Earth

Fewer New Yorkers are dying from the coronavirus than health experts had anticipated, a new study shows. Regional death rates have dropped from the highs seen at the start of the outbreak, partially due to a shift in the population contracting the disease toward those who are more resilient.

After New York became the epicenter for the pandemic in early March, with tens of thousands dying from COVID-19, experts had expected that the infection would remain as deadly in the following months.

Instead, a new investigation showed that by mid-August the death rate in those hospitalized with coronavirus-related illness had dropped from 27 percentage points to about 3 percentage points. Led by researchers at NYU Grossman School of Medicine, the study showed that a younger, healthier group of people were getting infected and were arriving at the hospital with less-severe symptoms than those infected in the spring.

However, the researchers' analysis showed that these factors accounted for only part of the improvement in survival. The rest, they suspect, resulted from health care providers' growing experience with the coronavirus. For example, physicians learned that resting COVID-19 patients on their stomachs rather than their backs and delaying the use of ventilators as long as possible were more effective practices, say the study authors. Drugs likely helped as well. In addition, other factors such as decreasing hospital volumes, less exposure to infection, and earlier testing and treatment, may have played a role.

"Our findings suggest that while COVID-19 remains a terrible disease, our efforts to improve treatment are probably working," says study lead author Leora Horwitz, MD, an associate professor in the Department of Population Health at NYU Langone Health. "Even in the absence of a silver-bullet treatment or vaccine, we are protecting more of our patients through a host of small changes," says Horwitz, who is also director of the Center for Healthcare Innovation and Delivery Science at NYU Langone.

New York was among the first states to grapple with a severe outbreak of COVID-19. By contrast, death rates in more recent waves in southern and western regions of the country, which also had younger, healthier coronavirus patients, have been lower, says Horwitz. However, it had remained unclear whether the virus was less deadly due to the different patient demographics or improved care.

Horwitz says the new study, publishing online next week in the Journal of Hospital Medicine, is the most detailed analysis to date of coronavirus death rates over time. By accounting for age, obesity, and other key factors, the researchers were able to eliminate some explanations from the analysis.

For the investigation, the research team analyzed 5,263 patient records of people treated for COVID-19 at NYU Langone hospitals in New York City and Long Island between March 1 and Aug. 8. Using a range of risk factors for the disease as well as indicators of the severity of the illness upon hospitalization, the study authors developed a model that predicted likelihood of death for each patient.

According to the findings, the likelihood of death was on average 22 percentage points lower in August than in March for most critically ill patients.

The average age of hospitalized COVID-19 patients also dropped from 63 to 47. In March, while 73 percent had chronic conditions like lung disease and diabetes, by mid-June only about 65 percent had such risk factors.

"Other pandemic hotspots should take hope from the lessons learned here in New York," says study senior author Christopher Petrilli, MD, an assistant professor in the Department of Medicine at NYU Langone. "If we can do better at managing the disease, they can too."

Still, he adds that the research team next plans to expand the investigation to hospitals outside of New York.

Petrilli also cautions that while death rates are improving, COVID-19 still causes symptoms in some people that continue long after hospital patients are sent home, including fatigue, blood clots, and lung damage.

EUGENE, Ore. - Oct. 23, 2020 - University of Oregon biologists have used the model organism Caenorhabditis elegans to identify molecular mechanisms that produce DNA damage in sperm and contribute to male infertility following exposure to heat.

In humans, the optimal temperature for sperm production is just below body temperature, in a range of about 90-95 degrees F. Human studies have found that exposure to temperatures as little as 1 degree C (1.8 F) above this normal range adversely affects male fertility, said Diana Libuda, a professor in the Department of Biology and Institute of Molecular Biology.

The phenomenon of heat-induced male infertility is well known, and the effects of modern exposures to heat such as hot tubs, tight clothing and excessive drive times have been extensively studied. The underlying mechanisms that damage sperm and impair fertilization are not completely understood.

"In both humans and C. elegans, relatively small increases in temperature are sufficient to reduce male fertility," said Libuda.

An increase of 2 C (3.6 F) above normal in C. elegans, a type of roundworm, led to a 25-fold increase in DNA damage in developing sperm compared to unexposed sperm. Eggs fertilized by these damaged sperm failed to produce offspring.

This basic research discovery is detailed in a paper published online Oct. 15 in the journal Current Biology by researchers in Libuda's UO lab. Postdoctoral researcher Nicole A. Kurhanewicz is the study's lead author.

The study provides a roadmap for scientists to pursue studies in mammals and humans to confirm if the same mechanisms contribute to male infertility, said R. Scott Hawley, a meiosis research expert who was not involved in the research.

Hawley, a member of the National Academy of Sciences and dean emeritus of the graduate school of the Stowers Institute for Medical Research in Kansas City, Missouri, had heard about preliminary findings at an academic conference.

"I think this is a hallmark paper because it shows an environmental effect that alters specific DNA sequences and the presumably the proteins that control their activity," Hawley said. "What Diana and Nicole's work has done is to clearly say what goes wrong, at the level of molecules, when sperm-making is altered by heat, at least in worms."

The paper also helps to understand how meiosis, the process that produces sex cells, differs between sperm and eggs.

Sperm, the smallest cell in a person's body, form by the billions at temperatures below body temperature and are produced throughout the entire adult lifespan. Eggs, the largest cells in a person's body, are formed internally, where a consistent temperature is maintained, and are produced only for a limited time during fetal development.

"We know that sperm development is very sensitive to increased temperature, while egg development is not affected," Kurhanewicz said. "The data presented in this paper suggest that another way egg and sperm develop differently is in how tightly they control the ability of mobile DNA elements, which are also known as 'jumping genes' or transposons, to move in the genome, and how sensitive to heat stress those mechanisms are in preventing that movement."

Transposons are DNA segments that move around and alter genetic information by inserting themselves in new positions. They also leave DNA damage in their wake. Movement of these "jumping genes" is normally repressed in developing sperm and eggs. However, this study found that with exposure to heat transposons are moving specifically in developing sperm.

The research team used microscopy to observe developing sperm and eggs under both normal and heat-stressed conditions. In the latter, the researchers saw higher amounts of DNA damage in sperm, but not eggs. Using next-generation genome sequencing, they also identified the locations of transposons across the whole genome with and without exposure to heat.

"We found that after heat shock, certain transposons are found in new and more variable locations in the male genome," Kurhanewicz said.

The study, Hawley said, not only shows that a small rise in temperature affects meiotic divisions but she also identifies a mechanism - not only where the error occurs but what the error is.

"This is where it gets exciting," he said. "If we can determine how much of a change is bad, and if you are really concerned about the environmental matters such as hot tubs or 'boxers versus briefs', this type molecular understanding may allow us to reframe the debate on solid scientific grounds."

Volume XX, Issue XX from @Oncotarget reported that TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule Ep CAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion.

Altogether, the research team's findings document TQs effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.

Dr. Hala Gali-Muhtasib from The Department of Biology, American University of Beirut, Lebanon and The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebanon and Dr. Wassim Abou-Kheir also from The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebano said, "Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States."

"Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States."

- Dr. Hala Gali-Muhtasib, The Department of Biology, American University of Beirut & The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut and Dr. Wassim Abou-Kheir, The Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut

The ability of TQ to target nine of the ten hallmarks of cancer as well as its efficacy, selectivity against colorectal cancer and lack of toxicity to normal tissues makes it potentially interesting for colorectal cancer therapy.

TQs ability to inhibit colorectal cancer growth and invasion and induce cell cycle arrest and apoptosis in colorectal cancer cell culture and animal models have been documented by this Research Team and others.

In this study, the authors focused on investigating TQs efficacy on human colorectal cancer HCT116 cells, which are sensitive and resistant to 5FU. The main aim was to study the effect of TQ on targeting the self-renewal capacity of colorectal CSCs enriched from the parental and 5FU-resistant cell lines using the advanced three-dimensional culture sphere-formation and propagation assay.

In vitro and in vivo studies revealed the significant inhibitory potential of TQ on colorectal cancer cells with stem-like properties, which was found to be mainly mediated by induction of apoptosis.

This study documents TQs promising effect on CRC cancer stem-like cells both in vitro and in vivo.

The Gali-Muhtasib/Abou-Kheir Research Team concluded in their Oncotarget Research Article, "our study demonstrated that low concentrations of TQ could target CSCs enriched from 5FU-sensitive and resistant colorectal cancer HCT116 cell lines, suggesting a promising effect of TQ on chemoresistant cells. This effect, when coupled with the apoptotic effects of TQ in human CRC cultures and xenografts, indicates that this relatively non-toxic and inexpensive compound merits further clinical investigation."

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DOI - https://doi.org/10.18632/oncotarget.27426

Full text - https://www.oncotarget.com/article/27426/text/

Correspondence to - Hala Gali-Muhtasib - amro@aub.edu.lb and Wassim Abou-Kheir - wa12@aub.edu.lb

Keywords -
thymoquinone,
colorectal cancer stem cells,
5-Fluorouracil resistance,
colonospheres,
apoptosis

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Journal

Oncotarget

DOI

10.18632/oncotarget.27426

In the largest study of its kind, researchers have found two common genetic variants that can be used to predict whether or not cancer patients might suffer severe adverse side-effects from the drug bevacizumab.

The study is unique because researchers found and analysed hundreds of thousands of genetic variations in all the genes of more than 1,000 patients with advanced breast, prostate or pancreatic cancer taking part in five clinical trials in the USA. This genome-wide association study (GWAS) is the largest such study in patients being treated with bevacizumab and it is to be presented at the 32th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics, which is taking place online.

Bevacizumab is a monoclonal antibody that targets a protein called vascular endothelial growth factor (VEGF) that helps cancer cells grow new blood supplies. By targeting VEGF, the drug reduces the supply of oxygen and nutrients so that the tumour shrinks or stops growing. It is used to treat a number of different cancers, often in combination with other drugs.

Federico Innocenti, associate professor at the Eshelman School of Pharmacy of the University of North Carolina in Chapel Hill, USA, who led the research, said: "VEGF inhibitors like bevacizumab have revolutionised cancer treatment, but because they work by impacting how the body builds and regulates blood vessels, side effects are usually vascular-related. Patients treated with bevacizumab can experience an increase in blood pressure and kidney problems caused by proteins leaking into urine. These toxicities are common, and have been observed in up to 40% of patients treated with bevacizumab. They can cause discomfort and harm to patients; they can develop quickly and become severe, even fatal; and they can lead to delaying or discontinuing treatment, which limits their efficacy.

"Currently, there is no way of identifying patients who are likely to experience these toxicities. Some of this risk is likely to be due to each individual patient's genetic make up, and so we set out to identify new genes and their variants that may improve the prediction and management of bevacizumab-induced adverse side effects.

"We characterised hundreds of thousands of genetic variations in more than 1,000 patients. We were not looking for variations in the tumour DNA, but rather the heritable DNA of the patients - the same DNA that determines inherited characteristics like eye colour, height and many others. A group of these patients experienced the side effects of high blood pressure and kidney toxicity, and so we compared the frequency of DNA variations between these patients and the patients who did not suffer these side effects. In this way we were able to discover a series of variations that increased or reduced the risk of these toxicities."

The researchers identified ten variations (known as SNPs) associated with high blood pressure and ten with kidney toxicity. Then, because it is important to test if the variation produces the same effect in as many other studies as possible, they investigated two variations linked to high blood pressure in a different group of 582 patients. One of these variations, called rs6770663, which is located in the KCNAB1 gene, was significantly associated with an increased risk of systolic blood pressure of 160mm Hg or more. [2]

"This finding is important, providing further evidence for the possible use of this variant as an indicator of the risk of toxicity from bevacizumab. It appears twice as often in patients experiencing high blood pressure as in those who do not," said Prof Innocenti. "In addition, KCNAB1 generates instruction for the production of a protein that regulates the function of potassium channels in blood plasma membranes. Reduced function of this protein increases blood vessel constriction, and we think that patients with rs6770663 have greater narrowing of the blood vessels in response to bevacizumab treatment, resulting in an increased risk of high blood pressure. The biological basis for this finding is quite strong."

For protein leaking into the urine (proteinuria) and causing kidney problems, the most significant variation was rs339947, located between the DNAH5 and TRIO genes. TRIO induces activity of a protein that contributes to damage in the kidney, which can lead to proteinuria. This has not yet been tested in another group of bevacizumab-treated patients and so requires further validation.

The findings will enable doctors to improve the treatment of their patients and avoid severe adverse side effects, for instance, by treating those with the rs6770663 variant with another drug, if available, by giving a reduced dose of bevacizumab to see what happens, by increased monitoring, or by giving bevacizumab with other drugs that stop blood pressure rising.

"rs6770663 can be regarded as a new, validated biological marker to predict high blood pressure caused by bevacizumab. Before treatment with bevacizumab, this variant can be searched for in the DNA of patients with a simple genetic test. If it is found, physicians can decide about various treatment options," said Prof Innocenti. "Early identification is a potential double win - it will help doctors identify who is at risk and apply different interventions. The rs6770663 variation is found in up to 20% of people of European origin, 30% of Asian origin, and 80% of people of African origin, so these findings can have an impact on a considerable number of people."

The researchers are continuing to validate rs6770663 and the other variants in different groups of patients, including those of different ethnicities. They are also investigating whether these variants can predict high blood pressure and kidney toxicity for other anti-cancer drugs.

"Efforts are now underway to set up a prospective observational study that will give doctors and patients a test to screen patients and update their treatment regimens as necessary. Interested clinicians and scientists should contact me," concluded Prof Innocenti.

William R. Sellers, Professor of Medicine at the Dana-Farber Cancer Institute, Harvard Medical School, USA, is co-chair of the EORTC-NCI-AACR Symposium on behalf of the NCI and was not involved with the research. He commented: "This study is a good example of how our increasing ability to study the human genome easily and in depth is producing findings that may have an impact, either immediately or fairly soon, on patient health and outcomes. Side effects from bevacizumab can be extremely debilitating, so if we can use a simple genetic test to identify which patients will experience toxicities and take appropriate measures to avoid these toxicities, this could help to provide better and more effective treatments for our patients."

A new international study led by Monash University climate scientists has revealed that ice loss in Antarctica persisted for many centuries after it was initiated and is expected to continue.

"Our study implies that ice loss unfolding in Antarctica today is likely to continue unbated for a long time - even if climate change is brought under control," said lead study authors Dr Richard Jones and Dr Ross Whitmore, from the Monash University School of Earth, Atmosphere and Environment.

The study, published today in Geology, outlines a cosmogenic surface-exposure chronology from Mawson Glacier, adjacent to a region of the Ross Sea that underwent dynamic marine-based ice sheet retreat following the Last Glacial Maximum.

The data records at least 220 meters of abrupt ice thinning between 7,500 and 4,500 years ago, followed by more gradual thinning until the last millennium.

The study presents new results of ice sheet thinning in the southwestern Ross Sea. The results show that abrupt ice loss of several hundred meters occurred at a similar rate and duration across multiple outlet glaciers in the Mid-Holocene, despite complex bed topography.

Both outlet glaciers demonstrate that abrupt deglaciation occurred across a broad region in the Mid-Holocene.

When compared to regional sea-level and ocean-temperature changes, the study data indicate that ocean warming most likely drove grounding-line retreat and ice drawdown, which then accelerated as a result of marine ice sheet instability.

"We show that part of the Antarctic Ice Sheet experienced rapid ice loss in the recent geological past," said Professor Andrew Mackintosh, who heads the Monash School of Earth, Atmosphere and Environment.

"This ice loss occurred at a rate similar to that being observed in rapidly changing parts of Antarctica today, and it was caused by the same processes that are considered to cause current and probable future Antarctic ice mass loss - ocean warming, amplified by internal feedbacks," he said.

"The retreat persisted for many centuries after it was initiated, which implies that ice loss unfolding in Antarctica today is likely to continue unabated for a long period."

Researchers find combo with probiotics may help them heal

Hamilton, ON (Oct. 21, 2020) - People with celiac disease may find themselves more comfortable with extra Thanksgiving turkey dinners.

An international team of researchers led by McMaster University has found that tryptophan, an amino acid present in high amounts in turkey, along with some probiotics, may help them heal and respond better to a gluten-free diet.

The study, published in Science Translational Medicine, set out to investigate whether the breakdown of tryptophan by gut bacteria was altered in celiac disease and whether this pathway could be targeted as a potential therapy.

The findings highlight the potential therapeutic value of targeting tryptophan metabolism in the gut in celiac disease to better control symptoms, despite the gluten-free diet, and accelerate intestinal healing.

"The only treatment for celiac disease is a strict adherence to a gluten-free diet, which is difficult to follow, and doesn't always lead to complete recovery of the gut or symptom resolution," says Elena Verdu, lead researcher of the study and a professor of medicine at McMaster's Farncombe Family Digestive Health Research Institute. She also holds the Canada Research Chair in Nutrition, Inflammation and Microbiota.

Tryptophan is an essential amino acid, which cannot be produced by the body and needs to be consumed through foods such as poultry, chocolate, bananas and cruciferous vegetables such as broccoli, cabbage and cauliflower.

Tryptophan is necessary for many functions in the body and can be broken down by bacteria in the gut, producing bioactive molecules (called "metabolites") that interact with receptors in the gut lining which control inflammation. One of these receptors is the aryl hydrocarbon receptor, or AhR, and suboptimal activation of this receptor has been implicated in chronic intestinal inflammation, including inflammatory bowel diseases such as ulcerative colitis and Crohn's disease.

"Celiac disease is the destruction of the lining of the upper gut, when a person with certain predisposing genes consumes gluten in the diet," said Heather Galipeau, co-author of the study and a research associate at the Farncombe Institute.

"However, not everyone with celiac genes and eating gluten will develop the disease."

Verdu added: "Our team at the Farncombe Institute has pioneered the study of impaired bacterial metabolism of wheat proteins, as an additional environmental driver in celiac disease."
The researchers studied three groups: patients with active celiac disease, patients two years after a gluten-free diet, and healthy people.

Celiac patients had evidence of lower bacterial metabolism of tryptophan, and their gut microbiota did not appropriately stimulate the AhR pathway which controls inflammation and protects the gut barrier.

These alterations were partially improved in patients after two years of a gluten-free diet. Using mice that express the genes for celiac disease, the authors showed that two strains of lactobacilli, bacteria known to breakdown tryptophan, activated AhR and reduced inflammation caused by gluten.

The study findings highlight the potential therapeutic value of targeting tryptophan metabolism in the gut in celiac disease to better control symptoms.

Future clinical studies would examine therapeutic strategies, such as tryptophan supplementation in combination with specific probiotics that produce AhR ligands from the diet, in celiac patients who do not respond to the gluten-free diet.

BROOKLYN, New York, Wednesday, October 21, 2020 - The identification of human migration driven by climate change, the spread of COVID-19, agricultural trends, and socioeconomic problems in neighboring regions depends on data -- the more complex the model, the more data is required to understand such spatially distributed phenomena. However, reliable data is often expensive and difficult to obtain, or too sparse to allow for accurate predictions.

Maurizio Porfiri, Institute Professor of mechanical and aerospace, biomedical, and civil and urban engineering and a member of the Center for Urban Science and Progress (CUSP) at the NYU Tandon School of Engineering, devised a novel solution based on network and information theory that makes "little data" act big through, the application of mathematical techniques normally used for time-series, to spatial processes.

The study, "An information-theoretic approach to study spatial dependencies in small datasets," featured on the cover of Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences, describes how, from a small sample of attributes in a limited number of locations, observers can make robust inferences of influences, including interpolations to intermediate areas or even distant regions that share similar key attributes.

"Most of the time the data sets are poor," Porfiri explained. "Therefore, we took a very basic approach, applying information theory to explore whether influence in the temporal sense could be extended to space, which allows us to work with a very small data set, between 25 and 50 observations," he said. "We are taking one snapshot of the data and drawing connections -- not based on cause-and-effect, but on interaction between the individual points -- to see if there is some form of underlying, collective response in the system."

The method, developed by Porfiri and collaborator Manuel Ruiz Marín of the Department of Quantitative Methods, Law and Modern Languages, Technical University of Cartagena, Spain, involved:

Consolidating a given data set into a small range of admissible symbols, similar to the way a machine learning system can identify a face with limited pixel data: a chin, cheekbones, forehead, etc.

Applying an information-theory principle to create a test that is non-parametric (one that assumes no underlying model for the interaction between locations) to draw associations between events and to discover whether uncertainty at a particular location is reduced if one has knowledge about the uncertainty in another location.

Porfiri explained that since a non-parametric approach posits no underlying structure for the influences between nodes, it confers flexibility in how nodes can be associated, or even how the concept of a neighbor is defined.

"Because we abstract this concept of a neighbor, we can define it in the context of any quality that you like, for example, ideology. Ideologically, California can be a neighbor of New York, though they are not geographically co-located. They may share similar values."

The team validated the system against two case studies: population migrations in Bangladesh due to sea level rise and motor vehicle deaths in the U.S., to derive a statistically principled insight into the mechanisms of important socioeconomic problems.

"In the first case, we wanted to see if migration between locations could be predicted by geographic distance or the severity of the inundation of that particular district -- whether knowledge of which district is close to another district or knowledge of the level of flooding will help predict the size of migration," said Ruiz Marín .

For the second case, they looked at the spatial distribution of alcohol-related automobile accidents in 1980, 1994, and 2009, comparing states with a high degree of such accidents to adjacent states and to states with similar legislative ideologies about drinking and driving.

"We discovered a stronger relationship between states sharing borders than between states sharing legislative ideologies pertaining to alcohol consumption and driving."

Next, Porfiri and Ruiz Marín are planning to extend their method to the analysis of spatio-temporal processes, such as gun violence in the U.S. -- a major research project recently funded by the National Science Foundation's LEAP HI program -- or epileptic seizures in the brain. Their work could help understand when and where gun violence can happen or seizures may initiate.

LOWELL, Mass. - The time has come for reform on how the United States deals with the electoral process, the environment and social justice, according to a new national poll released today by the UMass Lowell Center for Public Opinion that takes an in-depth look at the views of Americans age 18 to 39.

The poll found that the public favors reforms in a range of areas and that the movement for those changes is being driven by younger Americans.

Asked whether the Supreme Court should be expanded, a majority, 52 percent of Americans are in favor of increasing the number of justices from nine to 13. Support is strongest among millennials, 66 percent of whom favor expansion. Sixty-two percent of Gen Z respondents also favor the change. On whether Supreme Court justices should have term limits instead of a lifetime appointment, 72 percent of all surveyed favor limiting the time the justices spend on the court, with 79 percent of millennials and 62 percent of Gen Z in support of such a measure.

"It's no coincidence that as Joe Biden's lead has grown in the polls, the more comfortable Americans are with expanding the size of the Supreme Court. As the chance of Trump holding a second term and appointing more justices dwindles, the opposition to court-packing dwindles as well. Saying Americans are opposed to expanding the court used to be conventional wisdom; now it's a commonly held misconception," said John Cluverius, associate director of the Center for Public Opinion and assistant professor of political science.

On the subject of eliminating the Electoral College in favor of a national popular vote, millennials led the support at 64 percent, followed by 58 percent of all respondents and Gen Z at 54 percent. Millennials also most strongly favored the idea of the nation having more than two competitive political parties, with 71 percent in support, compared to 61 percent of all adults and 59 percent of Gen Z respondents. Sixty-four percent of millennials support ranked-choice voting, followed by 54 percent of Gen Z and 47 percent of all American adult respondents.

A majority of all of the respondents, especially those younger than 40, voiced support for reforms that would make it easier to vote. Sixty-nine percent of all adults surveyed support "no excuse" absentee balloting for all voters in future elections, with 77 percent of millennials and 75 percent of Gen Z in favor. On registering to vote at the polls, 64 percent of Americans are in favor, as are 76 percent of millennial respondents and 70 percent of Gen Z. Older voters, however, were the most likely to support term limits for members of Congress; overall 84 percent support them, with the weakest support among Gen Z (65 percent) and millennials (80 percent), and the strongest among baby boomers (age 56 to 74) with 94 percent and 92 percent of the Silent Generation (age 75 and older).

While millennials polled are more consistently reform-oriented and liberal in their attitudes than their Generation Z counterparts, both groups believe strongly that change is needed in how the nation is addressing climate change.

Eighty-five percent of millennials and 84 percent of Gen Z respondents said human activity contributes to climate change and 65 percent of Gen Z and 60 percent of millennials said the U.S. government has done too little to combat the effects of climate change. More than two-thirds of both groups believe laws should be put in place to prohibit new fossil fuel plants and pipelines. Forty percent of Gen Z and 41 percent of millennials attributed the wildfires that have heavily damaged areas of California to climate change, compared with 35 percent of all adults surveyed.

The poll also asked participants about social justice issues that are the source of debate in the U.S., including whether Blacks are treated less fairly than whites. Overall, 43 percent of Americans surveyed said Blacks are treated less fairly than whites, down eight points from a poll conducted by the Center for Public Opinion in August. On whether the Black Lives Matter protests around the country are generally peaceful or violent, a majority, 51 percent, said they are mostly or somewhat peaceful. Only 29 percent said they favor decreasing funding for police and reallocating funds to other programs.

On each of these issues, Gen Z respondents were the most ideologically liberal, with 54 percent (compared with 53 percent of millennials) saying Blacks are treated less fairly than whites, 70 percent (vs. 63 percent of millennials) saying Black Lives Matter protests have been mostly or somewhat peaceful and 47 percent (compared to 42 percent of millennials) who were in favor of so-called "defunding the police" reform efforts.

"What I find most interesting is that it is not always the youngest Americans who espouse the most liberal viewpoints. Here we see millennials, the oldest of whom are about to turn 40, as the driving force behind the vision for a more progressive future." said Joshua Dyck, director of the Center for Public Opinion and associate professor of political science.

The poll also found:

Trust in government in the overall population is quite low - only 24 percent of respondents trust the government ("almost always" - 5 percent, "most of the time" - 19 percent). However, the most trusting age cohorts are the youngest and oldest respondents: among Gen Z respondents, trust is at 31 percent, millennials 27 percent, Gen X 22 percent, baby boomers 19 percent and Silent Generation 30 percent.

A majority of Americans, 52 percent to 48 percent, are in favoring of canceling all student loan debt. Support is strongest among Gen Z respondents (66 percent) and millennials (66 percent), while Gen X respondents are split (51 percent). Thirty-eight percent of baby boomers and 31 percent of the Silent Generation oppose canceling student loan debt.

On whether it is safe to open schools in light of the COVID-19 pandemic, a majority of Americans said they feel it is not safe. Members of Gen Z were the most likely, 39 percent, to say it is safe followed by 30 percent of millennials.

Since the 1950s, "Africanized" honeybees have spread north and south across the Americas until apparently coming to a halt in California and northern Argentina. Now genome sequencing of hundreds of bees from the northern and southern limits shows a gradual decline in African ancestry across hundreds of miles, rather than an abrupt shift.

"There's a gradual transition at the same latitude in North and South America," said Erin Calfee, graduate student in the Department of Evolution and Ecology at the University of California, Davis, and first author on the paper, published Oct. 19 in PLOS Genetics. "There's a natural barrier that is likely maintained by many different genetic loci."

That barrier is mostly likely climate. Bees with majority African ancestry are unable to survive colder winters.

European colonists brought European species of honeybees (Apis mellifera) with them to the Americas as early as the 1600s. In addition to apiaries, these bees established in the wild alongside native bees.

In 1957, imported African honeybees of the subspecies Apis mellifera scutellata swarmed out of experimental hives in Brazil and started to rapidly spread, interbreeding with the resident European bees. Native to southern and eastern Africa, scutellata bees are known for their defensive behavior. They also carry some useful traits for beekeepers, such as resistance to Varroa mites.

Calfee, working with Professor Graham Coop and Associate Professor Santiago Ramirez from the Department of Evolution and Ecology and collaborators in Argentina, sequenced the genomes of bees collected at the northern and southern edges of the scutellata expansion.

They found that the bees at the northern and southern edges of the range have a highly variable mix of scutellata and European bee ancestry. The higher the latitude, the less scutellata ancestry is in the mix.

"The whole genome is tracking latitude and climate," Calfee said. There are likely many genes involved in climate sensitivity and winter survival, she said. But Calfee also finds that in some parts of the genome scutellata ancestry has spread far beyond these climate limits in both North and South America, evidence that some scutellata genes are advantageous and not tied to climate sensitivity. In contrast, the researchers did not find any evidence for selection for European ancestry in the spread of scutellata bees.

The findings challenge the idea of a binary difference between "Africanized" and "European" honeybees, Ramirez said. In fact, all of these introduced honeybees are hybrids to some degree.

Diversity a resource for breeding bees

The results of the study could be of interest for breeding bees for desirable traits, such as resistance to pathogens. Although the researchers looked only at gene sequences and not the resulting phenotypes (except for one, wing length), the results do show which genetic loci are important because they are under selection in the hybrid zones.

Scutellata bees and hybrids have a lot more genetic diversity than European bees, and the researchers found that they lost very little of this diversity in their expansion from Brazil to California.

"Beekeepers can potentially draw from this genetic variation to breed for desirable traits," Ramirez said. What started out as an invasion may become part of the solution to declining bee health.

"It makes sense but it's kind of surprising because we have 1.5 million (honeybee) colonies being brought into California every spring to pollinate crops," Ramirez said. Those domesticated bees are then trucked around the country, but they do not appear to have a large effect on the spread of African ancestry into feral honeybee populations.

A team of scientists at Texas A&M University, Baylor College of Medicine and Texas Children's Hospital have developed a way to more accurately both detect and monitor a common type of pediatric brain cancer, setting the stage for giving clinicians a real-time view into how the cancer responds to treatment.

Medulloblastoma (MB), the most common pediatric brain tumor, is currently diagnosed based on clinical symptoms, examination of magnetic resonance imaging (MRI) scans and tumor biopsies. It is then monitored through routine MRIs to measure physical changes in the tumor. Clinicians also perform repeated lumbar punctures, commonly known as spinal taps, to collect cerebrospinal fluid (CSF) that is tested for the presence of tumor cells.

"If there are no tumor cells in the CSF, clinicians likely believe their treatment is effective and continue the course. However, there is often inconsistency between the CSF test results and the patient's final outcome," said Jia Li, PhD, research assistant professor in the Center for Epigenetics & Disease Prevention (CEDP) at the Texas A&M Institute of Biosciences and Technology, and the first author of the study, published in Science Advances. "Therefore, it is highly desirable to have a more sensitive way to systematically estimate and monitor the tumor response after treatment and, at the same time, confidently detect tumor recurrence before there is evident anatomical changes in the tumor seen through MRI or CT scans."

In other words, clinicians want to be able to monitor the state of the tumor in patients so they can intervene at the earliest possible time if there is evidence that the tumor has recurred or is starting to grow aggressively again. Liquid biopsy--the method of detecting cancer DNA or other disease biomarkers in body fluids like blood--is increasingly being used to monitor adult cancers such as colorectal cancer and breast cancer. This technique is a relatively non-invasive way to assess cancer progression, response to therapy and recurrence. The current technology detects gene mutations associated with cancer within plasma. However, this approach is more challenging for pediatric brain cancers because these cancers often have very few mutations. According to the researchers, they can be described as being "genetically bland," meaning they don't harbor huge numbers of mutations to the DNA itself.

Instead, pediatric brain tumors frequently have epigenetic changes. In other words, instead of the DNA itself being changed by mutation, in the cancer cells, certain critical genes are turned on or turned off by epigenetic changes that regulate their activity. The presence of epigenetic abnormalities in pediatric brain cancers led the research team to reason that epigenetic markers in biological fluids such as CSF could be an effective way to detect and monitor these types of cancers.

The other problem with using liquid biopsy for pediatric brain cancer is that brain tumor DNA is scarcely detectable in plasma because of the blood-brain barrier, which prevents brain tumor DNA from being released into the blood stream. In contrast, CSF interacts with brain tumor cells in the central nervous system and can be used for liquid biopsy. However, CSF contains extremely low amounts of DNA, making it difficult to study.

Li, along with Yun Nancy Huang, PhD, MS, and Deqiang Sun, PhD, developed a new method to get around this issue and successfully profiled DNA methylation genome-wide from very low amounts of DNA in CSF. They used CSF samples obtained from a biobank built by physicians at Texas Children's Hospital over the course of 20 years. "Tumor cells in the CSF degrade during circulation, but DNA lasts much longer than cells, and so cell-free tumor DNA (ctDNA) can be found in the biobank samples," said Huang, who is an associate professor in the CEDP and a co-corresponding author of this study.

The researchers developed an experimental and computational method for analyzing this DNA. Their results revealed that the epigenetic marker, DNA methylation, can be detected in ctDNA from CSF, serving as a potential biomarker to report the status of the MB tumor and allow for prognosis.

"This is essentially a completely novel way of detecting DNA methylation in circulating DNA and using it for biomarker detection and quantitation in childhood cancer," said Peter Davies, MD, PhD, professor at the Texas A&M University College of Medicine and director of the Center for Translational Cancer Research at the Institute of Biosciences and Technology, and co-author of the study.

Eventually, this research will lead to development of a biomarker kit that clinicians will be able to use for monitoring pediatric brain tumor patients. Many steps lay ahead toward that end, but these findings have generated much interest from physicians and show promise for clinical application.

"The biobank built by physicians at Texas Children's Hospital is an invaluable resource," Davies said. "All the samples were donated by patients with informed consent, and ultimately, it's the willingness of patients and their families to allow their samples to be stored for future research that makes this kind of work possible."

"This is a classic example of using 'team science' to answer really important questions that couldn't be done without bringing together unique expertise," said CEDP Director Roderick Dashwood, PhD, FRSB, professor at the College of Medicine, and co-author of the study. "We have unique expertise in the Texas Medical Center, but you need to bring these outstanding people together. That includes physicians, bioinformaticians and epigenetic experts. Those individuals are often located at different institutions, but we're bringing them all together to address very important questions for clinical translation."

NOAA has published a peer-reviewed State of the Monument report that was jointly produced by the co-trustees of Papahānaumokuākea Marine National Monument. The report includes information on the status and trends of living resources, habitats, ocean conditions, maritime and cultural archaeological resources, and the human activities and natural events that affect them.

The data used in the report were collected from research over the last 10 years. Assessments of status and trends involved scientists and researchers from the monument's management agencies and partners, and were based on the most recent data available as well as expert opinion.

An unrivalled reef ecosystem

Located northwest of the main Hawaiian islands, Papahānaumokuākea Marine National Monument is virtually unpopulated. Because of its isolation, scale, and high degree of protection, the monument provides an unrivalled example of reef ecosystems still dominated by top predators such as sharks. This is not seen in most other island environments due to human activity.

Papahānaumokuākea is of great importance to Native Hawaiians, and has spiritual significance in Hawaiian cosmology. Cultural sites found on the islands of Nihoa and Mokumanamana are on both National and State Registers for Historic Places. Mokumanamana has one of the highest densities of sacred sites in the Hawaiian Archipelago.

The monument is also home to a variety of post-Western-contact historic resources, such as those associated with maritime heritage, the Battle of Midway, and 19th century commercial whaling.

Impacts

Impacts from local human uses have been relatively few, and the monument's reefs and other marine resources are considered to be in nearly pristine condition. However, some marine habitat has been impacted by derelict fishing gear, large storms, aggressive nuisance algae, and coral bleaching. Most marine areas of the monument have not been significantly affected and are in relatively good to fair condition.

The report states that terrestrial habitats have been affected by past human activities that altered soils and vegetation, introduced alien species, and left behind contamination on many of the islands. Without active management efforts to restore habitat, remove invasive species, abate contaminants and enhance the resilience of endangered species, resources would be in significantly poorer condition.

Some shallow coral reefs are reported to remain in good condition, while others have been impacted by localized natural disturbance events and coral bleaching. In contrast, deep-sea habitats remain in nearly pristine condition with little disturbance.

Monument-wide, inland and coastal water quality suggest relatively good conditions, but oceanic and atmospheric conditions have been affected by accelerated sea level rise, increased frequency of storms, and increased regional sea surface temperature.

Many threats to ecosystems are posed by human activities. In the past, a number of scientific, military, and commercial activities have threatened the area. Current uses are limited primarily to management activities by jurisdictional agencies, research, education, and Native Hawaiian practices. Until 2012, a small number of recreational trips were made to Midway Atoll National Wildlife Refuge.

Habitats for rare species

Many of the islands and shallow water environments are important habitats for rare species such as the threatened green turtle and the endangered Hawaiian monk seal, as well as the 14 million seabirds representing 21 species that breed and nest there.

Land areas also provide a home for four species of bird found nowhere else in the world, including the world's most endangered duck, the Laysan duck. Efforts to increase resilience of these species are ongoing, utilizing translocation strategies, habitat improvement and disease prevention.

Historic resources

The condition of maritime, historic, and cultural resources in the monument is declining, due to weathering, corrosion and erosion. Though little can be done to prevent deterioration from natural processes, the information they contain may be preserved through timely archaeological study, documentation, and conservation of artifacts.

Report informs management

The report provides valuable information for Papahānaumokuākea managers that will support future management planning, the identification of monument research priorities, and decision-making on permitted activities.

Through active conservation management efforts, progress has been made on several of the islands to reverse some negative impacts noted in the report.

Monument management is working to reduce threats through an ecosystem approach. This includes the implementation of an effective regulatory framework and permitting process, education and outreach, preventative measures to minimize risk, and response and restoration to damaged or degraded natural resources.

Changes in ocean chemistry, rising sea levels, and rising sea surface temperatures present threats to monument resources, such as corals. This report may prove useful to scientists studying broad scale phenomena effects on the Pacific region or Hawaiian archipelago.

Monument milestones

The report coincides with milestones for the monument in 2020 and 2021.

Papahānaumokuākea was inscripted as as a mixed (natural and cultural) World Heritage Site by the United Nations Educational, Scientific and Cultural Organization (UNESCO) in 2010. This year marks 10 years for the monument as the only mixed UNESCO World Heritage Site in the United States and the second World Heritage Site in Hawai?i.

In 2021, Papahānaumokuākea celebrates 15 years as a marine national monument. It is jointly administered by four co-trustees: NOAA, U.S. Fish and Wildlife Service, the State of Hawai?i, and the Office of Hawaiian Affairs. Management of the monument is overseen by NOAA's Office of National Marine Sanctuaries, NOAA Fisheries, U.S. Fish and Wildlife Service Ecological Services and Refuges Program, State of Hawai'i Divisions of Aquatic Resources and Forestry and Wildlife, and the Office of Hawaiian Affairs.

Scientists have developed a white paint that cools below the temperature of its ambient surroundings even under direct sunlight. Their research, published October 21 in the journal Cell Reports Physical Science, demonstrates a radiative cooling technology that could be used in commercial paints, that could be less expensive to manufacture, and that passively reflects 95.5% of sunlight that reaches its surface back into outer space. In contrast, commercial "heat rejecting paints" currently on the market only reflect 80%-90% of solar irradiation and cannot achieve below-ambient temperatures.

During the summer months and in regions with warm climates, most buildings rely on conventional air conditioning systems to transfer heat from the inside environment to the outdoors. These systems require energy, emit excess heat that transforms cities into "heat islands," and contribute to the climate crisis. But while scientists have sought to develop radiative cooling paints since the 1970s, previously developed paints have not been capable of reflecting enough sunlight to function as viable, commercializable alternatives to traditional air conditioners.

"It is a persistent task to develop a below-ambient radiative cooling solution that offers a convenient single-layer particle-matrix paint form and high reliability," says Xiulin Ruan, a professor at the School of Mechanical Engineering at Purdue University in Indiana and an author of the study. "This is critical to the wide application of radiative cooling and to alleviate the global warming effect."

To develop a commercially applicable radiative cooling paint, Ruan and colleagues used calcium carbonate fillers, an earth-abundant compound, instead of standard titanium dioxide particles, since the fillers have large band gaps (energy differences between the valence electron band and the bottom of the conduction electron band) that help minimize the amount of ultraviolet light the paint absorbs. The researchers also leverage a high particle concentration of 60%, which boosts sunlight scattering, as well as a broad particle size distribution instead of a single particle size for efficient broadband scattering.

To demonstrate how well these modifications enhanced the paint's radiative cooling abilities, the researchers performed cooling tests in West Lafayette, Indiana over a two-day period. The paint sample remained 10 ?C below ambient temperature at night and at least 1.7 ?C below the temperature of the ambient surroundings when the Sun was at its zenith. (The cooling power was shown to exceed 37W/m2 under direct sun.) Ruan and his team then performed a second test in which part of a pattern was painted with the novel paint while another part was painted using a commercial white paint of the same thickness. An infrared camera revealed that the calcium carbonate-based acrylic paint was able to maintain a lower temperature under direct sunlight than its commercial counterpart.

Ruan expects that the technology may benefit a wide range of industries, including residential and commercial buildings, data centers, warehouses, food storage, automobile, outdoor electrical equipment, military infrastructures, and utility vehicles. The paint may be applied directly to buildings to reducing cooling costs. Since the paint lacks metallic components, telecommunication companies may use it to prevent outdoor equipment from overheating, an important step toward enabling a 5G network.

"This paint may even be used to combat climate change since it rejects sunlight and radiates heat into space," says Ruan.

Next, the researchers plan to perform long-term reliability studies to test the paint's resistance to ultraviolet light exposure, dust, surface adhesion, water, and detergent in order to ensure its function as a commercial product.

"Our paint is compatible with the manufacturing process of commercial paint, and the cost may be comparable or even lower," says Ruan. "The key is to ensure the reliability of the paint so that it is viable in long-term outdoor applications."

Low levels of key, body-regulating chemicals in mothers during the first three months of pregnancy may interfere with the baby's brain development, a large American study shows.

These chemicals, or hormones, are produced in the thyroid gland in the neck and are known to influence fetal growth. Investigators have suspected that disruptions in their production, or hypothyroidism, may contribute to attention deficit/hyperactivity disorder (ADHD), which is the most common neurodevelopmental disorder of children in the U.S.

Led by an NYU Long Island School of Medicine researcher, the new investigation showed that children whose mothers were diagnosed with hypothyroidism shortly before or during the early stages of pregnancy were 24 percent more likely to have ADHD than children whose mothers did not have the diagnosis. The authors say their findings also show that boys born to hypothyroid women were four times more vulnerable to ADHD than girls whose mothers had hypothyroidism. Hispanic children born to hypothyroid mothers had the highest risk of any ethnic group studied.

"Our findings make clear that thyroid health likely has a much larger role in fetal brain development and behavioral disorders like ADHD than we previously understood," says study lead author Morgan Peltier, PhD. Peltier is an associate professor in the departments of Clinical Obstetrics, Gynecology, and Reproductive Medicine at NYU Winthrop Hospital, part of NYU Langone Health.

Among the study findings were that once a pregnancy had reached the second trimester, a woman's hypothyroidism had little effect on her children. A possible explanation, says Peltier, is that by this point, the fetus has begun to produce its own thyroid hormones and so is less vulnerable to its mother's deficiencies.

The new investigation, publishing Oct. 21 in the American Journal of Perinatology, followed 329,157 children from birth until age 17, all born in Kaiser Permanente Southern California hospitals. It is the first large-scale effort in the U.S. to examine a potential link between a mother's hypothyroidism and ADHD in her children, according to the study's authors. The authors also note that unlike previous research in Europe, the new American study included people of diverse ethnic backgrounds and observed the children for nearly two decades. This long study period, lead author Peltier says, allowed the researchers to better capture cases of ADHD in the children as they aged and progressed through school.

As part of the new research, the team analyzed children's medical records and collected key information about their mothers, including age during pregnancy, race, and household income. All children were evaluated for ADHD using the same criteria, which the authors say helped to prevent inconsistencies in how cases of the disorder were identified.

According to the findings, overall 16,696 children were diagnosed with ADHD. Hispanic children whose mothers had low thyroid hormone levels during pregnancy had a 45 percent increased risk for the neurodevelopmental disorder compared with a 22 percent increased risk in white children whose mothers had the same condition.

Peltier says his team's results are strong enough to warrant careful monitoring of pregnant women with low thyroid hormone levels. He adds that children whose mothers had low thyroid hormone levels during pregnancy could potentially benefit from earlier surveillance for signs of ADHD, such as inattention, hyperactivity, and difficulty focusing on a task. Previous research has found that swift intervention can help manage ADHD and make it easier for children to succeed in the classroom and in learning social skills.

The study team next plans to investigate whether hypothyroidism during pregnancy can raise the risk of other neurodevelopmental disorders, such as epilepsy, cerebral palsy, and difficulties with speech. They also intend to explore other factors that may increase the risk of ADHD in children, such as exposure during pregnancy to environmental toxins like flame retardants found in upholstered furniture, electronic devices, and other household appliances.

A small amount of molten rock located under tectonic plates encourages them to move. This is what scientists from the Laboratoire de géologie de Lyon: Terre, planètes et environnement (CNRS/ENS de Lyon/Université Claude Bernard Lyon 1) have recently discovered. Their new model takes into account not only the velocity of seismic waves but also the way in which they are attenuated by the medium they pass through. The velocity of tectonic plates near the surface is thus directly correlated with the quantity of magma present. This research is published on October 21, 2020 in Nature.

The lithosphere, the outer part of the Earth, is made up of the crust and part of the upper mantle. It is subdivided into rigid plates, known as tectonic or lithospheric plates. These move on a more fluid layer of the mantle, the asthenosphere. The lower viscosity of the asthenosphere allows the tectonic plates to move around on the underlying mantle, but until today the origin of this low viscosity remained unknown.

Seismic tomography produces three-dimensional images of the Earth's interior by analysing millions of seismic waves recorded at seismological stations spread across the surface of the globe. Since the 1970s, seismologists have analysed these waves with a view to identifying a single parameter: their propagation speed. This parameter varies with temperature (the colder the medium, the faster the waves arrive), composition, and the possible presence of molten rocks in the medium the waves pass through. Seismologists from the Laboratoire de géologie de Lyon: Terre, planètes et environnement (CNRS/ENS de Lyon/Université Claude Bernard Lyon 1) instead studied another parameter, wave attenuation, alongside the variation in wave propagation speeds. This analysis, which provides new information on the temperature of the medium traversed by the waves, makes it possible to ascertain the quantity of molten rock in the medium the waves pass through.

Their new model made it possible, for the first time, to map the amount of molten rock under tectonic plates. This work reveals that a small amount of molten rock (less than 0.7% by volume) is present in the asthenosphere under the oceans, not only where this was expected, i.e. under ocean ridges and some volcanoes such as Tahiti, Hawaii or Reunion, but also under all oceanic plates. The low percentage of molten rock observed is enough to reduce the viscosity by one or two orders of magnitude underneath the tectonic plates, thus "decoupling" them from the underlying mantle. Moreover, the seismologists from Lyon observed that the amount of molten rock is higher under the fastest-moving plates, such as the Pacific plate. This suggests that the melting of the rocks encourages the plates to move and the deformation at their bases. This research improves our understanding of plate tectonics and how it works.

CHAPEL HILL, NC - October 21, 2020 - Babies born with a faulty maternal copy of the UBE3A gene will develop Angelman syndrome, a severe neurodevelopmental disorder with no cure and limited treatments. Now, for the first time, scientists at the UNC School of Medicine show that gene editing and gene therapy techniques can be used to restore UBE3A in human neuron cultures and treat deficits in an animal model of Angelman syndrome.

This work, published in Nature and led by senior author Mark Zylka, PhD, Director of the UNC Neuroscience Center and W.R. Kenan, Jr. Distinguished Professor of Cell Biology and Physiology, lays important groundwork for a long-lasting treatment or cure for this debilitating disease, as well as a therapeutic path forward for other single-gene disorders.

"Our study shows how multiple symptoms associated with Angelman syndrome could be treated with a CRISPR-Cas9 gene therapy," Zylka said. "And we are now pursuing this with help of clinicians at UNC-Chapel Hill."

Angelman syndrome is caused by a deletion or mutation of the maternal copy of the gene that encodes the ubiquitin protein ligase E3A (UBE3A). The paternal copy of UBE3A is typically silenced in neurons, so the loss of maternal UBE3A results in a complete absence of the UBE3A enzyme in most areas of the brain. That's crucial because the enzyme targets proteins for degradation, a process that maintains normal function of brain cells. When that process goes awry, the result is Angelman syndrome, a brain disorder with symptoms that include severe intellectual and developmental disabilities, seizures, and problems with speech, balance, movement, and sleep.

"Turning on the paternal copy of UBE3A is an attractive therapeutic strategy because it could reverse the underlying molecular deficiency of the disease," Zylka said. However, the paternal gene is silenced by a long strand of RNA, produced in the antisense orientation to UBE3A, which blocks production of the enzyme from the paternal copy of the gene.

Members of the Zylka lab, including postdoctoral fellows Justin Wolter, PhD, and Giulia Fragola, PhD, set out to devise a way to use CRISPR-Cas9 to restore the UBE3A enzyme to normal levels by disrupting the antisense RNA. Preliminary data in cell cultures were promising, and Zylka received grants from the NIH, the Angelman Syndrome Foundation, and the Simons Foundation to test their findings in human neurons and in a mouse model of the disease.

In the Nature paper, co-first authors Wolter and Hanqian Mao, PhD, a postdoc in the Zylka lab, and UNC colleagues describe using an adeno-associated virus (AAV) gene therapy to deliver the Cas9 protein throughout the brain of embryonic mice that model Angelman syndrome. Because UBE3A is essential for normal brain development, early treatment is crucial. The researchers found that embryonic and early postnatal treatment rescued physical and behavioral phenotypes that model core deficits found in Angelman syndrome patients. Remarkably, a single neonatal injection of AAV unsilenced paternal Ube3a for at least 17 months, and the data suggest this effect is likely to be permanent. The researchers also demonstrated that this approach was effective in human neurons in culture.

"We were blown away when we got these results," Zylka said. "No other treatments currently being pursued for Angelman syndrome last this long, nor do they treat as many symptoms. I am confident others will eventually recognize the advantages of detecting the mutation that causes Angelman syndrome prenatally and treating shortly thereafter."

Wolter added, "The results of treating early were very promising. Since we learned we could reduce the severity of Angelman syndrome in mice, we are now focused on refining our approach in ways that will be suitable for use in humans."

While working to translate this research into the clinic, the Zylka lab will collaborate with researchers at the Carolina Institute for Developmental Disabilities (CIDD) to identify symptoms in babies that have the genetic mutation that causes Angelman syndrome.

Zylka's lab is working with CIDD researchers led by CIDD director Joseph Piven, MD, to use brain imaging and behavior observations to identify symptoms associated with Angelman syndrome in infants. Anecdotal reports suggest these infants have difficulty feeding and reduced muscle tone, but these and other early symptoms have not been rigorously characterized to date.

"The idea is to use genetic tests to identify babies that are likely to develop Angelman syndrome, treat prenatally or around the time of birth, and then use these early symptoms as endpoints to evaluate efficacy in a clinical trial," Zylka said. "Our data and that of other groups clearly indicate that prenatal treatment has the potential to prevent Angelman syndrome from fully developing."

As part of the Nature study, the researchers also found that the gene therapy vector blocked the antisense RNA by integrating into the genome at sites cut by CRISPR-Cas9. This so-called "gene trap" could be exploited to disrupt other long non-coding RNAs and genes.

Zylka added, "We are incredibly excited to keep this work moving forward with the hope of helping children and families overcome this debilitating condition. Support from the NIH, the Simons Foundation, and the Angelman Syndrome Foundation was essential for moving this work forward."