Earth

Researchers at TMIMS have revealed that PINK1 (a serine/threonine kinase) and Parkin (a ubiquitin ligating enzyme: E3) work together to ubiquitylate the outer membrane proteins of damaged mitochondria to induce selective autophagy called mitophagy. Dysfunction of this type of mitophagy causes a decrease in mitochondrial quality and an overproduction of ROS, and thus is linked to the development of hereditary recessive Parkinson's disease.

In cells, ubiquitin functions as a signal for selective autophagy. It has been suggested that autophagy-adaptor proteins, which bind to both the ubiquitin and factors for autophagosome formation, are involved in a selective autophagy. Mammalian cells encode five autophagy adaptors (p62, NBR1, TAX1BP1, NDP52, OPTN), and OPTN and NDP52 were reported to play critical roles in PINK1/Parkin-mediated mitophagy. However, the molecular mechanisms by which OPTN and NDP52 induce mitophagy remained obscure. It was also controversial whether PINK1 on damaged mitochondria and/or phosphorylated ubiquitin produced by PINK1 function as a direct autophagy signal or not. In this study, Yamano and colleagues at TMIMS clarified a novel mechanism by which the ubiquitin chain conjugated by PINK1/Parkin is read out as an autophagy signal.

First, Yamano and colleagues found that mitophagy can be induced by a linear ubiquitin chain artificially targeted on the outer mitochondrial membrane, or by a chemical compound called SNIPER that induces ubiquitylation of a specific mitochondrial outer membrane protein. These results indicate that a ubiquitin chain on the mitochondrial surface itself is essential and sufficient for mitophagy, and that PINK1 and phosphorylated ubiquitin are essential for Parkin activation, but not for mitophagy.

Next, the intracellular localizations of autophagy adaptor proteins (p62, NBR1, NDP52, OPTN) were examined following induction of Parkin-mediated mitophagy. All autophagy adaptor proteins are recruited on the damaged mitochondria. However, the researchers found that p62 and NBR1 evenly distributed throughout the mitochondria, whereas NDP52 and OPTN localized only on restricted areas of mitochondria. Since the autophagosome marker molecule LC3B also localized in this subdomain, it was expected that NDP52 and OPTN specifically accumulate at the contact site between ubiquitylated mitochondria and autophagosomes.

Next, Yamano and colleagues wanted to elucidate the molecular mechanisms how NDP52 and OPTN convert ubiquitylation to autophagic degradation signals. To address this issue, the researchers used Fluoppi system (Watanabe et al. Sci Rep 2017) in which protein-protein interactions can be detected as fluorescent-foci in cells. In the Fluoppi system, protein 'A' fused with a homooligomeric Ash tag and protein 'B' fused with a homo-tetrameric Azami Green (AG) are co-expressed. If 'A' interacts with 'B', they form phase-separated fluorescent foci in cells thorough the multivalent interactions such as the multimerization of Ash tag, the tetramerization of AG, and the interaction between 'A' and 'B'.

When a tandem ubiquitin fused with Ash tag and a autophagy-adaptor protein fused with AG were co-expressed in cells, fluorescent foci formed via a phase separation. As described above, NDP52 and OPTN localize at the putative contact sites between mitochondria and autophagosomes. Therefore, the researchers examined whether LC3 family proteins accumulate in the foci formed by the autophagy adaptor and ubiquitin. Unexpectedly, phase-separated foci formed by p62 or NBR1, rather than those by NDP52 or OPTN, contained more LC3 family proteins. Since p62 and NBR1 are dispensable for PINK1/Parkin-mediated mitophagy, these results suggest that the critical roles of OPTN and NDP52 in mitophagy are not solely derived from the binding ability to LC3.

Yamano and colleagues then searched for the autophagy-related proteins (ATG proteins) that cooperates with OPTN and ubiquitin. Although ATG13, ATG14, WIPI2, and ATG16L1 were not contained in the OPTN fluorescent foci, ATG9A was completely merged with the OPTN foci. Since ATG9A was not observed in the foci formed by other autophagy adaptors such as NDP52, p62, and NBR1, these results indicate that OPTN specifically interacts with ATG9A.

In order to narrow down the site essential for OPTN-ATG9A interaction, a series of deletion mutants and several amino acid substitutions of OPTN were constructed. The researchers finally revealed that the leucine zipper domain in OPTN is essential for ATG9A binding. In fact, OPTN possessing a mutation in the leucine zipper domain formed fluorescent "Fluoppi foci" with ubiquitin equivalent to wild-type OPTN, but the localization of ATG9A into the fluorescent foci was completely impaired.

Finally, Yamano and colleagues investigated whether the interaction between OPTN and ATG9A via the leucine zipper domain is important for mitophagy. Following 3 h of Antimycin/Oligomycin treatment, mitophagy activity was quantitatively monitored using MtKeima-FACS experiments. Mitophagy disappeared in cells lacking all autophagy adaptor proteins (penta KO cells). WT OPTN complemented this mitophagy defect, whereas OPTN possessing mutation in the leucine zipper domain only slightly recovered mitophagy (18% to WT OPTN). These results indicate that the OPTN-ATG9A interaction via leucine zipper domain is crucial for PINK1/Parkin-mediated mitophagy.

In 2019, another critical autophagy-adaptor protein, NDP52, has been reported to interact with FIP200, a component of autophagy initiation complex (Vargas et. al. Mol Cell 2019; Ravenhill et al. Mol Cell 2019). Yamano et al revealed in this study that OPTN binds to ATG9A (an important factor that supplies lipids to autophagic membranes), and PINK1/Parkin-induced mitophagy proceeds via two pathways; i.e., ubiquitin ? NDP52 ? FIP200 axis and ubiquitin ? OPTN ? ATG9A axis.

"Autophagy adaptors have been defined as proteins that can bind to both ubiquitin and LC3. However, recent works including this study highlight the importance of novel interactions between autophagy-adaptors and core machineries in autophagy." said Dr. Yamano. "In the future, we would like to apply this experimental approach to other autophagy adaptors to identify new interactants in a selective autophagy."

A new University of Alaska-led study provides the first evidence that declines in many of Alaska's chinook salmon populations can be attributed in part to climate-driven changes in their freshwater habitats.

Alaska chinook salmon runs have decreased during the past decade, leading to fisheries closures and prolonged economic and cultural impacts to local communities. With Alaska's climate warming twice as fast as the global average and experiencing changes in precipitation and streamflow, the research team set out to understand if changing conditions in fresh water -- where salmon spawn and rear -- played a role in recent declines of chinook populations in the Cook Inlet basin of Southcentral Alaska.

The study examined historic chinook populations and modeled environmental conditions to estimate how stream conditions affected salmon productivity from 1980 to 2009. By using fisheries catch and spawning abundance data collected by the Alaska Department of Fish and Game, along with stream temperature data collected by Cook Inletkeeper, researchers were able to investigate how freshwater habitat conditions varied for 15 different chinook populations.

Heavy rains in the late summer and fall -- when adult salmon spawn and their eggs incubate -- led to less production. However, above-average rainfall during juvenile rearing was beneficial. Productivity also declined substantially when stream temperatures rose above 64 degrees Fahrenheit for a week or longer during spawning. In particular, chinook productivity was very low during a period of poor freshwater conditions, including hot, dry summers and heavy fall rains, from 2003-2007. Salmon spawning during that five-year span produced 57% fewer surviving offspring than the previous long-term average, leading to population declines and fisheries closures in the late 2000s and early 2010s.

"Scientists have known for a long time that ocean conditions influence the size of Alaska chinook salmon runs, but until recently we did not have enough data from individual salmon streams to test for more localized factors like rainfall and water temperature," said Erik Schoen with the Institute of Arctic Biology at the University of Alaska Fairbanks, one of the study's lead authors. "By zooming in on distinct watersheds, we found that those freshwater conditions really do matter for the strength of salmon runs."

The findings were published July 9 in a paper in the journal Global Change Biology. Other lead authors included Leslie A. Jones and Rebecca Shaftel with the Alaska Center for Conservation Science at the University of Alaska Anchorage.

The effect of stream temperatures during juvenile rearing was highly variable among populations. When warm streams got warmer, productivity dropped. But when cold streams got warmer and better for rearing, productivity increased.

Those findings support predictions of previous studies that the effects of climate warming will vary across watersheds and habitats, harming some populations while benefiting others.

"Last year at this time, Alaska experienced a record heat wave, and we measured stream temperatures above 80 degrees in our warmer chinook systems," said study co-author Sue Mauger with Cook Inletkeeper, a Homer-based conservation organization. "Understanding stream-specific responses to climate change will be critical for better management of our valuable fisheries."

How does evolution impact ecological patterns? It helps smooth out the rough edges, says UConn Ecology and Evolutionary Biology Professor Mark Urban. Urban led an international team of researchers through a review of the history of ecological and evolutionary research to establish a framework to better understand evolution's impact on ecosystem patterns. The research is published as a perspective in the Proceeding of the National Academy of Sciences.

Urban says the project started years ago in the course of his field research when he encountered a trend that he had trouble explaining.

"Ever since I was a grad student I've been thinking about how evolution across landscapes happens, and then how it affects the ecology of those systems. At some point I was struggling to describe a pattern that I was seeing in the amphibian system I work in," he says.

Urban explains that historically, ecologists and evolutionary biologists have worked fairly isolated from one another. The reason is due to assumptions that evolution happens over time periods and distances that have little immediate impact on ecological systems. Ecologists and evolutionary biologists go to their own academic meetings and conferences and publish in their own journals, says Urban, and as a result, members of the fields rarely collaborate. However, Urban suspected the explanation for the puzzling pattern he was seeing relied on a merging of the disciplines.

Urban partnered with colleagues from across the globe, calling on experts from evolutionary biology and ecology, to tackle the question. The project involved an extensive review of the literature, a process that Urban says at times felt unending, yet quite fun. The process was also exciting because early on, the researchers began to notice patterns supporting their hypothesis that local adaptation alters spatial patterns.

Sean Giery, co-author and a former UConn post-doctoral researcher who's now an Eberly Research Fellow at Pennsylvania State University says, "Finding new evidence in old scientific papers was always rewarding. And collectively, these efforts show that the effects of evolution on how much communities and ecosystems vary across landscapes simply can't be overlooked."

The impetus for the undertaking, Urban says, came from a familiar figure: the salamander.

Salamander populations adapt to predators via different strategies -- from changes in body shape and size to the types and quantities of foods that they eat, which suggests a connection between evolution and ecology.

"In particular, I got excited by the evolution of foraging traits, because that could have a clear ecological impact," Urban says.

For example, Urban found that salamanders evolve to forage more in a pond with limited resources, and as a result they amplify the original ecological pattern of low resources by eating more of the already limited resources. In other cases, local adaptation of other traits dampens existing spatial patterns. Urban next turned to the existing literature to find out how general these patterns were, not just in salamanders, but in everything from bacteria to birds.

Based on a review of 500 studies, the authors found evolutionary adaptations at the local level can amplify, dampen, or even create new ecological patterns across landscapes. They identified 14 different mechanisms that affect the direction of evolution's impact, but overall the researchers found that evolution tended to dampen or smooth out variations.

"Evolution clearly plays an important role at these large scales, especially by reducing the effects of abiotic factors and biotic interactions that can limit the abundance and distribution of species. By dampening the impacts of these effects, evolution tends to reduce ecological heterogeneity across space," says Giery.

Adds Urban: "Our exhaustive review indicated that evolution usually dampens ecological spatial patterns, characterizing 85% of studies. Consequently, we do not observe the true spatial heterogeneity of nature because evolution has smoothed it out and hidden its rough edges. Evolution makes the world less ragged, which to me is a pretty cool take-home message."

An example of the smoothing can be seen again with salamanders, says Urban: "The salamanders that ate more also tended to dampen out the effect of the predator on the overall diversity of species across ponds. The prey salamander was eating different species than the predator, so in the end evolution actually maintains similar diversities of species across ponds even though, ecologically, the predator strongly decreases diversity."

Urban says these spatial patterns can be seen everywhere: "The interesting thing to me is that anyone can walk through nature and see these spatial patterns -- maybe different vegetation types. We see all of this spatial variation and we think of it as just being ecological or physical, just part of the environment and that's it. But that environmental spatial variation may be affected by the evolution of the organisms in the environment and that is what we are finding in experiments around world."

Giery says, "I'm pleased to have been a part of this project. And I'm excited to see how our efforts will influence the way people think about the role of evolution in ecological dynamics in space. This seems like one of those rare instances where a relatively simple idea is still transformative. Working on developing this idea has changed how I see and think about natural systems. I imagine our perspective will have the same impact on others."

Urban says the next step is experiments to further test the framework. The hope is the coauthors and readers will go out and test this: "We are really just at the tip of the iceberg."

In topological materials, electrons can display behaviour that is fundamentally different
from that in 'conventional' matter, and the magnitude of many such 'exotic' phenomena is
directly proportional to an entity known as the Chern number. New experiments establish
for the first time that the theoretically predicted maximum Chern number can be reached
-- and controlled -- in a real material.

When the Royal Swedish Academy of Sciences awarded the Nobel Prize in Physics 2016 to
David Thouless, Duncan Haldane and Michael Kosterlitz, they lauded the trio for having
"opened the door on an unknown world where matter can assume strange states". Far from
being an oddity, the discoveries of topological phase transitions and topological phases of
matter, to which the three theoreticians have contributed so crucially, has grown into one of the most active fields of research in condensed matter physics today. Topological materials hold the promise, for instance, to lead to novel types of electronic components and superconductors, and they harbour deep connections across areas of physics and mathematics. While new phenomena are discovered routinely, there are fundamental aspects yet to be settled. One of those is just how 'strong' topological phenomena can be in a real material. Addressing that question, an international team of researchers led by PSI postdoctoral researcher Niels Schröter provide now an important benchmark. Writing in Science, they report experiments in which they observed that in the topological semimetal palladium gallium (PdGa) one of the most common classifiers of topological phenomena, the Chern number, can reach the maximum value that is allowed in any metallic crystal. That this is possible in a real material has never been shown before. Moreover, the team has established ways to control the sign of the Chern number, which might bring new
opportunities for exploring, and exploiting, topological phenomena.

Developed to the maximum

In theoretical works it had been predicted that in topological semimetals the Chern number
cannot exceed a magnitude of four. As candidate systems displaying phenomena with such
maximal Chern numbers, chiral crystals were proposed. These are materials whose lattice
structures have a well-defined handedness, in the sense that they cannot transformed into
their mirror image by any combination of rotations and translations. Several candidate
structures have been studied. A conclusive experimental observation of a Chern number of
plus or minus four, however, remained elusive. The previous efforts have been hindered by
two factors in particular. First, a prerequisite for realizing a maximal Chern number is the
presence of spin-orbit coupling, and at least in some of the materials studied so far, that
coupling is relatively low, making it difficult to resolve the splittings of interest. Second,
preparing clean and flat surfaces of relevant crystals has been highly challenging, and as a
consequence spectroscopic signatures tended to be washed out.

Schröter et al. have overcome both of these limitations by working with PdGa crystals. The
material displays strong spin-orbit coupling, and well-established methods exist for
producing immaculate surfaces. In addition, at the Advanced Resonant Spectroscopies
(ADRESS) beamline of the Swiss Light Source at PSI, they had unique capabilities at their
disposal for high-resolution ARPES experiments and thus to resolve the predicted tell-tale
spectroscopic patterns. In combination with further measurements at the Diamond Light
Source (UK) and with dedicated ab initio calculations, these data revealed hard and fast
signatures in the electronic structure of PdGa that left no doubt that the maximal Chern
number has been realized.

A hand on the Chern number

The team went one step further, beyond the observation of a maximal Chern number. They
showed that the chiral nature of the PdGa crystals offers a possibility to control the sign of
that number as well. To demonstrate such control, they grew samples that were either leftor right-handed (see the figure). When they looked then at the electronic structures of the two enantiomers, they found that the chirality of the crystals is reflected in the chirality of the electronic wave function. Taken together, this means that in chiral semimetals the
handedness, which can be determined during crystal growth, can used to control topological
phenomena emerging from the behaviour of the electrons in the material.
This sort of control opens a trove of new experiments. For example, novel effects can be
expected to arise at the interface between different enantiomers, one with Chern number +4 and the other one with -4. And there are real prospects for applications, too. Chiral topological semimetals can host fascinating phenomena such as quantized photocurrents. Intriguingly, PdGa is known for its catalytic properties, inviting the question about the role of topological phenomena in such processes.

Finally, the findings now obtained for PdGa emerge from electronic band properties that are
shared by many other chiral compounds -- meaning that the corner of the "unknown world
where matter can assume strange states" into which Schröter and colleagues have now
ventured is likely to have a lot more to offer.

The analysis of Tropical Cyclone Cristina's cloud top temperatures revealed some bands of thunderstorms were developing and wrapping around the center of the storm's circulation.

Banding thunderstorms are generally an indication that a tropical cyclone is getting more organized.

How Tropical Cyclones Form

Tropical cyclones are like giant engines that use warm, moist air as fuel. The warm, moist air over the ocean rises upward from near the surface. As the warm air rises, it causes an area of lower air pressure near the surface. Air from surrounding areas with higher air pressure pushes in to the low-pressure area. Then that "new" air becomes warm and moist and rises, too. As the warm air continues to rise, the surrounding air swirls in to take its place. As the warmed, moist air rises and cools off, the water in the air forms clouds. The whole system of clouds and wind spins and grows, fed by the ocean's heat and water evaporating from the surface.

NASA Uses Infrared Light to Analyze Storms

One of the ways NASA researches tropical cyclones is by using infrared data that provides temperature information. Cloud top temperatures provide information to forecasters about where the strongest storms are located within a tropical cyclone (which are made of hundreds of thunderstorms).

Tropical cyclones do not always have uniform strength. Some quadrants of a tropical cyclone contain more powerful thunderstorms than other quadrants. Temperature data indicates where those strongest storms are located. The stronger the storms, the higher they extend into the troposphere, and the colder the cloud temperatures.

On June 8 at 4:20 p.m. EDT (2020 UTC) NASA's Aqua satellite analyzed the storm using the Atmospheric Infrared Sounder or AIRS instrument. AIRS found temperatures as cold as or colder than minus 63 degrees Fahrenheit (minus 53 degrees Celsius). NASA research has shown that cloud top temperatures that cold indicate strong storms that have the capability to create heavy rain.

Those cold temperatures were found around the center and in a developing band of thunderstorms northeast of the center. Satellite data showed the center was located underneath the northeastern side of the main area of convection due to moderate vertical wind shear. The AIRS image also showed banding features were developing across the northern portion of the circulation. One band of thunderstorms northeast of center brought rainfall to part of the coast of southwestern Mexico.

Cristina's Status on July 9, 2020

Overnight from July 8 to July 9 although deep convection and strong thunderstorm development had been increasing, the overall cloud pattern and structure of the storm changed little and it continued to lack banding features.

At 5 a.m. EDT (0900 UTC) on July 9, the center of Tropical Storm Cristina was located near latitude 16.8 degrees north and longitude degrees 109.4 west. That is about 370 miles (590 km) west-southwest of Manzanillo Mexico. The estimated minimum central pressure is 995 millibars.

NOAA's National Hurricane Center (NHC) said Cristina was moving toward the west-northwest near 12 mph (19 kph), and this motion with an increase in forward speed is expected during the next few days. On the forecast track, Cristina will remain well offshore of the coast of Mexico.

Maximum sustained winds were near 65 mph (100 kph) with higher gusts.  Some strengthening is forecast and Cristina could become a hurricane by Friday.

Tropical cyclones/hurricanes are the most powerful weather events on Earth. NASA's expertise in space and scientific exploration contributes to essential services provided to the American people by other federal agencies, such as hurricane weather forecasting.

The AIRS instrument is one of six instruments flying on board NASA's Aqua satellite, launched on May 4, 2002.

For updated forecasts, visit: http://www.nhc.noaa.gov

Skoltech scientists in collaboration with researchers from the University of Stuttgart showed that the concentration of short-lived ions (H3O+ and OH-) in pure liquid water is much higher than that assumed to evaluate the pH, hence significantly changing our understanding of the dynamical structure of water.

Figure: infrared spectra of light (red), heavy (blue), semiheavy (gray) water, and ionic species that have been identified in the current study. Red, white and black circles depict oxygen, hydrogen and deuterium atoms, respectively. Arrows show the directions of species vibrational deformation.

Intrinsic ionic species of liquid water play an important role in the redox processes, catalytic reactions and electrochemical systems. A low-barrier tunneling of hydrogen atom between the H2O molecules, caused by nuclear quantum effects, is expected to generate short-lived excess proton states. However, to date, there has been no information on the concentration of such excess protons states in pure water.

Skoltech scientists in collaboration with German researchers measured the ion-molecular composition of liquid water on the sub-picosecond time scale. The result surprised scientists as they observed that up to several percent of H2O molecules were temporarily ionized.

"We used water isotopologues: ordinary (H2O), heavy (D2O), and semi-heavy (HDO) water, to identify excess-proton states. By gradually substituting the hydrogen atoms (H) with deuterium (D), we changed the relative concentration of excess-proton-related species, such as HD2O+, DH2O+, H3O+ and D3O+, and identified their contributions to the cumulative infrared absorption. We found concentration-dependent spectral features near molecular bending modes of semi-heavy water spectra that no known model was able to explain. We associated these features with excess protons that may be expected to exist on the picosecond time scale," said one of the co-authors, Prof. Henni Ouerdane from the Skoltech Center for Energy Science and Technology (CEST).

"While previous studies of water structure were based on crystallographic experiments, and did not reflect the dynamics of water, our research brings new insights into the intricate water structure at ultra-short time scale. The finding anticipates new effects of electric field interaction with water, as well as other anomalous properties of water," concluded the lead author, Dr. Vasily Artemov, Senior Research Scientist at CEST.

On April 15, 2019, the world watched helplessly as black and yellow smoke billowed from the Notre Dame cathedral in Paris. The fire started just below the cathedral's roof and spire, which were covered in 460 tons of lead -- a neurotoxic metal, dangerous especially to children, and the source of the yellow smoke that rose from the fire for hours. The cathedral is being restored, but questions have remained about how much lead the fire emitted into the surrounding neighborhoods, and how much of a threat it posed to the health of people living nearby.

A new study, published today in GeoHealth, used soil samples collected from neighborhoods around the cathedral to estimate local amounts of lead fallout from the fire. Lead levels in the soil samples indicated that nearly a ton of lead dust dropped down within one kilometer (0.6 miles) of the site, and areas downwind of the fire had double the lead levels than sites that were outside the path of the smoke plume. The study concludes that, for a brief time, people residing within a kilometer and downwind of the fire were probably more exposed to lead fallout than measurements by French authorities indicated.

Early evidence suggested that the fire increased lead exposure in Paris. Air quality measurements taken 50 kilometers away from the cathedral found that lead particulates in the air were 20 times higher than usual in the week after the fire. However, a small set of measurements by France's Regional Health Agency, posted weeks after the fire, found that all the samples collected outside of the out-of-bounds area around the cathedral had lead levels below France's limit of 300 milligrams per kilogram of soil. At the time, there were fears that the health agency was underplaying the potential health impacts and not being transparent enough.

"There was a controversy -- were children being exposed or not from this fallout?" said Lex van Geen, a geochemist at Columbia University's Lamont-Doherty Earth Observatory and lead author on the new study. "So I thought, whether I get a 'yes' or a 'no,' it's worth documenting."

In December 2019 and February 2020, van Geen collected 100 soil samples from tree pits, parks and other locations around the cathedral, and in particular to the northwest, where most of the smoke traveled on the day of the fire. When lead enters soil, it tends to stay put, so it can preserve the signal of the fallout for much longer than hard surfaces such as roads and sidewalks, which get swept and flushed by rain.

"It wasn't a particularly glamorous expedition," said van Geen. "I got plenty of strange looks from people wondering why this old guy was scooping up soil, trying to avoid the dog poop, and putting some of the soil in paper bags. But it got done."

Non-contaminated soil would be expected to contain less than less than 100 milligrams of lead per kilogram of soil. However, in samples collected within a kilometer the cathedral's remains, the levels averaged 200 mg/kg. And in the northwest direction downwind of the fire, the lead was significantly higher, averaging nearly 430 mg/kg -- double that of the surrounding area, and surpassing France's 300 mg/kg limit.

Because the sample sites weren't uniformly distributed, co-authors Yuling Yao and Andrew Gelman from Columbia University's Statistics Department used statistical methods to predict the overall distribution of lead, calculate the averages inside and outside of the plume, and estimate the total amount of lead that fell near the fire. By their calculations, 1,000 kilograms (2,200 pounds) of lead settled within a kilometer of the cathedral. That's six times higher than the current estimate for the amount of lead fallout between 1 and 20 kilometers of the site.

"Our final estimation of the total amount of excess lead is much larger compared with what has been reported earlier by other teams," said Yao. "Of course, we are measuring slightly different things, but ultimately all disagreement in scientific findings shall be validated by more data, especially when they have profound policy and public health consequences. I hope our work sheds some light in that direction."

It is difficult to ascertain how this lead may have affected human health, because too few soil, dust, and blood samples were collected immediately after the fire, said van Geen. The impacts are likely much lower than those of leaded gasoline, which was entirely phased out by the year 2000. Nevertheless, lead could have posed a brief but significant health hazard to children living downwind of the fire.

On June 4, seven weeks after the fire, the French government made blood tests available at a local hospital on an on-demand basis. This only occurred after a child in a nearby apartment was found to have a concerning level of lead in their blood. (Subsequent investigation identified a different source of lead as the more likely culprit in this case.) Soil and dust tests were similarly delayed and limited in scope.

To van Geen, the government showed it had the means to respond but it didn't do so quickly enough. He says that the urgency of the situation should have been more clearly conveyed with pro-active collection and posting of environmental and blood-lead data. This would have induced more parents downwind of the fire to remove indoor dust with wet wipes at home and prevent kids from playing in soil, thereby reducing their chances of exposure.

INDIANAPOLIS- Indiana University School of Medicine researchers Milan Radovich, PhD, and Bryan Schneider, MD, have discovered that the presence of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in the plasma of women's blood who have undergone chemotherapy prior to surgery for the treatment of stage 1, 2 or 3 triple negative breast cancer are critical indicators for the prediction of disease recurrence and disease-free survival. Their findings, published today in the prestigious international peer-reviewed journal, JAMA Oncology allow for a stratification of patients in clinical trials around the world, that didn't exist prior to their discovery. The pair also spoke about their findings as part of a JAMA Oncology podcast.

"These findings from the Vera Bradley Foundation Center for Breast Cancer Research, located at IU School of Medicine, enable a scientific basis for predicting relapse and disease-free survival, which are both important questions for women who live in constant fear of their disease returning," said Jay L. Hess, MD, PhD, MHSA and dean of IU School of Medicine. "The discoveries reflect our long history as leaders in genomics, bioinformatics and medical innovation."

Specifically, Radovich and Schneider, who are also researchers at the IU Melvin and Bren Simon Comprehensive Cancer Center, along with colleagues from the Hoosier Cancer Research Network, analyzed plasma samples taken from the blood of 196 women, as part of a preplanned secondary analysis of women who were participants in clinical study BRE12-158. This is the largest known data set of patients to date.

They discovered that the detection of ctDNA was significantly associated with poorer outcomes on three important measures for patients: distant disease-free survival, disease-free survival and overall survival. When the presence of ctDNA was combined with the presence of CTCs, the outcomes were even worse.

* At two years post-surgery and chemotherapy, distant disease-free survival for women with the presence of ctDNA in their blood was 56 percent, when compared with 81 percent for women without ctDNA.

* Patients with the presence of both ctDNA and CTCs at two years had a 52 percent likelihood of distant disease-free survival versus 89 percent who were negative for both markers.

Approximately one-third of patients will achieve remission from their triple negative breast cancer, following surgery and chemotherapy. However, two-thirds will have residual disease, putting them at high risk of relapse. These findings will be the focus of the PERSEVERE study, which will stratify women with triple negative breast cancer based on being ctDNA positive and assign them a targeted therapy matched to the patient's genomic sequencing. The study is powered to help discover a personalized therapy for patients at high risk for relapse and for whom no treatments currently exist. More information about the PERSEVERE study will be provided in the coming months.

"A diagnosis of triple negative breast cancer is very scary to the patient. The discovery and utilization of circulating tumor DNA and circulating tumor cells to better predict recurrence, by Drs. Schneider and Radovich, has provided a huge step forward toward more certainty for treatment decision making," said Mary Lou Smith, co-founder of the Research Advocacy Network. "This significant scientific advancement will help personalize treatments for those still battling residual disease."

"Since uncovering these findings in women diagnosed with triple negative breast cancer, we have learned that others are applying this stratification of patients based on ctDNA and CTCs to other cancers, including breast and colon," said Radovich.

"This is an important step forward in the treatment of women with triple negative breast cancer, who have not had much scientific evidence to point to--until now--for treatment of their disease," said Schneider. "We are going to use these findings and continue on until we find a treatment that works for each individual woman. This effort not only involves finding the best way to kill cancer, but to minimize side effects."

As a further testament to the significance of these findings, Radovich presented the initial findings as part of an oral, plenary session on December 13, 2019, at the San Antonio Breast Cancer Symposium, the most influential gathering of breast cancer researchers and physicians in the world.

ITHACA, N.Y. - Across the globe, approximately 50 million people are living with dementia. The two most common forms are Alzheimer's disease and frontotemporal lobar degeneration (FTLD), which develop when neurons in specific parts of the brain stop functioning - triggering memory loss and other behavioral or personality changes.

Without a cure, the World Health Organization predicts that number could rise by as many as 10 million cases per year. However, predicting the onset of these diseases is tricky because neurodegeneration can start years before people present any outward symptoms.

Cornell researchers including Fenghua Hu, associate professor in the Department of Molecular Biology and Genetics and member of the Weill Institute for Cell and Molecular Biology, are taking a closer look at the factors that cause Alzheimer's, FTLD and similar diseases. Hu's latest study, "A role of the frontotemporal lobar degeneration risk factor TMEM106B in myelination," was published June 23 in the journal Brain.

"I want to have a better understanding of the molecular and cellular mechanisms of neurodegeneration," Hu said. "I hope that our research can facilitate therapeutic development of treatment options for patients suffering from neurodegenerative diseases and other brain disorders."

Her team started by investigating a specific gene, called TMEM106B, which had been previously identified as a risk factor for several neurodegenerative diseases, including Alzheimer's and FTLD. Researchers also knew that a particular mutation in that gene caused a neurological defect known as hypomyelinating leukodystrophy, which creates a myelin deficit in the brain, leading to the deterioration of both motor skills and mental acuity.

Myelin is the fatty tissue that wraps around nerve fibers, or axons, in the nervous system. Like insulation, this tissue forms a sheath that surrounds the nerve fibers, protecting them from damage and allowing electrical impulses to be quickly transmitted along the nerve.

Hu wanted to see exactly how that one mutation in TMEM106B could cause so much damage. She also wanted to learn more about how the gene regulates the formation and maintenance of the myelin sheath under normal conditions.

"We found that the mutation associated with the disease is a loss-of-function mutation," Hu said.

This distinction is critical since the Hu lab saw that TMEM106B is expressed in the cells that are responsible for forming the protective myelin tissue. Those cells are called oligodendrocytes, and within them, TMEM106B resides in the lysosome - a tiny organelle that acts as a cellular recycling center.

Like the stomach, the lysosome must maintain a specific pH to keep its enzymes active. As oligodendrocytes build the myelin sheath, lysosomes remove any extraneous materials. They can also store myelin's main membrane protein and deposit it in areas surrounding the nerve fibers.

Hu's team discovered that the TMEM106B mutation prevented the gene from regulating both the pH inside the lysosome and the movement of the lysosome itself - inhibiting the oligodendrocytes' ability to build compact myelin layers.

Using a mouse model, Hu also noticed that an overall TMEM106B deficiency led to abnormal lysosome movement within the oligodendrocytes. This created defects in the myelin sheath, and the team observed behavioral changes, including poor motor coordination.

Additional research will examine the exact mechanism by which TMEM106B regulates lysosome function and will demonstrate how the mutation leads to the known neurological defects.

"We want to explore whether the gene's regulation of myelination contributes to its association with neurodegenerative diseases, including Alzheimer's, FTLD and other age-related dementia," Hu said.

Living close to natural green space can mitigate some of the changes in infant gut bacteria associated with formula feeding, according to new research published in the journal Environment International.

"Not every infant can be breastfed," said Anita Kozyrskyj, pediatrics professor at the University of Alberta. "This is one of the first pieces of evidence for a nature-related intervention that could possibly help promote healthy gut microbial composition in infants who are not breastfed."

"We consider breastfeeding to be the desirable state, and we know that a breastfed infant is at reduced likelihood of many conditions later in life--for example, developing respiratory infections and becoming overweight," said Kozyrskyj, who is principal investigator for SyMBIOTA, a research team that studies how changes in infant gut microbiota can lead to the development of obesity, allergies and asthma in children.

The researchers examined fecal samples taken during routine home visits from 355 four-month-old infants who are part of the CHILD Cohort Study--a national study that is following nearly 3,500 Canadian children from before birth to adolescence with the goal of discovering root causes of allergies, asthma and chronic disease.

The babies' postal codes were then cross-referenced with the City of Edmonton's urban Primary Land and Vegetation Inventory (uPLVI), which maps natural green spaces in the city, including natural forest, grasslands, wetlands, lakes, rivers and ravines.

"We found that the infants who lived within 500 metres of a natural environment were less likely to have higher diversity in their gut bacteria," she said. "It may seem counterintuitive, but a young breastfed infant has lower gut microbial diversity than a formula-fed infant because formula feeding increases the number of different gut bacteria."

The results applied only to infants living close to natural spaces, regardless of whether there was a man-made park in the neighbourhood.

The researchers found the greatest association was for formula-fed infants living in a home with a pet. Though the exact mechanism is not understood, they hypothesize that families who walk their dog may use natural areas more often, or that pets may bring healthy bacteria into the home on their fur.

"We know that when you introduce a pet into the home, it does change the types of microbes that are found in household dust," Kozyrskyj pointed out.

The researchers found that 54 per cent of the infants lived close to a natural environment and 18 per cent of the babies were exclusively formula-fed. Nine per cent were both formula-fed and had pets in the home. The results were adjusted for the type of delivery (caesarean section or natural), the season, and the age and education level of the mothers.

They did not distinguish between the type of pets the families owned, but Kozyrskyj said, "We think it's a dog effect."

"Even if you live in a highrise, if you have a dog you go out and use the natural spaces near your home. It's likely that the pet is the conduit."

The researchers reported an increased presence of Proteobacteria--the type of bacteria more often found in nature--in the guts of all of the babies.

While numerous studies have examined the impact of living close to natural green spaces on the skin and gut microbiota of adults, this is the first study to cross-reference proximity to natural green spaces with the gut bacteria of infants.

"We had this wonderful opportunity for data linkage between the unique natural assets map, the home locations of infants in the CHILD birth cohort and information on the composition of their gut bacteria," Kozyrskyj said.

Kozyrskyj said the research team included a geographer, a city planner, pediatrics and obstetrics specialists, and international environmental and microbiome scientists.

"It takes an interdisciplinary team to do this kind of research," she said. "That's what made the project so rich in terms of the interpretation of the results and the kinds of questions that could be asked."

Kozyrskyj said the next step for this research will be to follow the formula-fed infants who are exposed to natural areas throughout childhood and track the impact on their health.

She said she often receives emails from new mothers who are unable to breastfeed and are concerned about their children's futures. Based on these results, she will now advise them to take their babies out to natural areas and consider getting a pet.

Expansion stress can have an alarming impact on breast cancer cells by creating conditions that could lead to dangerous acceleration of the disease, an interdisciplinary team of University of Alabama at Birmingham researchers has found.

As breast tumors grow, biomechanical forces in the tumor microenvironment, or TME, cause elevated compression at the tumor interior, tension at the periphery and altered interstitial fluid flow -- promoting aggressive growth, invasion and metastasis. Biomechanical forces also may modulate the immune response through cancer cell-immune cell crosstalk.

The UAB researchers -- Joel Berry, Ph.D., associate professor in the Department of Biomedical Engineering; Jessy Deshane, Ph.D., associate professor in the UAB Department of Medicine's Division of Pulmonary, Allergy and Critical Care Medicine; Roy Koomullil, Ph.D., associate professor in the Department of Mechanical Engineering; and Selvarangan Ponnazhagan, Ph.D., professor in the Department of Pathology -- created a novel, tissue-engineered, three-dimensional breast cancer mimetic system.

This system recapitulates the in vivo growth of breast cancer cells in the presence of tumor-associated fibroblasts, endothelial cells and immune cells, within a physiologically relevant extracellular matrix. The researchers found that biomechanical forces significantly altered the proteome of breast cancer cells and enhanced exosome production. Tumor cell-secreted exosomes, one of the intercellular mediators of signaling in the TME, are now recognized as key regulators of tumor progression.

In the study, the exosomes directly promoted aggressive tumor cell growth, induced immune suppression and altered immune cell polarization in the TME. Furthermore, the researchers recently engineered an oscillatory compression device for real-time application of biomechanical force on orthotopic mammary tumors in vivo, which allowed them to observe exosome-mediated immunosuppression and aggressive tumor growth in mice.

Preliminary analyses of exosome migration, immune cell uptake and polarization superimposed onto a novel computational algorithm indicated the significance of exosome concentration gradient and time in predicting the kinetics of protumorigenic events, linking biomechanical force, exosome release by tumor cells, exosome uptake and polarization of immune cells in the TME.

(Philadelphia, PA) - The human heart is like a sponge, able to expand and grow, increasing its capacity to take up blood. In theory, an enlarged heart can also squeeze out more blood, with more power, than an average-sized heart. But in reality, for most people, this growth - known as cardiac hypertrophy - is abnormal and signals trouble.

Cardiac hypertrophy is brought on by various factors, high blood pressure in particular. Existing treatments only delay the inevitable - that the spongy heart muscle becomes thicker and stiffer over time, culminating in heart failure, in which the heart can no longer contract strongly enough to pump blood through the body.

A greater understanding of the molecular mechanisms driving abnormal heart growth promises to turn this around, however, and in new work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) cast fresh light on a key molecular regulator in the heart known as FoxO1. In a paper published online July 9 in the journal Circulation, the Temple scientists are the first to show that FoxO1 attaches to and activates a wide array of genes in heart cells, leading to widespread increases in growth signaling, specifically within the heart.

"FoxO1 is a major transcription factor that regulates genes involved in metabolism and growth," said Jessica Pfleger, PhD, Instructor in the Center for Translational Medicine at LKSOM and lead author of the new study. "In the heart, however, its activity has been alternately linked to increased and decreased growth, and as a result, there has been uncertainty about what FoxO1 activation means in terms of cardiac hypertrophy."

Figuring out what FoxO1 does in the heart is critical, as pharmaceutical companies are zeroing in on such targets for the development of new therapies for cardiac hypertrophy. In order for those novel therapies to do their jobs effectively, however, a clearer knowledge of FoxO1 activation and its downstream effects is needed.

In the new study, Dr. Pfleger and colleagues investigated FoxO1 using a so-called transverse aortic constriction mouse model. In these animals, cardiac hypertrophy develops as a result of blood pressure overload and stress on the heart, thereby roughly mimicking the development of cardiac hypertrophy in humans with high blood pressure. The researchers carried out genome-wide analyses on the animals' heart tissue, looking specifically for areas where FoxO1 binds to DNA and switches genes on or off.

The team's analyses revealed that FoxO1 binds widely to genes throughout the heart cell genome.

"Its genomic binding was widespread, yet specific," Dr. Pfleger explained. "FoxO1 binding increased especially during pathological growth of the heart. This really makes sense, because in order for the heart to grow, a majority of genes need to be activated, which requires a huge increase in gene expression."

The study is also the first to show in animals that loss of FoxO1 expression in the heart prevents cardiac overgrowth caused by chronically elevated blood pressure. The researchers landed on this discovery after they eliminated FoxO1 from heart cells cultured in the laboratory and observed that the cells no longer increased in size in response to growth-inducing molecules.

"Our observations primarily shed light on understudied mechanisms of pathological heart growth," Dr. Pfleger said. "Therapeutically, more work is required to properly target FoxO1, since it is intimately involved in the activation of numerous genes associated with heart growth."

Dr. Pfleger and colleagues next plan to investigate other molecules linked to abnormal heart growth.

"Other factors, in addition to FoxO1, regulate cardiac hypertrophy, and teasing out their roles could give us greater insight into which mechanisms may be most therapeutically relevant," Dr. Pfleger added.

Photonics, or the science of manipulating light, has various applications in modern electronics--such as in information technology, semiconductors, and health-based devices. Thus, researchers globally have been focused on finding novel approaches to spur advances in the field of photonics. But, the challenge lies in optimizing the process of "photon generation" as desired, which is crucial to all photonics-based applications.

In a recent study published in Nano Letters, a team of researchers at Daegu Gyeongbuk Institute of Science and Technology (DGIST), led by Professor J.D. Lee, developed a novel mechanism to maximize the efficiency of photon conversion in 2D materials. The scientists achieved this by exploring a method called "nonlinear second-harmonic generation" (SHG), an optical process wherein two photons with the same frequency interact with a nonlinear material and generate a new photon with twice the energy, thus resulting in frequency doubling. "The efficient generation of photons is a crucial part of developing photonic devices. In our study, we developed an ultrafast process of photon conversion in an atomistic-layer material to innovate photonics-based applications."

In their study, the scientists focused on a 2D material called tungsten diselenide (WSe2), owing to its intriguing band characteristics. For instance, this material consists of various "resonant points" that sensitively respond to the absorption of light particles called "photons." Prof Lee says, "We focused on this feature of WSe2 and revealed a new process to convert the "color" in photons through the maximized dual resonant mode."

Based on SHG, the researchers proposed a novel method called "dual-resonant optical sum frequency generation" (SFG), in which they selected two resonant points in WSe2 called A and D excitons, respectively. Using this method, the researchers found that when WSe2 is irradiated using two excitation pulses (ω1 and ω2), with one of the two pulses (ω1) being tuned to A exciton and their sum frequency (ω1 + ω2) to the D exciton, the signal is 20 times higher than the single-resonant mode! Not just this, the intensity that was produced by this method was found to be 1 order of magnitude higher than SHG under the same conditions. These findings were then confirmed using various techniques, including density functional theory and optical experiments. Prof Lee states, "Our proposed dual-resonant SFG method provides new scientific insights into not only nonlinear spectroscopic and microscopic methods but also nonlinear optics and technology using two-dimensional semiconductors."

These findings show tremendous potential for the development of advanced photonic devices. Prof Lee concludes, "Our study can potentially take photonics-based applications to the next level--for example, cheaper diagnostic methods through better optical imaging instruments in the near future."

Interest in deep-sea mining for copper, cobalt, zinc, manganese and other valuable metals has grown substantially in the last decade and mining activities are anticipated to begin soon. A new study, led by University of Hawai'i (UH) at Mānoa researchers, argues that deep-sea mining poses significant risks, not only to the area immediately surrounding mining operations but also to the water hundreds to thousands of feet above the seafloor, threatening vast midwater ecosystems. Further, the scientists suggest how these risks could be evaluated more comprehensively to enable society and managers to decide if and how deep-sea mining should proceed.

Currently 30 exploration licenses cover about 580,000 square miles of the seafloor on the high seas and some countries are exploring exploitation in their own water as well. Most research assessing the impacts of mining and environmental baseline survey work has focused on the seafloor.  

However, large amounts of mud and dissolved chemicals are released during mining and large equipment produces extraordinary noise--all of which travel high and wide. Unfortunately, there has been almost no study of the potential effects of mining beyond the habitat immediately adjacent to extraction activities.

"This is a call to all stakeholders and managers," said Jeffrey Drazen, lead author of the article and professor of oceanography at UH Mānoa. "Mining is poised to move forward yet we lack scientific evidence to understand and manage the impacts on deep pelagic ecosystems, which constitute most of the biosphere. More research is needed very quickly."

The deep midwaters of the world's ocean represent more than 90% of the biosphere, contain 100 times more fish than the annual global catch, connect surface and seafloor ecosystems, and play key roles in climate regulation and nutrient cycles. These ecosystem services, as well as untold biodiversity, could be negatively affected by mining.

This recent paper, published in the Proceedings of the National Academy of Science, provides a first look at potential threats to this system.

"The current study shows that mining and its environmental impacts may not be confined to the seafloor thousands of feet below the surface but could threaten the waters above the seafloor, too," said Drazen. "Harm to midwater ecosystems could affect fisheries, release metals into food webs that could then enter our seafood supply, alter carbon sequestration to the deep ocean, and reduce biodiversity which is key to the healthy function of our surrounding oceans."
  

In accordance with UN Convention on the Law of the Sea (UNCLOS), the International Seabed Authority (ISA) is required to ensure the effective protection of the marine environment, including deep midwater ecosystems, from harmful effects arising from mining-related activities. In order to minimize environmental harm, mining impacts on the midwater column must be considered in research plans and development of regulations before mining begins.

"We are urging researchers and governing bodies to expand midwater research efforts, and adopt precautionary management measures now in order to avoid harm to deep midwater ecosystems from seabed mining," said Drazen.

A new study sheds light on proteins in particles called extracellular vesicles, which are released by tumor cells into the bloodstream and promote the spread of cancer. The findings suggest how a blood test involving these vesicles might be used to diagnose cancer in the future, avoiding the need for invasive surgical biopsies.

The research is a large-scale analysis of what are known as palmitoylated proteins inside extracellular vesicles, according to Dolores Di Vizio, MD, PhD, professor of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine at Cedars-Sinai. Di Vizio is co-corresponding author of the study, published online June 10 in the Journal of Extracellular Vesicles.

Extracellular vesicles have gained significant attention in the last decade because they contain proteins and other biologically important molecules whose information can be transferred from cell to cell. They are known to help cancer metastasize to distant sites in the body, but exactly how this happens is not clear.

To learn more about this process, the research team looked into a process called palmitoylation, in which enzymes transfer lipid molecules onto proteins. Palmitoylation can affect where proteins are located within cells, their activities and their contribution to cancer progression.

The investigators examined two types of extracellular vesicles, small and large, in samples of human prostate cancer cells. Using centrifuges, they separated the extracellular vesicles from the other cell materials and analyzed the levels of palmitoylation and the types of proteins present.

The team found extracellular vesicles derived from the cancer cells contained palmitoylated proteins that are associated with the spread of cancer. Further, when the team chemically suppressed the palmitoylation process, the level of some of these proteins went down in the extracellular vesicles.

"Our results suggest that protein palmitoylation may be involved in the selective packaging of proteins to different extracellular vesicle populations in the body," Di Vizio said. "This finding raises the possibility that by examining these proteins in extracellular vesicles in the bloodstream, we may be able to detect and characterize cancer in a patient in the future without performing a surgical biopsy."

Di Vizio said the next step in the research is to conduct a study in collaboration with her Cedars-Sinai colleagues and industry partners that will use advanced technologies, including mass spectrometry and flow cytometry, with the goal of identifying clinically significant prostate cancer at diagnosis. 

In addition to Di Vizio, Wei Yang, PhD, associate professor of Surgery at Cedars-Sinai, and Andries Zijlstra, PhD, are co-corresponding authors for the study. Zijlstra completed the research while working at Vanderbilt University Medical Center in Nashville. Javier Mariscal, PhD, a postdoctoral scientist in Di Vizio's laboratory, is the study's first author.

Funding: Research reported in this publication was supported by the National Institutes of Health under award number R01CA218526 and by the U.S. Department of Defense.

DOI: 10.1080/20013078.2020.1764192

Journal

Journal of Extracellular Vesicles

DOI

10.1080/20013078.2020.1764192