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Transcatheter aortic valve replacement (TAVR) procedures had a high rate of success and low risk of death or disabling stroke at 30 days in patients with a bicuspid, or two-leaflet, aortic valve, according to research presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

TAVR is a procedure in which operators thread surgical equipment to the aorta through an artery in the chest or groin to replace a patient's malfunctioning valve with an artificial one. The procedure has become increasingly popular in recent years as a less-invasive alternative to open-heart valve replacement surgery. However, few studies have examined its safety in patients with a bicuspid valve, a condition affecting roughly 2-5% of people in which two of the three flaps in the aortic valve are fused together.

A bicuspid valve is more likely to become narrowed or leaky, known as stenosis. Valve replacement, either through TAVR or open-heart surgery, is the main treatment option available for people with severe aortic stenosis, which causes fatigue and other symptoms and raises the risk of other heart problems when left untreated. The new study is the first to prospectively examine TAVR's safety for treating severe aortic stenosis in relatively young, healthy patients--in whom open-heart surgery would pose a low risk--who have a bicuspid valve. It also is one of the first studies involving such patients in which doctors used a newer self-expanding artificial valve.

"TAVR with a self-expanding prosthesis is a very viable and safe procedure in low-risk bicuspid patients and achieved excellent early results," said Basel Ramlawi, MD, cardiothoracic surgeon at Valley Health System in Virginia and the study's co-principal investigator. "Though additional follow-up is necessary to determine long-term outcomes, early results suggest this procedure can be performed successfully in low-risk individuals with a good outcome."

The study prospectively tracked 150 patients who underwent TAVR at 25 medical centers in the U.S. On average, patients were 70 years old and had a Society of Thoracic Surgeons risk score (which reflects the risk of dying during or shortly after open heart surgery) of 1.4%.

Thirty days after their procedure, just 1.3% of patients had died or experienced a disabling stroke, the study's primary safety endpoint. Patients also had an overall device success rate of 95.3%, reflecting a low rate of major complications, ill-fitting valves or the need for additional procedures. The vast majority (99.3%) of patients survived the procedure, 96% showed correct positioning of the valve and 100% had mild or no aortic regurgitation (blood leaking around the valve).

Bicuspid valves can have several different shapes, which are named according to the Sievers classification system. The study found 84.6% of those with a Sievers type 0 valve had trace or no aortic regurgitation and the rest had only mild aortic regurgitation, a high rate of success that Ramlawi said was somewhat unexpected due to the perceived complexity of operating on valves with this shape.

"This is the first study that shows the self-expanding valve works well for patients with both type 1 and type 0 bicuspid valves," Ramlawi said. "The medical community has perceived type 0 bicuspid valves as more challenging to treat, so those data are especially encouraging."

The researchers plan to continue to track outcomes in the patients for 10 years to assess the long-term efficacy of the TAVR-implanted valves. Ramlawi said that the study was limited by the fact that all patients received TAVR, rather than providing a randomized comparison between TAVR and open-heart surgery. In addition, the study was conducted in medical centers that perform a high volume of TAVR procedures, and it is unclear whether a similarly high success rate would be achievable in centers with less TAVR experience.

What do chocolate, migratory birds, flood control and pandas have in common? Many countries benefit from ecosystem services provided outside their nations. This can happen through economic relationships, biological and geographical conditions, but we hardly know how and where these ecosystem service flows occur. Scientists at the Helmholtz Centre for Environmental Research (UFZ) and the German Centre for integrative Biodiversity Research (iDiv) show in a recent study, published in the journal Global Environmental Change, how interregional ecosystem service flows can be identified and quantified.

"Ecosystem services are not constrained by borders," says Prof. Aletta Bonn, who works on ecosystem services at the UFZ and iDiv. "For example, one country benefits from agricultural products originating from other continents or flood protection provided by floodplains in a neighbouring country." These close links between distant regions arising from ecosystem services are known as telecoupling. Understanding these flows can help to recognise the value of intact nature, identify global drivers of biodiversity loss or soil erosion in distant regions, and develop measures for more sustainable management. "It is important to understand the interlinkages and the environmental costs caused by domestic consumption of ecosystem services in other countries," says Aletta Bonn. "This information can then be used in political decisions, such as fair trade standards, environmentally and socially acceptable certification, and financial compensation measures." But how can ecosystem service flows be identified, quantified and ultimately balanced between countries? The researchers investigated these issues in their recent study. As part of this, they examined the extent to which Germany uses ecosystem services that are provided in other countries.

"In previous work, we had already developed a conceptual framework for quantifying interregional ecosystem service flows," says Aletta Bonn. "Here, we differentiated between four types of flows which were examined for Germany in more detail." The scientists assessed trade flows using cocoa imports as an example and their impact on biodiversity in the producing countries. "It turns out that approximately 85 percent of imported cocoa comes from only five mainly West African countries - Ivory Coast, Ghana, Nigeria, Cameroon and Togo. Significant impacts on biodiversity are considered for Cameroon and Ecuador due to cocoa trade with Germany," says Dr. Janina Kleemann, former UFZ researcher and now at Martin Luther University Halle-Wittenberg. In the "migratory species" category, the scientists investigated the importance of migratory birds for German agriculture. "Our results indicate that Africa's tropical and subtropical climate zones provide a habitat for the majority of migratory bird species that make an important contribution to pest control in German agricultural landscapes," explains Janina Kleemann. Ecosystem services associated with flood protection are assigned to the "passive biophysical flow" category. Here, the researchers concluded that Germany benefits by almost two-thirds from flood regulation provided in other countries' floodplains, and in return also exports around 40 percent flood regulation to downstream neighbouring countries such as the Netherlands. In the "information flows" category, the loan of a Chinese giant panda to Berlin Zoo served as a case study. The research team highlighted the political, economic, scientific and cultural aspects of this exchange for the relationship between Germany and China.

"To place our study on a sound basis, we collaborated in an interdisciplinary, international team of ecologists, economists, geographers and social scientists," explains Aletta Bonn. The UFZ study is one of the first studies to identify, systematically quantify and assess several interregional ecosystem service flows for a specific country using examples. Awareness and understanding of these flows is the first step towards fairly balancing ecosystem services use and sustainable resource management. "When we know how and to what extent we influence global biodiversity with our consumption patterns and international trade, we can make better decisions regarding individual and national consumption of resources and develop adequate measures for sustainable management," says Aletta Bonn. "Our study clearly demonstrates that countries such as Germany bear a global responsibility to protect and conserve biological diversity worldwide."

A new approach brings the hope of new therapeutic options for suppressing seasonal influenza and avian flu: On the basis of an empty - and therefore non-infectious - shell of a phage virus, researchers from Berlin have developed a chemically modified phage capsid that "stifles" influenza viruses. Perfectly fitting binding sites cause influenza viruses to be enveloped by the phage capsids in such a way that it is practically impossible for them to infect lung cells any longer. This phenomenon has been proven in pre-clinical trials, also involving human lung tissue. Researchers from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Freie Universität Berlin, Technische Universität Berlin (TU), Humboldt-Universität (HU), the Robert Koch Institute (RKI) and Charité-Universitätsmedizin Berlin were involved in this groundbreaking work. The results are also being used for the immediate investigation of the coronavirus. The findings have now been published in Nature Nanotechnology.

Influenza viruses are still highly dangerous: The World Health Organization (WHO) estimates that flu is responsible for up to 650,000 deaths per year worldwide. Current antiviral drugs are only partially effective because they attack the influenza virus after lung cells have been infected. It would be desirable - and much more effective - to prevent infection in the first place.

This is exactly what the new approach from Berlin promises. The phage capsid, developed by a multidisciplinary team of researchers, envelops flu viruses so perfectly that they can no longer infect cells. "Pre-clinical trials show that we are able to render harmless both seasonal influenza viruses and avian flu viruses with our chemically modified phage shell," explained Professor Dr. Christian Hackenberger, Head of the Department Chemical Biology at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) and Leibniz Humboldt Professor for Chemical Biology at HU Berlin. "It is a major success that offers entirely new perspectives for the development of innovative antiviral drugs."

Multiple bonds fit like hook-and-loop tape

The new inhibitor makes use of a feature that all influenza viruses have: There are trivalent receptors on the surface of the virus, referred to as hemagglutinin protein, that attach to sugar molecules (sialic acids) on the cell surface of lung tissue. In the case of infection, viruses hook into their victim - in this case, lung cells - like a hook-and-loop fastener. The core principle is that these interactions occur due to multiple bonds, rather than single bonds.

It was the surface structure of flu viruses that inspired the researchers to ask the following initial question more than six years ago: Would it not be possible to develop an inhibitor that binds to trivalent receptors with a perfect fit, simulating the surface of lung tissue cells?

We now know that this is indeed possible - with the help of a harmless intestinal inhabitant: The Q-beta phage has the ideal surface properties and is excellently suited to equip it with ligands - in this case sugar molecules - as "bait". An empty phage shell does the job perfectly. "Our multivalent scaffold molecule is not infectious, and comprises 180 identical proteins that are spaced out exactly as the trivalent receptors of the hemagglutinin on the surface of the virus," explained Dr. Daniel Lauster, a former PhD student in the Group of Molecular Biophysics (HU) and now a postdoc at Freie Universität Berlin. "It therefore has the ideal starting conditions to deceive the influenza virus - or, to be more precise, to attach to it with a perfect spatial fit. In other words, we use a phage virus to disable the influenza virus!"

To enable the Q-beta scaffold to fulfill the desired function, it must first be chemically modified. Produced from E. coli bacteria at TU Berlin, Professor Hackenberger's research group at FMP and HU Berlin use synthetic chemistry to attach sugar molecules to the defined positions of the virus shell.

Virus is deceived and enveloped

Several studies using animal models and cell cultures have proven that the suitably modified spherical structure possesses considerable bond strength and inhibiting potential. The study also enabled the Robert Koch Institute to examine the antiviral potential of phage capsids against many current influenza virus strains, and even against avian flu viruses. Its therapeutic potential has even been proven on human lung tissue, as fellow researchers from the Medical Department, Division of Infectiology and Pneumology, of Charité were able to show: When tissue infected with flu viruses was treated with the phage capsid, the influenza viruses were practically no longer able to reproduce.

The results are supported by structural proof furnished by FU scientists from the Research Center of Electron Microscopy (FZEM): High-resolution cryo-electron microscopy and cryo-electron microscopy show directly and, above all, spatially, that the inhibitor completely encapsulates the virus. In addition, mathematical-physical models were used to simulate the interaction between influenza viruses and the phage capsid on the computer. "Our computer-assisted calculations show that the rationally designed inhibitor does indeed attach to the hemagglutinin, and completely envelops the influenza virus," confirmed Dr. Susanne Liese from the AG Netz of Freie Universität Berlin. "It was therefore also possible to describe and explain the high bond strength mathematically."

Therapeutic potential requires further research

These findings must now be followed up by more preclinical studies. It is not yet known, for example, whether the phage capsid provokes an immune response in mammals. Ideally, this response could even enhance the effect of the inhibitor. However, it could also be the case that an immune response reduces the efficacy of phage capsids in the case of repeated-dose exposure, or that flu viruses develop resistances. And, of course, it has yet to be proven that the inhibitor is also effective in humans.

Nonetheless, the alliance of Berlin researchers is certain that the approach has great potential. "Our rationally developed, three-dimensional, multivalent inhibitor points to a new direction in the development of structurally adaptable influenza virus binders. This is the first achievement of its kind in multivalency research," emphasized Professor Hackenberger. The chemist believes that this approach, which is biodegradable, non-toxic and non-immunogenic in cell culture studies, can in principle also be applied to other viruses, and possibly also to bacteria. It is evident that the authors regard the application of their approach to the current coronavirus as one of their new challenges. The idea is to develop a drug that prevents coronaviruses from binding to host cells located in the throat and subsequent airways, thus preventing infection.

Berlin university alliance at its best

Cooperation between scientists from different disciplines played a major role in the discovery of the new influenza inhibitor. Biologists, chemists, physicists, virologists, medical scientists and imaging specialists from three Berlin universities HU, Freie Universität Berlin and TU, the Robert Koch Institute, Charité and, last but not least, FMP were all involved in the project. "In my opinion, such a complex project could only have been undertaken in Berlin, where there truly are experts for every issue," stated Professor Dr. Andreas Herrmann, Head of Molecular Biophysics at HU Berlin. "It was the Berlin university alliance at its best," he added, "and I hope that the follow-up studies will be equally successful."

More than 1 out of 3 heart doctors in the U.S. report feeling burned out, according to results of a new survey presented at the American College of Cardiology's Annual Scientific Session Together with World Congress of Cardiology (ACC.20/WCC).

"More than a third of cardiologists reported being burned out and nearly 44% were stressed, and this is alarming," said Laxmi Mehta, MD, director of preventative cardiology and women's cardiovascular health at Ohio State University and the study's lead author. "Not only can burnout affect the quality of care they provide to patients, it also has many other negative personal and professional ramifications."

Supporting clinician wellness by providing potential solutions to alleviate some of the job pressures associated with burnout has become a strategic priority for the American College of Cardiology (ACC) Mehta, who serves as chair of the ACC Membership Committee's Clinician Well-being Workgroup, said. The current survey was developed after several add-on questions specific to burnout were included on the ACC's most recent Professional Life Survey and revealed that roughly one-quarter of cardiologists reported burnout in 2015. Mehta and her team wanted to dig deeper and launched a survey focused solely on this issue to gauge how common stress and burnout are, explore whether certain cardiologists are more likely to experience symptoms and identify what might be exacerbating these feelings.

"These data give us a baseline of where we are, as well as insights into the associated practice factors that are affecting cardiologists," Mehta said.

The mini-Z survey was sent via email to 19,348 cardiologists, fellows-in-training and cardiovascular team members. Of the 2,025 cardiologists who responded to the survey (1,652 men, 362 women, 11 declined), 35.4% reported burnout and 43.9% said they are stressed. While it was up to the respondents to define what "burnout" meant to them, they were given prompts to assess the degree to which they felt overloaded. Of those who did report burnout, 23.9% said they were experiencing one or more symptoms, such as emotional exhaustion, 9.9% said they had chronic symptoms of burnout and 1.6% said they felt completely burned out to the point of needing to seek outside help.

Mid-career cardiologists who had between eight and 21 years of experience most often reported being burnt out (45.3%) when compared with early or late-career cardiologists (35.4% and 31.5%, respectively), which Mehta said was surprising given that these cardiologists tend to be more established and likely more productive at this stage. Burnout was also more common in women than men, occurring in 45.3% vs. 33.5%, respectively, and may be due to the pressures women feel juggling a career while trying to raise a family, though Mehta said there may be other factors that play a role and should be explored.

Not surprisingly, how much time cardiologists clock each week was directly associated with burnout--those working more than 60 hours a week reporting higher rates of exhaustion and other symptoms of burnout (41.5%), followed by those working 40-60 hours a week (29.5%); cardiologists who work less than 40 hours a week were least likely to experience symptoms of burnout (17.9%).

Cardiologists who are burnt out and stressed were more likely to report a hectic work environment, lack of control over workload and insufficient time for documentation. It also seems that doctors aren't immune to 24-hour work cycles given remote access to work emails and other technology. Those who report being burned out or more stressed tended to have higher electronic medical record usage at home. Cardiologists who felt burned out more frequently spent less than an hour a week on personal time.

"Cardiology remains a highly desirable medical specialty to pursue, but adverse work environments are consistently associated with burn out," Mehta said. "We need to remember work-life balance is important and to take care of our patients and ourselves."

This study is limited in that it relied on self-reported symptoms and participants' own interpretation of burnout, which is popularly defined as "the loss of passion for work, depersonalization and dissatisfaction with personal accomplishments while working in a stressful environment."

As a natural extension of this work, Mehta and her team plan to examine how stress and burnout affect the full care team and identify factors that can predict burnout and then work with the ACC on addressing potential solutions.

Oncotarget Volume 11, Issue 12 reported outside its natural niche, the cultured prostate cancer stem cells lost their tumor-inducing capability and stem cell marker expression after approximately 8 transfers at a 1:3 split ratio.

To characterize the iPS87 cell line, cells were stained with antibodies to various markers of stem cells including: ALDH7A1, LGR5, Oct4, Nanog, Sox2, Androgen Receptor, and Retinoid X Receptor.

This research thus characterizes the iPS87 cell line as a cancer-inducing, stem cell-like cell line, which can be used in the development of novel treatments for prostate cancer.

Dr. Daniel J. Donoghue from the Department of Chemistry and Biochemistry and the Moores UCSD Cancer Center at the University of California San Diego, La Jolla, San Diego, CA 92093, USA said, "The American Cancer Society advises that prostate cancer is the second leading cause of cancer death for men in America."

"The American Cancer Society advises that prostate cancer is the second leading cause of cancer death for men in America."

- Dr. Daniel J. Donoghue, Department of Chemistry and Biochemistry and the Moores UCSD Cancer Center at the University of California San Diego

These authors hypothesize that the disease is initiated, maintained, and progresses, as a disease of prostate cancer stem cells located in the outer/basal layer of the prostate glands.

Clinical treatment of prostatic adenocarcinoma mostly recognizes and targets the more differentiated cells which, although derived from the immortal cancer stem cells, may no longer be immortal themselves.

This approach may postpone disease progression, but recurrent/metastatic prostate cancer is nevertheless non-curable, due to failure to eliminate the underlying cancer stem cell population.

Patient needle-biopsy samples and prostatectomy tissue were examined for six stem cell-specific cell markers: CD44, CD133, Oct4, ALDH7A1, Nanog and LGR5, to verify the stem cell nature of the cancerous cells/tissues.

Figure 1: H&E stained sections from mice orthotopically injected with iPS87 cells. H&E stained sections were examined to identify tumor invasion. (A) Normal prostate; (B) non-invading tumor in prostate; (C) tumor invasion of prostate; (D) seminal vesicle tumor; (E) normal kidney; (F) tumor invasion of kidney; (G) normal lung; (H) lung tumor; (I) normal diaphragm (top) and tumor adjacent to diaphragm (bottom); (J) undifferentiated tumor mass with necrosis.

Antibody-stained prostate cancer tissue taken at the time of prostatectomy was indistinguishable from the images obtained from the same cancer tissue stained with H&E, suggesting that the prostate cancer cells at the time of prostatectomy are mostly composed of classes of stem cells.

The Donoghue Research Team concluded in their Oncotarget Research Paper, "with the positive staining of five documented stem cell markers, we conclude that the iPS87 cell line is indeed stem cell-like. The expression of the Androgen Receptor suggests that the iPS87 cells possess a stem cell progenitor- or a stem cell transit-amplifying genotype. This could potentially facilitate studies of the responsiveness of this potently tumorigenic cell to Androgen Deprivation Therapy (ADT)."

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DOI - https://doi.org/10.18632/oncotarget.27524

Full text - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=27524&path%5B%5D=90169

Correspondence to - Daniel J. Donoghue - ddonoghue@ucsd.edu

Keywords -
prostate cancer,
stem cells,
androgen independent,
androgen deprivation therapy,
castration resistant prostate cancer

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Working in the Arctic Fram Strait, scientists from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) have found microplastic throughout the water column with particularly high concentrations at the ocean floor. Using model-based simulations, they have also found an explanation for this high level of pollution. According to their findings, the two main ocean currents in Fram Strait transport the microscopically small plastic particles into the region between Greenland and Spitsbergen from both the Arctic and the North Atlantic. While passing through the Strait, many particles eventually drift to the seafloor, where they accumulate. The experts report on this phenomenon in a study just released in the esteemed journal Environmental Science & Technology.

Located between the northeast coast of Greenland and the Svalbard archipelago, Fram Strait is the only deep passage between the Arctic and Atlantic Oceans. In its waters, which reach depths of 5,600 metres, two opposing currents flow right by one another like an underwater highway. In the eastern "lane" the West Spitsbergen Current transports warm water north from the Atlantic, while in the other lane the East Greenland Current moves sea ice and frigid water south from the Arctic. This extraordinary combination of circumstances is most likely the reason why experts from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research while collecting water and seafloor samples at the Arctic deep-sea observatory HAUSGARTEN in Fram Strait, detected extremely high quantities of microplastic particles in the sediment, and intermediate levels in the water column in the summer of 2016.

Major quantities of microplastic in the deep sea and near marginal ice zone

"We found the highest concentration of microplastic particles in water at our northernmost sampling spot near the sea-ice edge," reports AWI biologist and first author Mine Tekman. In the area technically referred to as the marginal ice zone, one cubic metre of surface water contained more than 1,200 microplastic particles, though this hardly came as a surprise to the researchers. "From previous studies we knew that the Arctic sea ice can contain as much as 12,000 microplastic particles per litre of meltwater. When this ice reaches the end of its journey and melts in the northern Fram Strait, it most likely releases its microplastic load into the sea, which would explain the high concentration in the surface waters," she adds.

In contrast, the level of pollution was 16,000 times higher in sediments at the bottom of Fram Strait. The analysis of sediment samples with a Fourier-transform infrared spectrometer (FTIR) revealed up to 13,000 microplastic particles per kilogramme of sediment. "This large quantity of particles and the various types of plastic we found in the sediment confirm that microplastic is continually accumulating on the seafloor of Fram Strait. In other words, the deep sea in this region is a sink for microscopically small plastic particles," says AWI deep-sea expert and co-author Dr Melanie Bergmann.

Inflows of plastic waste from north and south alike

This view was confirmed by ocean circulation modelling, in which the experts simulated the microplastic particles' route to Fram Strait. Depending on the particle size, type of plastic, sinking speed and water depth, some particles travelled up to 650 kilometres before coming to rest on the ocean floor. "The results of our model disprove the notion that microplastic particles could rapidly and almost vertically sink to the bottom," says Melanie Bergmann. In fact, the plastic waste is caught by the ocean currents and can drift for tremendous distances. Especially the aggregation with organic material like algal remains is what causes the particles to sink from the surface through the water column to the seafloor.

With regard to Fram Strait, this means the majority of the plastic particles stockpiled at its bottom likely originate from remote regions; for instance, the East Greenland Current transports microplastic from the Arctic Ocean to the eastern Greenland slope. While collecting samples in its basin, the researchers above all found ethylene-vinyl acetate, a type of plastic used e.g. for coatings, lacquers, paper, packaging and shoe soles. In contrast, the West Spitsbergen Current carries particles from waters south of Spitsbergen into Fram Strait. This finding was also reflected in the plastic mix found in the respective samples.

It should also be mentioned that more than half of all plastic particles identified were smaller than 25 micrometres in diameter, roughly half the thickness of a fine human hair. "This high percentage of truly minute particles is of course troubling, as it immediately raises the question of how marine organisms respond to these minuscule bits of plastic waste," says Melanie Bergmann. To answer this question, British colleagues are currently investigating whether the crustaceans in the AWI's Arctic zooplankton samples have consumed any plastic.

For their part, the AWI experts now want to explore how the microplastic levels in Fram Strait change throughout the year. To this end, they'll use devices referred to as sediment traps, which are moored at the AWI's Arctic deep-sea observatory HAUSGARTEN and catch the various particles and marine snow that gradually descend from the sea surface, all through the year.

"The study that's just been released offers an important snapshot in which analyses with infrared microscopes allowed us to gain a solid overview of plastic pollution in Fram Strait," says Gunnar Gerdts, an AWI microbiologist and Head of the Microplastic Analysis Group. The experts determined that 39 percent of the particles suspended in the water came from polyamide, which is used to produce e.g. fibres for textiles and fishing nets, while nearly a quarter of all particles in the water column were identified as synthetic rubber (ethylene-propylene-diene rubber), an elastic type of plastic used e.g. in automotive and machine-building, as pond liner, for sealing roofs and house fronts, and as filler in artificial turf. In the seafloor sediments, the team primarily found particles made of chlorinated polyethylene (CPE), which is used e.g. in the manufacture of cables, hoses, films and antilock braking systems (ABS).

Scientists have developed a way of extracting a richer palette of colours from the available spectrum by harnessing disordered patterns inspired by nature that would typically be seen as black.

Colours that we see in nature often come from nanoscale patterns that reflect light back in particular ways. A butterfly's wing, for example, might appear blue because tiny grooves in the surface of the wing cause only blue light to be reflected.

When surfaces appear black or white, however, it's often because the nanoscale structures are completely disordered, causing all the light to be either absorbed or reflected.

A team of researchers led by the University of Birmingham has now found a way to control the way light passes through these disordered surfaces to produce vivid colours.

The team, which includes colleagues in Ludwig Maximilian University of Munich, Germany, and Nanjing University in China, has compared the method to techniques that artists have exploited for centuries. Among the most famous examples of this is the fourth-century Roman Lycurgus cup, made from glass that appears green when light shines on it from the front, but red when light shines through it from behind.

In a modern advance, the research team demonstrated a way of finely controlling this effect to produce extraordinarily precise colour reproduction.

The different colours in the image are represented in different thicknesses of a transparent material - such as glass - on a lithographic plate. On top of this, the researchers deposited the disordered layer - in this case made of random clusters of gold nanoparticles. Finally, beneath this layer, the team placed a mirrored to form a transparent cavity. The cavity is able to trap particles of light, or photons, inside. The photons behave like waves inside the cavity, resonating at different frequencies beneath the lithographic surface and releasing different colours according to the length of each wave.

By using this technique, the team was able to reproduce a Chinese water colour painting with exquisite colour accuracy.

Lead researcher, Professor Shuang Zhang, explains: "The different ways in which nature can produce colour are really fascinating. If we can harness them effectively, we can open up a treasure trove of richer, more vivid colours than we have yet seen."

Co-author Dr Changxu Liu adds: "In physics, we're used to thinking that randomness in nanofabrication is bad, but here we show that randomness can lead to be superior to an ordered structure in some specific applications. Also, the light intensity within the random structures that we produced is really strong - we can use that in other areas of physics such as new kinds of sensing technologies."

WHAT:

Researchers at the National Institutes of Health have discovered in mice what they believe is the first known genetic mutation to improve cognitive flexibility--the ability to adapt to changing situations. The gene, KCND2, codes for a protein that regulates potassium channels, which control electrical signals that travel along neurons. The electrical signals stimulate chemical messengers that jump from neuron to neuron. The researchers were led by Dax Hoffman, Ph.D., chief of the Section on Neurophysiology at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). It appears in Nature Communications.

The KCND2 protein, when modified by an enzyme, slows the generation of electrical impulses in neurons. The researchers found that altering a single base pair in the KCND2 gene enhanced the ability of the protein to dampen nerve impulses. Mice with this mutation performed better than mice without the mutation in a cognitive task. The task involved finding and swimming to a slightly submerged platform that had been moved to a new location. Mice with the mutation found the relocated platform much faster than their counterparts without the mutation.

The researchers plan to investigate whether the mutation will affect neural networks in the animals' brains. They added that studying the gene and its protein may ultimately lead to insights on the nature of cognitive flexibility in people. It also may help improve understanding of epilepsy, schizophrenia, Fragile X syndrome, and autism spectrum disorder, which all have been associated with other mutations in KCND2.

NEW YORK -- Columbia scientists have provided new insights into how mutations in a gene called TBK1 cause amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that robs patients of movement, speech and ultimately, their lives. The researchers found that ALS-associated mutations in TBK1 can have both positive and negative effects on the progression of disease in mice genetically modified to have ALS-like symptoms.

These findings, reported today in Neuron, provide both genetic and mechanistic insights that could lead to novel strategies for the development of treatments for ALS.

"One of the greatest challenges to finding a cure for ALS is using genetic data to understand the disease's underlying mechanisms," said the study's senior author, Tom Maniatis, PhD, a principal investigator at Columbia's Mortimer B. Zuckerman Mind Brain Behavior Institute. "For example, neurodegenerative diseases such as ALS involve multiple cell types that are constantly changing as the disease progresses, so a drug that is beneficial in the early stages of the disease could detrimental at later times. Our study provides a glimpse into the complex relationship between ALS genetics and its mechanisms, and highlights the challenge in developing safe and effective drugs to treat the disease," commented Dr. Maniatis, the Isidore S. Edelman Professor of Biochemistry at Columbia's Vagelos College of Physicians and Surgeons.

ALS is a disease of the spinal cord, which can be triggered by the accumulation of misfolded proteins in motor neurons, the nerve cells in the spinal cord that drive movement.

The human TBK1 gene is one of more than 25 genes that have been shown associate with or cause ALS when bearing a mutation. TBK1 is a central player in multiple cellular functions, including autophagy, a process that removes misfolded proteins, damaged bits of cells and bacterial pathogens. TBK1 is also required for the antimicrobial interferon response, which protects cells from bacterial and viral infections.

"TBK1 helps cells clear away clumps of misfolded proteins and defends the body against invading viruses and bacteria," said Valeria Gerbino, PhD, an associate research scientist in the Maniatis lab, and the paper's lead author. "And because individuals with certain mutations in TBK1 have ALS, we wanted to develop a deep, mechanistic understanding of how these mutations affect cellular functions in the spinal cord during the course of the disease."

Working in partnership with The Jackson Laboratory, Drs. Maniatis and Gerbino inserted ALS-causing TBK1 mutations in mice. These mice showed no signs of motor neuron disease.

"This was not surprising, as only a few of the many human ALS mutations tested thus far in mice by other ALS researchers have resulted in motor neuron disease," said Dr. Maniatis, who is also director of Columbia's Precision Medicine Initiative.

In an attempt to overcome this problem, the researchers inserted TBK1 mutations into an already established mouse model of ALS: the SOD1 mouse. Dr. Gerbino and collaborators at the Zuckerman Institute then tracked disease progression in these mice.

These new mice displayed striking differences in disease progression compared to mice that only bear the SOD1 mutations. Specifically, the disease onset began earlier.

"We found that mice bearing both SOD1 and TBK1 mutations experienced earlier movement abnormalities compared to those bearing only SOD1 mutations," said Dr. Gerbino. "A closer examination of the mice also revealed damage to motor neurons and the loss of muscle connections earlier than expected."

To further investigate this phenomenon, the scientists examined another group of SOD1 ALS mice, in which the TBK1 gene was deleted only in motor neurons, and not in other cells in the spinal cord. The team found that the absence of TBK1 activity in motor neurons alone led to the loss of autophagy in these cells. This loss led to an increase in the accumulation of harmful proteins, earlier death of motor neurons, and lost neuron-muscle connections. These observations demonstrated that early disease onset was a consequence of losing TBK1 in motor neurons.

Paradoxically, however, disease progression slowed down later in disease, and mice with TBK1 loss of function in all cells lived 25 percent longer than both the mice bearing only SOD1, as well as those mice for which the TBK1 gene was deleted only in motor neurons.

The team next investigated precisely how TBK1 mutations influenced other cells in the spinal cord. The researchers discovered that the interferon response was suppressed in glial cells, namely astrocytes and microglia. The interferon response, while critical for defense against infections in healthy people, can be toxic if over produced (as in the case of ALS mice), and can trigger a cascade of cellular processes that are toxic to motor neurons.

"The loss of TBK1 in microglia and astrocytes clearly diminishes the interferon response in the spinal cord of ALS mice," said Dr. Maniatis, who is Evnin Family Scientific Director and Chief Executive Officer at the New York Genome Center. "This correlates with significantly extending their lives."

"Our study provides an example of how multiple pathways within and between cells can be targeted through manipulation of a single gene, and how modifying these pathways in ALS can be beneficial -- or detrimental -- at different stages of disease progression," Dr. Gerbino added.

Dr. Maniatis argues that this type of foundational, discovery-driven research will move the needle toward treatments that focus on the underlying mechanisms driving ALS and its devastating symptoms.

"All neurodegenerative diseases ultimately begin with genes," said Dr. Maniatis. "As we continue to gather critical genetic information, we can identify mutations, like those in TBK1, which will provide additional mechanistic insights. These genes and the pathways they control will hold the key to developing drugs that make a difference in the life of ALS patients."

What The Study Did: In this study of 72,000 adolescents and young adults, higher risk of youth overdose was associated with exposure to family members with opioid prescriptions and young people's own opioid prescriptions.

Authors: Anh P. Nguyen, Ph.D., of the Institute for Health Research, Kaiser Permanente Colorado, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(10.1001/jamanetworkopen.2020.1018)

Editor's Note:  The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

Cervical cancer screening rates in Japan were significantly affected in the years following the devastating Great East Japan Earthquake of 2011, Tohoku University scientists report in the journal PLOS ONE.

"Conflicts and disasters, and the social isolation that often follows, have a major impact on healthcare and lead to delays in the diagnosis and treatment of cancers," says Tohoku University's Yasuhiro Miki, who specializes in disaster obstetrics and gynecology.

On March 11, 2011, Miyagi Prefecture in eastern Japan experienced a 9.0 magnitude earthquake, followed by a destructive tsunami that affected its coastal areas. Miki and colleagues at Tohoku University, led by disaster scientist Kiyoshi Ito, examined how the earthquake affected cervical cancer screening rates in Miyagi Prefecture.

Across Japan, approximately 15 women per 100,000 people are affected by cervical cancer. This rate is higher than that in countries such as the US (6.5) and South Korea (8.4), and similar to that in India (14.7) and the Philippines (14.9). Also, less than 1% of girls in Japan have received the human papillomavirus vaccine, which protects against cervical cancer. This means that cervical cancer screening is of particular importance for early detection and diagnosis. Even so, cervical cancer screening rates are lower in Japan (42.3% of women aged 20-69) compared to other countries (80% in the US and the UK, for example).

In the five years after the 2011 disaster, cervical cancer screenings dropped by more than 3% in four areas of Miyagi Prefecture covered by mobile van testing. In the coastal city of Onagawa, for example, cervical cancer screening dropped 7% following the disaster. While rates improved slightly over the years, they were still 6.9% lower in 2016 compared to pre-earthquake levels. Similar trends, though less severe, were found in other areas of the prefecture; with rates significantly lower in coastal areas compared to non-coastal ones.

"Cervical cancer screening is essential for maintaining good health, but in many affected areas, the rates markedly decreased in the year following the earthquake," says Miki. "More problematically, the decline in cervical cancer screening rates did not even recover in some areas five years after the earthquake."

The issue is not specific to Japan. Researchers in the US had previously observed fewer women were diagnosed with cervical cancer in areas affected by Hurricane Katrina in the five years following 2005, compared to the five years preceding it. Those diagnosed also had more advanced disease, suggesting that the cervical cancer screening services were not being fully utilized.

"Long term monitoring of women's health is needed after a disaster," Miki says. "Measures need to be taken to restore screening rates in all affected areas."

The team recommends further studies to understand why screening rates were affected more in some areas compared to others.

Research just published by the Linterman lab shows that the immune system of older mice can be given a helping hand by applying immunology expertise and some genital wart treatment (don't try this at home just yet)!

Mice and humans show similar age-dependent changes in their immune system so this finding offers hope for easily increasing the robustness of vaccination response in the older population.

As we age, the function of our immune system declines, rendering us more susceptible to infections, and making us less able to generate protective immunity after vaccination. By understanding the cellular and molecular mechanisms that underpin this poor response in older individuals, researchers in the Linterman lab were able to repurpose an existing treatment for genital warts, and demonstrate that this was effective in overcoming the age-related effects on two of the many cell types making up our immune system. The research is published online in the journal eLife.

Dr Michelle Linterman, a group leader in the Institute's Immunology research programme, said: "The current coronavirus pandemic highlights that older members of our families and communities are more susceptible to the morbidity and mortality associated with infectious diseases. Therefore, it is imperative that we understand how the immune system in older people works, and to explore how we might be able to boost their immune responses to vaccines to ensure they work well in this vulnerable part of our society."

Vaccines work by generating antibodies that are able to block the ability of pathogens to infect us. Antibody secreting cells are produced in the germinal centre, immune reaction hubs that forms after infection or vaccination. With age, the magnitude and quality of the germinal centre reaction declines.

Immune cells called T follicular helper cells are essential to the germinal centre response. In this study the team used mice and humans to investigate why T follicular helper cell numbers decline with age, and if there is a way to boost them upon vaccination.

"The germinal centre response is a highly collaborative process that requires multiple cell types to interact at the right place and the right time. Therefore, it made sense to us that defects in one or more of these cell types could explain the poor germinal centre response observed in older individuals after vaccination," explains Dr Linterman.

The researchers found that older mice and humans form fewer T follicular helper cells after vaccination, which is linked with a poor germinal centre response and antibody response. By developing our understanding of the cellular and molecular events occurring in the germinal centre after vaccination, the researchers identified that T follicular helper cells in older mice and people received less stimulatory interactions from their immune system co-workers. By using a cream (imiquimod, currently used to treat genital warts in humans) on the site of immunisation to boost the number of stimulatory cells, they were able to restore the formation of T follicular helper cells in older mice and also rescue the age-dependent defects in another immune cell type (dendritic cells). Encouragingly, this demonstrates that the age-related defects in T follicular helper cell formation in ageing are not irreversible, and can be overcome therapeutically.

The full picture and evaluation of whether this approach will work as an intervention in humans requires more research into why the germinal centre response changes with age, and what can be done to overcome this. Once achieved, it could be that clinical trials are established to incorporate this knowledge into new vaccine formulations for older people.

Growing consumption of energy and fossil fuels over four decades did not play a significant role in increasing life expectancy across 70 countries.

New research, led by the University of Leeds, has quantified the importance of different development factors to improvements in physical health on an international scale.

Because a country's energy use is highly correlated with life expectancy at any single point in time, it has generally been assumed that growth in energy use is required for increases in life expectancy.

However, the findings of the new research revealed an unexpected paradox. Whilst energy and fossil fuel emissions were indeed strongly correlated with life expectancy at any single point in time, over a long period they were not found to be closely linked.

Between 1971 and 2014, increases in carbon emissions and primary energy use per person accounted for at most a quarter of the improvements in international life expectancy. International life expectancy improved by 14 years overall, meaning that expanded fossil fuel use and ensuing emissions accounted for less than 4 of these years.

Increases in energy use were, however, tied to 90% of growth in national incomes, measured as Gross Domestic Product (GDP) per person.

In the context of the climate crisis and the need to dramatically reduce global energy use, these findings provide reassurance that countries could improve their citizens' lives without requiring more energy consumption.

The research was published today in Environmental Research Letters.

Lead author Professor Julia Steinberger, from the University of Leeds, said: "Increased use of fossil fuels and primary energy may have helped make countries richer, but it was not responsible for much improvement in human health.

"Our results directly counter the claims by fossil fuel companies that their products are necessary for well-being. Reducing emissions and primary energy use, while maintaining or enhancing the health of populations, should be possible."

Co-author Dr William Lamb, from the Mercator Research Institute on Global Commons and Climate Change (MCC), said: "In terms of achieving the Sustainable Development Goals, the challenge is to provide affordable, reliable, and clean energy for all, while ensuring that people enjoy open and equitable opportunities to cover their basic needs, such as nutrition, health care, education, safe water, clean air, among others."

Co-author Dr Marco Sakai, from the University of York, said: "We have to recognise the dual emergency that we face as humanity today. We need to not only stop climate change as soon as possible, but we also need at the same time to bring billions of people out of poverty across the world. Now we have evidence that we don't need to keep injecting fossil fuels into our economies or pursuing everlasting economic growth to face this dual emergency.

"So the question essentially comes down to this: should our societies be prioritising fossil-fuelled economic growth, or instead use clean energy to prioritise people's lives?"

The researchers also found that the growth in a country's income - its gross domestic product (GDP) per person - was only responsible for a minor portion of improvements in life expectancy - at most 29%.

Conversely, a different measure of the economy that removes the differences in the cost of living across countries, called purchasing power parity (PPP), was more closely tied to life expectancy over the 44-year period. Increases in PPP were tied to over half of the increases in life expectancy over the study period.

On this point, Dr Sakai said: "What this suggests is the importance of eradicating extreme levels of inequality within and across countries. Solving this dual challenge does not require adding more stuff in our economies, but prioritising wellbeing and distributing existing resources more equally."

The research was led by the University of Leeds along with Mercator Research Institute on Global Commons and Climate Change, Germany, and the University of York.

Development paradox

Previous research has established that there is a close correlation between a country's energy use and its average life expectancy at any one point in time.

However, the researchers used a new analysis method, called Functional Dynamic Composition, to understand how energy use, the economy and well-being, change over time, to establish the extent to which they are influencing each other.

Their new method cannot show causality, only association. However, a lack of association is evidence of a lack of causation.

The findings suggest that prioritising economic growth and burning increasing amounts of fossil fuels are not going to lead to significant improvements in human lifespan. Instead development efforts should focus directly on wellbeing goals such as satisfying human needs, including healthcare, good nutrition, and safe dwellings powered by clean energy.

Dr Lamb said: "The implications of this for the climate crisis are profound: rapidly decreasing emissions, even through reductions in energy use, need not be catastrophic in terms of our well-being, so long as human needs, such as food and household electricity, are prioritised.

"In short, this research shows we need to prioritise human well-being and acting on climate change over economic growth, because more fossil fuels do not lead to healthier lives."

What does improve wellbeing?

Whilst total primary energy use and carbon emissions accounted for a small proportion of improvements in life expectancy (26% and 22% respectively), a separate measure, residential electricity, accounted for 60% of the wellbeing improvements.

Residential electricity provides a measure of the amount of high quality and versatile energy being used directly within households.

The final development indicator included in the analysis was a measure of nutrition - the amount of calories per person in a country's food supply. Food supply was found to account for 45% of wellbeing improvements - despite itself only growing by a modest 18% during the period covered by the study.

Professor Steinberger said: "At this moment in history - when we are overconsuming and destroying environmental systems, whilst simultaneously trying to bring billions out of poverty to a good standard of living - it is vital that we re-orient our priorities so that people and planet can prosper as one.

"In terms of policies and politics, we need to face the reality that feeding fossil fuels to the economy is far less beneficial to human development outcomes than directly satisfying human needs."

In the future's warmer climate, large, abrupt and frequent changes in ocean ventilation may be more likely than currently assumed, according to a new study. While current climate assessments recognize the severe impact that disruption of North Atlantic Deep Water (NADW) ventilation would have on global climate, disruption to this ocean phenomenon is generally considered to be a low probability tipping point. Now, results from this study suggest a need to reevaluate the long-held notion of warm-climate NADW stability and to consider rapid changes as a possible - if not intrinsic - feature of variability during warm climates. Atlantic meridional overturning circulation (AMOC) and NADW ventilation play a crucial role in mediating the distribution and storage of atmospheric carbon dioxide and heat, as well as in mediating Atlantic-spanning climate patterns. Previous modeling studies and proxy reconstructions of deep ocean circulation during the last several glaciations have suggested relative stability during the warmer interglacial periods. Eirik Galaasen and colleagues present a new high-resolution ocean sediment record recovered from the ocean bottom off the southern tip of Greenland, which provided a 500,000-year record of deep ocean circulation. The high sedimentation rate at the core site allowed the authors to evaluate AMOC and NADW variation at a sub-centennial resolution. Galaasen et al. discovered that disruptions to NADW stability have been relatively frequent during warm climate interglacials. Importantly, the results indicate that large perturbations in ocean circulation are more easily triggered than previously thought and have occurred in past climate conditions similar to those projected for the future. According to Thomas Stocker in a related Perspective, a comprehensive assessment concerning these tipping points and their risks is lacking. "To provide robust and actionable information to decision-makers and people, this should also be a priority for the 7th assessment cycle of the IPCC," Stocker writes.

If circulation of deep waters in the Atlantic stops or slows due to climate change, it could cause cooling in northern North America and Europe - a scenario that has occurred during past cold glacial periods.

Now, a Rutgers coauthored study suggests that short-term disruptions of deep ocean circulation occurred during warm interglacial periods in the last 450,000 years, and may happen again.

Ironically, melting of the polar ice sheet in the Arctic region in a warmer world, resulting in more fresh water entering the ocean and altering circulation, might have caused previous coolings. Still, a rapid deep freeze like in the 2004 movie "The Day After Tomorrow" is highly unlikely.

The study, published in the journal Science and led by scientists at the University of Bergen in Norway, follows a 2014 study on the same topic.

"These findings suggest that our climate system, which depends greatly on deep ocean circulation, is critically poised near a tipping point for abrupt disruptions," said co-author Yair Rosenthal, a distinguished professor in the Department of Marine and Coastal Sciences and Department of Earth and Planetary Sciences at Rutgers-New Brunswick. "Although the disruptions in circulation and possible coolings may be relatively short-lived - lasting maybe a century or more - the consequences might be large."

The warm North Atlantic Current - the northernmost part of the Gulf Stream - flows into the Greenland Sea. It becomes progressively colder and saltier due to heat loss to the air, eventually sinking and forming the North Atlantic Deep Water formation - a mass of deep, cold water that flows southward. Melting of the polar ice sheet in the Arctic region would result in more fresh water entering the ocean and disrupting that circulation pattern, potentially causing cooling in northern areas of Europe and North America.

In their 2014 study, the scientists presented evidence of disruptions in the North Atlantic Deep Water formation during the last interglacial period (the Eemian) about 116,000 to 128,000 years ago. Increased freshwater entering the Arctic region due to melting of the polar ice sheet in a warmer world may have disrupted circulation, which normally brings warmer water to the ocean off northern regions of North America and Europe. Such disruptions seem to last around a century or more.

The latest study covers three other warm interglacial periods within the past 450,000 years. During all of them, regardless of the degree of global warming, the scientists found similar century-long disruptions of the North Atlantic Deep Water formation. And they found that such disruptions are more easily achieved than once believed and took place in climate conditions similar to those we may soon face with global warming.

Next steps include validating the scientists' observations with evidence from other sites near Greenland during other warm intervals.