odds of developing type 2 diabetes, a new Edith Cowan University (ECU) study has found.

The study, published today in the Journal of Clinical Endocrinology and Metabolism, revealed that people who ate at least two serves of fruit per day had higher measures of insulin sensitivity than those who ate less than half a serve.

Type 2 diabetes is a growing public health concern with an estimated 451 million people worldwide living with the condition. A further 374 million people are at increased risk of developing type 2 diabetes.

The study's lead author, Dr Nicola Bondonno from ECU's Institute for Nutrition Research, said the findings offer fresh evidence for the health benefits of fruit.

"We found an association between fruit intake and markers of insulin sensitivity, suggesting that people who consumed more fruit had to produce less insulin to lower their blood glucose levels," said Dr Bondonno.

"This is important because high levels of circulating insulin (hyperinsulinemia) can damage blood vessels and are related not only to diabetes, but also to high blood pressure, obesity, and heart disease.

"A healthy diet and lifestyle, which includes the consumption of whole fruits, is a great strategy to lower your risk of developing type 2 diabetes."

Fresh is best

The study examined data from 7,675 Australians participating in the Baker Heart and Diabetes Institute's AusDiab Study and assessed fruit and fruit juice intake and the prevalence of diabetes after five years.

Dr Bondonno said they did not observe the same beneficial relationship for fruit juice.

"Higher insulin sensitivity and a lower risk of diabetes was only observed for people who consumed whole fruit, not fruit juice," she said.

"This is likely because juice tends to be much higher in sugar and lower in fibre."

Dr Bondonno said that it's still unclear exactly how fruit contributes to insulin sensitivity, but it is likely to be multifaceted.

"As well as being high in vitamins and minerals, fruits are a great source of phytochemicals which may increase insulin sensitivity, and fibre which helps regulate the release of sugar into the blood and also helps people feel fuller for longer," she said.

"Furthermore, most fruits typically have a low glycaemic index, which means the fruit's sugar is digested and absorbed into the body more slowly."

The study builds on Dr Bondonno's research into the health benefits of fruit and vegetables, particularly those that contain a key nutrient known as flavonoids. The research is part of ECU's Institute of Nutrition Research.