Earth

Denver--(Embargoed for 7 a.m. EST August 8, 2020) The combination of first-line nivolumab and ipilimumab demonstrated an improvement of overall survival for patients with unresectable malignant pleural mesothelioma compared to platinum-based chemotherapy, according to research presented today at the International Association for the Study of Lung Cancer Virtual Presidential Symposium.

The study is presented by Paul Baas, M.D., from The Netherlands Cancer Institute and The University of Leiden, in Amsterdam. Watch a video of Dr. Baas explaining his research here: https://vimeo.com/443190432/32a40271f0

Nivolumab is an immunotherapy that works as a checkpoint inhibitor, blocking a signal that prevents activation of T cells from attacking the cancer. Ipilimumab is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system. When administered in combination, this dual immunotherapy has shown clinical benefit in 6 different tumor types, including mesothelioma.

Malignant pleural mesothelioma is a highly aggressive cancer with a five-year survival rate of less than 10 percent. Current standard of care treatment is chemotherapy with few treatment advances in the last 15 years.

In this large phase III study, Dr. Baas and the global study investigators randomly assigned more than 600 patients: 303 to the nivolumab + ipilimumab arm and 302 to the chemotherapy arm. The study had a minimal follow up of close to two years. Two-year overall survival rates were 40.8% for the patients in the experimental treatment arm vs 27.0% in chemotherapy arm. Of the 30.3% of patients in the study-combination group who experienced grade 3-4 adverse events, 15% discontinued therapy compared with 7.4% of the 32.0% of patients in chemotherapy group.

"CheckMate 743 met its primary endpoint of statistically improved OS with nivolumab + ipilimumab vs standard of care chemotherapy in first-line treatment of patients with mesothelioma," said Dr. Baas. "These clinically meaningful data represent the first positive phase 3 trial of immunotherapy in first-line MPM and should be considered as a new standard of care."

A new publication on the impacts of deep-seabed mining by 13 prominent deep-sea biologists, led by University of Hawai'i at Mānoa oceanography professor Craig Smith, seeks to dispel scientific misconceptions that have led to miscalculations of the likely effects of commercial operations to extract minerals from the seabed.

The deep sea, ocean depths below 650 feet (200 metres), constitutes more than 90% of the biosphere, harbors the most remote and extreme ecosystems on the planet, and supports biodiversity and ecosystem services of global importance. Interest in deep-seabed 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.

"As a team of deep-sea ecologists, we became alarmed by the misconceptions present in the scientific literature that discuss the potential impacts of seabed mining," said Smith. "We found underestimates of mining footprints and a poor understanding of the sensitivity and biodiversity of deep-sea ecosystems, and their potential to recover from mining impacts. All the authors felt it was imperative to dispel misconceptions and highlight what is known and unknown about deep seabed mining impacts."

In addition to the impacts of mining on ecosystems in the water above extraction activities, as detailed in another UH-led study published last month, Smith and co-authors emphasize deep-seabed mining impacts on the seafloor, where habitats and communities will be permanently destroyed by mining.

"The bottom line is that many deep-sea ecosystems will be very sensitive to seafloor mining, are likely to be impacted over much larger scales than predicted by mining interests, and that local and regional biodiversity losses are likely, with the potential for species extinctions," said Smith.

The scope of mining impacts from full scale mining, however, will not be well understood until a full-scale mining operation is conducted for years. The geographic scale and ecosystem sensitivities to mining disturbance occurring continuously for decades cannot be simulated or effectively studied at a smaller scale, according to the authors.

"All the simulations conducted so far do not come close to duplicating the spatial scale, intensity and duration of full-scale mining," said Smith. "Further, the computer models use ecosystem sensitivities derived from shallow-water communities that experience orders of magnitude higher levels turbidity and sediment burial (mining-type perturbations) under natural conditions than the deep-sea communities targeted for mining."

Much of the planned deep-seabed mining will be focused in the Pacific Ocean, near Hawai'i, and also near Pacific Island nations. Hawai'i and Pacific Island nations are likely to particularly suffer from any negative environmental impacts, but may benefit economically from deep-seabed mining, creating a need to understand the trade-offs of such mining.

"Polymetallic-nodule mining (as currently planned) may ultimately impact 500,000 square kilometers of deep seafloor in the Pacific, an area the size of Spain, yielding perhaps the largest environmental footprint of a single extractive activity by humans," said Smith. "Addressing the misconceptions and knowledge gaps related to deep-sea mining is the first step towards effective management of deep-seabed mining."

The researchers aim to work closely with regulators and society to help manage deep-seabed mining and emphasize the need to proceed slowly with seabed mining until impacts are fully appreciated.

People hoping to get a handle on future droughts in the American West are in for a disappointment, as new USC-led research spanning centuries shows El Niño cycles are an unreliable predictor.

Instead, they found that Earth's dynamic atmosphere is a wild card that plays a much bigger role than sea surface temperatures, yet defies predictability, in the wet and dry cycles that whipsaw the western states. The study, published Monday in Science Advances, is a detailed assessment of long-term drought variability.

The findings are significant for water management, agriculture, urban planning and natural resources protection. Recent droughts have claimed many lives and caused damaging crop losses, making drought forecasting a high priority. Meanwhile, the West faces rapid population growth at the same time that forecasts show dry times ahead due to global climate change.

"The main finding is not terribly hopeful for short-term drought prediction," said Julien Emile-Geay, a study author and associate professor of Earth sciences at the USC Dornsife College of Letters, Arts and Sciences. "We found that, historically speaking, year-to-year droughts in the western United States were less predictable than previous studies have claimed."

New study examines 1,000 years of droughts in the West and beyond

Emile-Geay and postdoctoral scholar Michael Erb, who is lead author from USC and now at Northern Arizona University, joined with other scientists at the University of Washington and Columbia University to produce the study.

The researchers set out to answer the question: What determines droughts in the West?

They examined North American droughts and global conditions spanning more than 1,000 years. Megadroughts, which lasted decades, and dry spells predate the Industrial Revolution, American expansion on the continent or European colonialism. For example, a megadrought in the late 13th century likely contributed to the dispersal of the Anasazi people.

The prevailing explanation is that the El Niño-Southern Oscillation plays a key role in these drought episodes. The oscillation is a two-sided coin based on water conditions in the eastern equatorial Pacific Ocean. El Niño conditions occur when sea temperatures in the region are warmer than normal and are associated with wet years in the American Southwest; La Niña conditions occur when water is cooler than normal and are associated with dry years in the Southwest.

But the scientists found that rule of thumb didn't jibe well with all drought cycles of the past. While it's true there's a correlation between La Niña and drought, these ocean water conditions accounted for only about 13% of the variability, the study says.

"La Niña proved to not be the only game in town," Emile-Geay said. "La Niña is part of the game, but not the biggest part."

A notable example of this phenomenon occurred in 2015-16, an El Niño year when Southern California did not receive the increased precipitation that was predicted. Instead, the relief came unexpectedly the following year, a La Niña year that should have been drier than normal.

What other variables can lead to drought?

The scientists also examined other drought influencers, including water temperatures in the Atlantic Ocean and volcanic activity. While those phenomena can influence drought conditions, they are too weak or episodic to explain many droughts.

Instead, the study says droughts can originate in the atmosphere. The air around Earth is highly dynamic and influenced by more variables than the ocean alone.

"The atmosphere creates a lot of variations in moisture supply on its own, and it can cook up droughts all by itself, without being told what to do by the ocean," Emile-Geay said.

But while the past is key to the future, it does not hold all the keys. In the future, research says carbon emissions will continue to trap heat and warm the surface, and the West will experience increasingly dry conditions as a result.

"Our study suggests that the atmosphere will continue to add a strongly unpredictable element to moisture conditions in the southwestern United States, on top of drying induced by global warming," Emile-Geay said. "That is, the Southwest is headed for a drier future overall but with the atmosphere adding a wildcard that may, at times, make things better or worse for the people and ecosystems that depend on that water."

The study integrates numerous sources of information spanning centuries to support the findings. The dataset, called the Last Millennium Reanalysis, aggregates climate models, modern temperature measurements and nearly 3,000 climate proxies, such as tree rings, corals, and ice cores. The reanalysis was developed by scientists at USC, the University of Washington and the University of Colorado, with the support of the National Oceanic and Atmospheric Administration. According to the NOAA, the reanalysis aimed to "transform the ways in which the climate community investigates low-frequency climate."

KANSAS CITY, MO--Since its discovery, scientists have been using the much-lauded gene editing tool CRISPR to alter the DNA of model organisms and uncover the functions of thousands of genes. Now, researchers at the Stowers Institute for Medical Research in Kansas City, Missouri, and the Andalusian Center of Developmental Biology at Pablo de Olavide University in Seville, Spain, have harnessed the technology to target gene messages (messenger RNA) involved in early vertebrate development.

By disrupting gene messages (RNA) instead of the underlying genes (DNA), researchers can study genes that might previously have been difficult or impossible to manipulate because they were essential to life or involved in a critical stage of biological development. This approach also allows targeting of maternally-contributed gene RNAs, which are deposited in the egg to kick off the earliest genetic programs.

The study, which appears online August 7, 2020, in the journal Developmental Cell, establishes the use of CRISPR-Cas technology to target RNA in embryonic animal models in a specific and systematic manner. The findings demonstrate the technique can be applied to a broad range of aquatic and terrestrial models including zebrafish, medaka, killifish, and mice.

"The exciting thing about this study is not just what we found, but what we can do," says Ariel Bazzini, PhD, an assistant investigator at the Stowers Institute and co-leader of the study. "We still don't understand how genes jumpstart the earliest stages of development. Now we can find out by targeting their RNA messages, one by one."

"We are also very excited about the the low cost of the technique," Bazzini says. "Any lab working with zebrafish or other animal embryos could use this method. Indeed, we have already distributed the reagents and protocol to several labs around the world."

Before development even begins, egg must first meet sperm. The resulting embryo carries half the genes from the mother and half from the father. In addition to its genome, the embryo has components such as RNA and proteins provided by the mother.

"That maternal contribution is a mystery that many of us want to solve," says Bazzini. However, attempts to systematically target RNA in zebrafish, the model organism of choice for many developmental biologists, have been unsuccessful. The aptly-named RNA interference method, which has been a mainstay in studies of gene function, does not work in zebrafish, or other fish or frogs. Other methods using synthetics strips of genetic code known as morpholinos or antisense oligonucleotides have sometimes been associated with toxicity and off-target effects.

So when Bazzini and his collaborator and friend Miguel A. Moreno-Mateos, PhD, a professor at Pablo de Olavide University, noticed reports that CRISPR technology had been employed to degrade RNA in yeast, plants, and mammalian cells, they were eager to give it a try. Moreno-Mateos was a postdoc in Antonio Giraldez's lab at Yale University at the same time as Bazzini, and is considered an expert on the optimization of CRISPR-Cas technology in vivo.

The CRISPR-Cas13 system depends on two ingredients - a short RNA sequence known as a "guide" RNA, and an enzyme called Cas13 (part of the Cas, or CRISPR-associated, family of proteins) that cuts any RNA messages in the cell that could line up and bind to that guide sequence. The researchers tested four different Cas13 proteins that had been successfully used in previous studies. They found that the Cas13 proteins were either inefficient or toxic to the developing zebrafish, except for one protein, called RfxCas13d.

They then examined whether targeting RNA with CRISPR-RfxCas13d in zebrafish embryos could recreate the same defects as altering the organism's underlying DNA. For example, when they targeted the RNA of the tbxta gene, which is necessary for growing a tail, the zebrafish embryos were tailless.

The researchers went on to show that the CRISPR system could efficiently target a variety of RNAs, both those provided by the mother as well as those produced by the embryo, decreasing RNA levels by an average of 76%. Collaborators within and outside of Stowers helped derive that statistic, and showed that the technique also works in killifish, medaka, and mouse embryos.

"The CRISPR-RfxCas13d system is an efficient, specific and inexpensive method that can be used in animal embryos in a comprehensive manner," says Moreno-Mateos, who is also co-leader of the study. "With this tool we will help to understand fundamental questions in biology and biomedicine."

One of the fundamental questions the researchers hope to pursue is the role that RNA plays in the earliest hours of development. The RNAs left behind by the mother have to be removed at precisely the same time that the genome of the embryo comes online; otherwise, the embryo never develops.

"We think this tool could have a profound effect on our understanding of infertility and developmental problems in general," says Bazzini.

"The Stowers facilities and collaborative environment have allowed us to test CRISPR technology in other animal model systems," Bazzini says. "When I joined Stowers about four years ago, I would have never predicted that my lab would be doing experiments in mouse or killifish models. It's been a fun adventure!"

Other coauthors from the Stowers Institute include Gopal Kushawah, PhD, Michelle DeVore, Huzaifa Hassan, Wei Wang, PhD, Timothy J. Corbin, Andrea M. Moran, and Alejandro Sánchez Alvarado, PhD.

This research was funded by the Stowers Institute for Medical Research, Pablo de Olavide University, Consejo Superior de Investigaciones Cientificas, and Junta de Andalucia. Additional support included the Ramon y Cajal program (RyC-2017-23041) and grants (BFU2017-86339-P, PGC2018-097260-B-I00, and MDM-2016-0687) from the Spanish Ministerio de Ciencia, Innovación y Universidades; the Springboard program from Centro Andaluz de Biología del Desarrollo; Genome Engineer Innovation 2019 Grant from Synthego; the Pew Innovation Fund; Innovate Peru (grant 168-PNICP-PIAP-2015); and FONDECYT (travel grant 043-2019).

Lay Summary of Findings

CRISPR is a gene-editing tool that has enabled researchers to study the function of different genes in model organisms. Scientists at the Stowers Institute for Medical Research in Kansas City, Missouri, and the Andalusian Center of Developmental Biology at Pablo de Olavide University in Seville, Spain, have now harnessed this powerful technology to target gene messages in animal model embryos to gain a better understanding of the genetic programs that direct early stages of vertebrate development.

In a report published online August 7, 2020, in Developmental Cell, the Stowers team, led by Assistant Investigator Ariel Bazzini, PhD, and collaborators show that the technology, called CRISPR-Cas13, is able to target RNA - DNA's chemical cousin that carries messages needed to construct proteins - in embryonic animal models in a specific and systematic manner, allowing researchers to study the role of RNA in the earliest hours of development. The researchers show that the CRISPR-Cas13 method is effective in zebrafish, killifish, medaka, and mouse embryos, and thus could be used to explore early developmental genetic programs in a broad range of animal species.

Each cigarette smoked a day by heavier smokers increases the risk of contracting some diseases by more than 30 per cent, according to a new international study published today.

The Australian Centre for Precision Health based at the University of South Australia led the study, which links heavier smoking* with 28 separate health conditions, revealing a 17-fold increase in emphysema, 8-fold increase in atherosclerosis (clogged arteries) and a 6.5-fold higher incidence of lung cancer.

The findings, published in EClinicalMedicine, analysed hospital data and mortality statistics from more than 152,483 ever* smokers in the UK Biobank to look how heavier smoking affects disease risks.

Chief Investigator, UniSA Professor Elina Hypponen, says the risk of suffering respiratory diseases, cancers and cardiovascular diseases increased with each cigarette smoked per day.

The links between heavier smoking and emphysema, heart disease, pneumonia and respiratory cancers were particularly high, but the researchers also found associations with many other respiratory diseases, renal failure, septicaemia, eye disorders, and complications of surgery or medical procedures.

"Tobacco smoking is the leading preventable cause of death worldwide and smokers typically die 10 years earlier than non-smokers," Professor Hypponen says.

"Despite a global decline in smoking over the last 20 years, an estimated 20 per cent of the world's population aged over 15 years are still smoking tobacco."

In the US alone, smokers number 40 million, with 16 million of those living with a disease caused by smoking. This costs their economy more than $300 billion per annum," Prof Hypponen says.

The most recent statistics from Australia show that about 13.8 per cent of its adult population (2.6 million people) are daily smokers. Despite a 10 per cent reduction since1995, smoking is estimated to kill 19,000 Australians a year, accounting for nine per cent of the total burden of disease and $137 billion in annual medical costs.

Several known smoking outcomes, including stroke, were not identified in the study, which only counted cases above 200 for each health condition.

"We only looked at how heavier smoking further affects diseases risks in a group of people who are all at least past smokers, so compared to never smokers, the health effects are going to be even more notable. Other factors, including when people start smoking or how long they have smoked, may also affect the health consequences arising from smoking," Professor Hypponen says.

"In the past 20 years, the proportion of people smoking a pack or more per day has decreased in countries such as the US and Australia, while there has been an increase in those smoking less than 10 cigarettes per day.

"While this reflects progress, our study shows that each additional cigarette smoked matters, notably increasing the risks of cancer, respiratory, circulatory and many other diseases."

DALLAS - Aug. 7, 2020 - UT Southwestern scientists have developed a genetically engineered mouse and imaging system that lets them visualize fluctuations in the circadian clocks of cell types in mice. The method, described online in the journal Neuron, gives new insight into which brain cells are important in maintaining the body's master circadian clock. But they say the approach will also be broadly useful for answering questions about the daily rhythms of cells throughout the body.

"This is a really important technical resource for advancing the study of circadian rhythms," says study leader Joseph Takahashi, Ph.D., chair of the department of neuroscience at UT Southwestern Medical Center, a member of UT Southwestern's Peter O'Donnell Jr. Brain Institute, and an investigator with the Howard Hughes Medical Institute (HHMI). "You can use these mice for many different applications."

Nearly every cell in humans - and mice - has an internal circadian clock that fluctuates on a roughly 24-hour cycle. These cells help dictate not only hunger and sleep cycles, but biological functions such as immunity and metabolism. Defects in the circadian clock have been linked to diseases including cancer, diabetes, and Alzheimer's, as well as sleep disorders. Scientists have long known that a small part of the brain - called the suprachiasmatic nucleus (SCN) - integrates information from the eyes about environmental light and dark cycles with the body's master clock. In turn, the SCN helps keep the rest of the cells in the body in sync with each other.

"What makes the SCN a very special kind of clock is that it's both robust and flexible," says Takahashi. "It's a very strong pacemaker that doesn't lose track of time, but at the same time can shift to adapt to seasons, changing day lengths, or travel between time zones."

To study the circadian clock in both the SCN and the rest of the body, Takahashi's research group previously developed a mouse that had a bioluminescent version of PER2 - one of the key circadian proteins whose levels fluctuate over the course of a day. By watching the bioluminescence levels wax and wane, the researchers could see how PER2 cycled throughout the animals' bodies during the day. But the protein is present in nearly every part of the body, sometimes making it difficult to distinguish the difference in circadian cycles between different cell types mixed together in the same tissue.

"If you observe a brain slice, for instance, almost every single cell has a PER2 signal, so you can't really distinguish where any particular PER2 signal is coming from," says Takahashi.

In the new work, the scientists overcame this problem by turning to a new bioluminescence system that changed color - from red to green - only in cells that expressed a particular gene known as Cre. Then, the researchers could engineer mice so that Cre, which is not naturally found in mouse cells, was only present in one cell type at a time.

To test the utility of the approach, Takahashi and his colleagues studied two types of cells that make up the brain's SCN - arginine vasopressin (AVP) and vasoactive intestinal polypeptide (VIP) cells. In the past, scientists have hypothesized that VIP neurons hold the key to keeping the rest of the SCN synchronized.

When the research team looked at VIP neurons - expressing Cre in just those cells, so that PER2 luminesced green in VIP cells, while red elsewhere - they found that removing circadian genes from the neurons had little overall effect on the circadian rhythms of the VIP neurons, or the rest of the SCN. "Even when VIP neurons no longer had a functioning clock, the rest of the SCN behaved essentially the same," explains Yongli Shan, Ph.D., a UTSW research scientist and lead author of the study. Nearby cells were able to signal to the VIP neurons to keep them in sync with the rest of the SCN, he says.

When they repeated the same experiment on AVP neurons, however - removing key clock genes - not only did AVP neurons themselves show disrupted rhythms, but the entire SCN stopped synchronously cycling on its usual 24-hour rhythm.

"What this showed us was that the clock in AVP neurons is really essential for the synchrony of the whole SCN network," says Shan. "That's a surprising result and somewhat counterintuitive, so we hope it leads to more work on AVP neurons going forward."

Takahashi says other researchers who study circadian rhythms have already requested the mouse line from his lab to study the daily cycles of other cells. The mice might allow scientists to hone in on the differences in circadian rhythms between cell types within a single organ, or how tumor cells cycle differently than healthy cells, he says.

"In all sorts of complex or diseased tissues, this can let you see which cells have rhythms and how they might be similar or different from the rhythms of other cell types."

Spontaneous mutations of a single gene are likely to cause serious developmental disorders of the excretory organs and genitalia. This is shown in an international study led by the University of Bonn and published in the journal Frontiers in Cell and Developmental Biology. The researchers also owe their findings to an unusual model organism: the zebrafish.

One in 10,000 newborns is born with malformations of the bladder, intestines or genitals. These symptoms are part of the so-called bladder exstrophy epispadias complex, abbreviated BEEC. Since the disorder tends to run in families, it is assumed to have a genetic cause. However, up to now there has been disagreement as to exactly which genetic material is affected or whether there are even several genes involved.

The recently published study sheds light on this issue. Four years ago, researchers led by Prof. Dr. Heiko Reutter from the Institute of Human Genetics at the University of Bonn discovered a gene that is abnormal in sick children. The gene bears the cryptic abbreviation SLC20A1. "We have now taken a closer look at its function," explains Magdalena Rieke, who is completing her doctorate under Prof. Reutter.

The researcher also benefited from the expertise of a university working group that only marginally deals with congenital malformations: Prof. Dr. Benjamin Odermatt researches the cause of neurological diseases at the Section of Neuroanatomy. The zebrafish serves as a model organism. Not only because it can be easily kept in an appropriate habitat and reproduces quickly: Many of its genes are also found in a very similar form in humans.

Zebrafish as genetic model

This also includes SLC20A1. "We used an active substance in the animals to prevent the gene from being translated into proteins," explains Rieke. "As a result, the growing larvae showed disrupted development of their excretory organs. This indicates that SLC20A1 really does appear to play a central role in the correct formation of these organs, and has done so for many millions of years." The researchers were furthermore able to show that the gene is also active in human embryos, particularly in structures involved in the formation of the excretory organs and genitalia.

In human patients, the researchers found three different mutations of SLC20A1. These anomalies often occur spontaneously. Therefore, even children whose parents are completely healthy may be affected. Rieke and her colleagues were able to demonstrate the effect of one of these mutations in human cell cultures: It interferes with the controlled degradation of cells, the "programmed cell death", a very important step in tissue remodeling.

During embryonic development, not only are masses of new cells produced, but some are also deliberately destroyed. This is for instance how the opening of the intestine to the outside, the anus, is created. Researchers refer to the process of programmed cell death as apoptosis. "This association might explain why mutations in SLC20A1 can cause such severe developmental disorders," speculates Rieke.

Impaired protein folding

SLC20A1 contains the building instructions of a protein that is located in the cell membrane, the fat-like envelope that surrounds the cells. This protein resembles a long worm that has arranged its body in numerous tight loops that repeatedly run from the outside of the membrane to the inside and back. Computer models suggest that at least one of the mutations discovered prevents correct folding. This is thought to severely disrupt protein function, and thus also the activation of apoptosis.

It is not yet possible to derive immediate insights for the treatment of BEEC directly from the results. "However, it is essential that we gain a better understanding of the disease mechanism for any possible prevention or therapy," stresses Rieke, who herself works as an assistant doctor in the field of pediatric and adolescent medicine. In addition to various working groups from Bonn and Germany, research institutions from Sweden, Great Britain, Italy, India and the Netherlands were also involved in the study. It is thus also an example of successful international cooperation.

A group of researchers from three Japanese universities has discovered why the western subarctic Pacific Ocean, which accounts for only 6 percent of the world's oceans, produces an estimated 26 percent of the world's marine resources.

Japan neighbors this ocean area, known for rich marine resources including salmon and trout. The area, located at the termination of the global ocean circulation called the ocean conveyor belt, has one of the largest biological carbon dioxide draw-downs of the world's oceans.

The study, led by Hokkaido University, the University of Tokyo and Nagasaki University, showed that water rich in nitrate, phosphate and silicate - essential chemicals for producing phytoplankton - is pooled in the intermediate water (from several hundred meters to a thousand meters deep) in the western subarctic area, especially in the Bering Sea basin. Nutrients are uplifted from the deep ocean through the intermediate water to the surface, and then return to the intermediate nutrient pool as sinking particles through the biological production and microbial degradation of organic substances.

The intermediate water mixes with dissolved iron that originates in the Okhotsk Sea and is uplifted to the surface - pivotal processes linking the intermediate water and the surface and that maintain high surface biological productivity. This finding defies the conventional view that nutrients are simply uplifted from the deep ocean to the surface.

The study relied on ocean data obtained by a research vessel that surveyed the marginal seas (the Okhotsk Sea and the Bering Sea) where, the group believed, large-scale mixture of seawater occurs due to the interaction of tidal currents with the rough topography. This voyage was made in collaboration with a Russian research team because many of the areas surveyed fall inside Russia's exclusive economic zone. The obtained data was then combined with data collected by Japanese research vessels.

Analysis of the data showed that nitrate and phosphate re-produced through microbial degradation of organic substances accumulate in high concentrations in intermediate water in the entire subpolar Pacific region.

The researchers also found that the vertical mixing magnitude near the Kuril Islands and the Aleutian Islands is far stronger than that in the surrounding open seas. This study demonstrated that large-scale vertical mixing in the marginal seas breaks the density stratification to mix ocean water, transporting nutrients from the intermediate water to the surface.

"Our findings should help deepen understanding about the circulation of carbon and nutrients in the ocean and ecological changes caused by climate change," says Associate Professor Jun Nishioka of Hokkaido University, who led the study.

A key component of the Gulf Stream has markedly slowed over the past century--that's the conclusion of a new research paper in Nature Communications published on August 7. The study develops a method of tracking the strength of near-shore ocean currents using measurements made at the coast, offering the potential to reduce one of the biggest uncertainties related to observations of climate change over the past century.

"In the ocean, almost everything is connected," said Christopher Piecuch, an assistant scientist in the Physical Oceanography Department at the Woods Hole Oceanographic Institution (WHOI) and author of the study. "We can use those connections to look at things in the past or far from shore, giving us a more complete view of the ocean and how it changes across space and time."

Piecuch, who specializes in coastal and regional sea level change, used a connection between coastal sea level and the strength of near-shore currents to trace the evolution of the Florida Current, which forms the beginning of the Gulf Stream. The Gulf Stream flows north along the Southeast Atlantic Coast of the United States and eventually east into the North Atlantic Ocean, carrying heat, salt, momentum, and other properties that influence Earth's climate. Because nearly continuous records of sea level stretch back more than a century along Florida's Atlantic Coast and in some parts of the Caribbean, he was able to use mathematical models and simple physics to extend the reach of direct measurements of the Gulf Stream to conclude that it has weakened steadily and is weaker now than at any other point in the past 110 years.

One of the biggest uncertainties in climate models is the behavior of ocean currents either leading to or responding to changes in Earth's climate. Of these, one of the most important is the Atlantic Meridional Overturning Circulation, or AMOC, which is a large system or "conveyor belt" of ocean currents in the Atlantic that includes the Gulf Stream and that helps regulate global climate. Piecuch's analysis agrees with relationships seen in models between the deeper branches of the AMOC and the Gulf Stream, and it corroborates studies suggesting that the deeper branches of AMOC have slowed in recent years. His method also offers the potential to monitor ocean currents like the Gulf Stream from the coast, complementing existing but difficult-to-maintain moored instruments and expensive research cruises.

"If we can monitor something over the horizon by making measurements from shore, then that's a win for science and potentially for society," said Piecuch.

As the most abundant constituent in Earth's atmosphere, dinitrogen (N2) is the main nitrogen source of N-containing compounds in the Earth. Therefore, N2 fixation and activation are essential both for nature and humans. Nevertheless, the high bond dissociation energy (942 kJ/mol) and large HOMO-LUMO gap (10.82 eV) make N2 exhibit extremely low reactivity and be regarded as an inert gas.

Currently, the N2 activation and conversion in nature and industry mainly rely on two pathways, in which ammonia (NH3) is the product. In nature, nitrogenase metalloenzymes transfer N2 into NH3 at ambient temperature and pressure. In industry, more than 170 million metric tons of NH3 is produced from the Haber-Bosch process annually, in which N2 reacts with dihydrogen (H2) under harsh condition in the presence of metal catalysts. This NH3 synthesis process consumes about 1-2% of the world's annual energy supply along with the huge CO2 emission.

Compared to NH3-based N2 fixation process, an alternative route of N2 fixation is the direct conversion of N2 into N-containing organic compounds under mild condition. This approach is always targeted because it provides the potential solution to develop a sustainable system with reduced fossil-fuel requirements.

In a new review published in the National Science Review, Zhenfeng Xi et al. summarize the previous works of transition-metal mediated direct conversion of N2 into organic compounds via N-C bond formation at metal dinitrogen complexes. The review is organized by the coordination modes of the complexes (end-on, side-on, end-on-side-on, etc.) that are involved in the N-C bond formation steps, and each part is arranged in terms of reaction types (N-alkylation, N-acylation, cycloaddition, insertion, etc.) between metal dinitrogen complexes and carbon-based substrates. Besides, earlier works on one-pot synthesis of organic compounds from N2 via ill-defined intermediates are also briefed by the authors.

Besides the homogeneous stoichiometric thermochemical reaction systems, the sporadically reported syntheses involving photochemical, electrochemical, heterogeneous thermo-catalytic reactions are also discussed in this overview.

In the review, the authors point out that some synthetic cycles about direct conversion of N2 into organic compounds have also been developed in recent decades. However, all of these reactions are stoichiometric and the catalytic system for the direct introduction of N2 into organic compounds has not been realized yet. The main factors that prevent these complete synthetic cycles from becoming catalytic process are the rigorous reaction conditions of the N-C bond formation and N-containing organic compounds releasing steps in these cycles, which are incompatible with the preparation steps for metal dinitrogen complexes.

To provide readers with perspectives of future research particularly in direct catalytic and efficient conversion of N2 into N-containing organic compounds under mild conditions, the authors likewise outline the potential development directions. They forecast that the research topics of "new reaction types and systems for N-C bond formation", "polynuclear metal species cooperative N2 scission and functionalization", "main group elements promoted N-C bond formation", "photochemistry and electrochemistry involved N-C bond formation", "heterogeneous catalysis systems for conversion of N2 into organic compounds" would get more attention in the future.

Baltimore, MD-- New work led by Carnegie's Meredith Wilson and Steve Farber identifies a potential therapeutic target for clogged arteries and other health risks that stem from an excess of harmful fats in the bloodstream. Their findings are published by PLOS Genetics.

"Cardiovascular disease occurs when lipids from the blood plasma are deposited in the walls of blood vessels, ultimately restricting blood flow," explained Farber, who specializes in elucidating how cells process lipids. "This complex disease affects about a third of the world's population, so improving our understanding of the mechanisms that regulate the levels of blood lipids has important public health implications."

Fat molecules, also called lipids, such as cholesterol and triglycerides are shuttled around the circulatory system by a protein called Apolipoprotein-B, or ApoB for short. These complexes of lipid and protein are called ApoB-containing lipoproteins and are essential for transporting lipids from the intestine and liver to the tissues of the body. However, because they can also cause cardiovascular disease, they are commonly known as "bad cholesterol."

In this new research, Wilson, Farber and their colleagues--including Carnegie's Aidan Danoff, Monica Hensley, Vanessa Quinlivan, James Thierer and Frederick Tan--focused on a protein that is critical for the synthesis of ApoB-containing lipoproteins. This protein, called MTP, or microsomal triglyceride transfer protein, is highly conserved in animals, from insects to humans. MTP loads lipids onto ApoB, a key initial step in the synthesis of ApoB-containing lipoproteins.

Normally, MTP can transfer different types of lipids to ApoB, including triglycerides, which are a major source of energy, and phospholipids, the building-blocks of membranes in the cell. However, the researchers revealed for the first time a mutation in MTP that blocks the loading of triglycerides, but not phospholipids, onto ApoB.

"The separation of these two transfer functions was unexpected and is important, because high triglyceride levels in lipoproteins are correlated with bad clinical outcomes like diabetes and heart disease," said lead author Wilson.

Previously identified mutations in MTP that prevent both transfer functions of the protein cause a malabsorption syndrome, in which the intestines have difficulty absorbing fats and fat-soluble vitamins from the diet. This can result in gastrointestinal distress or more serious problems, such as malnutrition or severe weight loss. However, zebrafish with this newly identified mutation do not exhibit malabsorption or growth defects, because they can still transfer phospholipids to make ApoB-containing lipoproteins.

For years, MTP has been considered a possible therapeutic target to help lower triglyceride levels in the blood and prevent cardiovascular disease. However, the existing chemical inhibitors of MTP are too effective and block all MTP function, which can cause intestinal fat malabsorption and a dangerous accumulation of fat in the liver.

"Our study opens the door for the design of more specific MTP inhibitors that mimic this new mutation and selectively block triglyceride transfer to ApoB," concluded Wilson. "Our data suggests that this type of inhibitor could reduce circulating triglyceride levels without the risk of unpleasant and serious side effects in the intestine and liver."

EUGENE, Ore. - Aug. 7, 2020 - Young children naturally like sugar and salt in food and develop food preferences based on what their parents serve them, but new research suggests that how parents view self-regulation also is a contributing factor.

Food systems with calorie-dense and nutrient-poor meal offerings are a major factor contributing to global obesity and are a major challenge to parents of young children, notes study lead author T. Bettina Cornwell, Phillip H. Knight Chair and head of the Department of Marketing in the University of Oregon's Lundquist College of Business.

The research, published online ahead of print in the Journal of Public Policy & Marketing, explored the underlying dynamics of parental food preferences and how they are passed along to children by example at family mealtime.

"A parent's preference for sugar, fat and salt in their diet influences the amount of junk food they provide children in a typical week and in turn, this influences the child's preference for sugar, fat and salt," Cornwell said. "We show that regularly providing three- to five-year-old children with junk food influences their preferences for the same tastes. It also makes them less willing to eat vegetables."

In the research, the four-member team developed two studies to explore how rigidly set parents are toward strategies of growth, learning and toward self-control. These mindsets, or lay theories, underlie everyday ideas about behavior, Cornwell said. At play is how limited or unlimited self-control is seen and whether it is fixed or malleable.

In the first study, researchers used self-report surveys from the parents of 81 preschool children to assess whether the frequency of exposure to junk food helps transmit parental tastes to the children. A solid connection was found, Cornwell said.

The second study dug deeper to see if parents' lay theories influenced how often parents exposed their children to junk food and what their children ate at school. Researchers drew from survey responses from 122 parent-children pairs and direct observations of preschoolers choosing vegetables during their lunchtime.

Again, the researchers identified strong results. Children who were often exposed to fast and highly processed food at home were less likely to eat vegetables at preschool.

"A parent's preference for sugar, fat and salt in their diet as well as their views of self-control come together to influence their choice to regularly give a child junk food," Cornwell said. "Parents with a lower preference for sugar, fat and salt and with a growth mindset regarding developing self-control tend to limit the amount of junk food they provide to their children."

The overall findings, Cornwell said, are clear: What parents do at home when it comes to meal selection influences the food choices their children make away from home.

Parents, she said, should explore their own beliefs about self-control to understand how they influence their children's developing food preferences. Doing so, she said, may help parents improve their own diets in a way that benefits how their children eat.

There also are implications for the food industry.

Food manufacturers and brand managers, meanwhile, need to recognize that their heavy reliance on hyperpalatable products - those high in fat, salt and sugars that combine to override the ability to control consumption - often make it hard for children meet guidelines for healthy daily diets.

"Eating even a single fast food or processed meal as currently found in the marketplace makes it hard, if not impossible, for children to fall within the U.S. dietary guidelines for the entire day," Cornwell said. "Products should be reformulated to be less hyperpalatable and new healthier products should be developed.

As part of attempts to curtail the Covid-19 pandemic, paper masks are increasingly being made mandatory. Their relative effectiveness is no longer in question, but their widespread use has a number of drawbacks. These include the environmental impact of disposable masks made from layers of non-woven polypropylene plastic microfibres. Moreover, they merely trap pathogens instead of destroying them. "In a hospital setting, these masks are placed in special bins and handled appropriately," says László Forró, head of EPFL's Laboratory of Physics of Complex Matter. "However, their use in the wider world - where they are tossed into open waste bins and even left on the street - can turn them into new sources of contamination."

Researchers in Forró's lab are working on a promising solution to this problem: a membrane made of titanium oxide nanowires, similar in appearance to filter paper but with antibacterial and antiviral properties.

Their material works by using the photocatalytic properties of titanium dioxide. When exposed to ultraviolet radiation, the fibers convert resident moisture into oxidizing agents such as hydrogen peroxide, which have the ability to destroy pathogens. "Since our filter is exceptionally good at absorbing moisture, it can trap droplets that carry viruses and bacteria," says Forró. "This creates a favorable environment for the oxidation process, which is triggered by light."

The researchers' work appears today in Advanced Functional Materials, and includes experiments that demonstrate the membrane's ability to destroy E. coli, the reference bacterium in biomedical research, and DNA strands in a matter of seconds. Based on these results, the researchers assert - although this remains to be demonstrated experimentally - that the process would be equally successful on a wide range of viruses, including SARS-CoV-2.

Their article also states that manufacturing such membranes would be feasible on a large scale: the laboratory's equipment alone is capable of producing up to 200 m2 of filter paper per week, or enough for up to 80,000 masks per month. Moreover, the masks could be sterilized and reused up a thousand times. This would alleviate shortages and substantially reduce the amount of waste created by disposable surgical masks. Finally, the manufacturing process, which involves calcining the titanite nanowires, makes them stable and prevents the risk of nanoparticles being inhaled by the user.

A start-up named Swoxid is already preparing to move the technology out of the lab. "The membranes could also be used in air treatment applications such as ventilation and air conditioning systems as well as in personal protective equipment," says Endre Horváth, the article's lead author and co-founder of Swoxid.

Scientists have unveiled a correlation between high blood lead levels in children and methylation of genes involved in haem synthesis and carcinogenesis, indicating a previously unknown mechanism for lead poisoning.

Lead poisoning is a well-documented disease, the incidence of which has drastically reduced since the use of lead has been curtailed. Nevertheless, many areas across the world still have unsafe levels of lead in the environment. Lead poisoning causes symptoms such as abdominal pain, kidney failure and infertility, among others, but the most damaging effects are seen in children, where it causes neurological and developmental deterioration; however, a number of mechanisms behind it have been elusive.

In the current work, published in the journal Environmental Research, scientists at Hokkaido University collaborated with colleagues at the University of Zambia to investigate blood lead levels in 140 children aged 2 to 10 years in Kabwe, Zambia. Children were chosen from townships close to and distant from an old, highly polluted lead-zinc mine. According to a survey conducted by the Blacksmith Institute (now, Pure Earth), due to this mine, Kabwe was considered one of the 10 most polluted places on Earth in 2013.

Blood lead levels were measured in all children. The scientists discovered that children living closer to the mine had blood levels that were three times higher than that of children living further away. They then used a technique called methylation-specific polymerase chain reaction (MSP) to determine the methylation of the DNA sequences. Methylation is a process by which methyl (CH3) groups are added to DNA; this modification generally causes the activity of genes to reduce.

Increased blood lead levels correlated positively with aberrant, increased methylation of DNA responsible for the expression of genes. The genes affected were ALAD, which synthesizes a key compound in the development of red blood cells; and p16, a tumour suppressor gene, which is frequently inactivated in different types of cancer.

This study has established the correlation between blood lead levels and aberrant methylation of DNA. It has also revealed a major healthcare issue in children in the region. Future work in this area would involve large-scale studies to determine the true extent of lead poisoning, as well as setting up an effort to provide children in the region with the necessary care and treatment. "The ultimate goal is," Dr. Yohannes says, "to achieve a lead-free population to ensure a healthy future."

Dr. Yared B. Yohannes, Assistant Professor Shouta Nakayama, and Professor Mayumi Ishizuka from the Laboratory of Toxicology were the key contributors to this research. The laboratory has been studying lead poisoning in Kabwe for over half a decade. Their research is part of ongoing collaborations with eight African countries on the project Clarification of the Effect of Continued Environmental Contamination in Africa on Humans and Animals.

One in four puppies in the UK may be being acquired before the recommended minimum age--a figure that is considerably higher than what has been reported before--suggests research published in the latest edition of Vet Record.

Separating a puppy from its mother too early may have long-term consequences on physiological and behavioural development that risks behavioural problems later in life, a major reason why dogs are given up or left in shelters, warns the author of a linked comment.

In the UK many welfare and veterinary organisations, such as the Animal Welfare Foundation, Blue Cross, PDSA and the Dogs Trust, recommend that puppies shouldn't be separated from their mothers until they are at least 8 weeks (56 days) old. There are legal restrictions on selling a puppy under this age in the UK.

Their guidance also recommends that prospective buyers should view the puppy with its mother, and this has been enshrined in English law since 2018.

The researchers wanted to find out if particular factors were associated with the acquisition of puppies under the age of 8 weeks and without viewing the puppy's mother.

They drew on data for 2392 puppies collected between May 2016 and February 2019 as part of 'Generation Pup', a long term UK study of dog health, behaviour, and welfare.

The data were obtained from three questionnaires, with details around the process of acquisition completed by owners before or after they had acquired their puppy. In all, 1844 puppies were eligible for inclusion in the final analysis.

The responses showed that 1 in 4 (461) puppies had been acquired before they were 8 weeks old, a proportion that is considerably higher than what has been reported before. Around 1 in 12 (149; just over 8%) had been acquired without viewing the puppy's mother. Just 30 (just over 1.5%) had been acquired under 8 weeks of age and without viewing the mother.

Five factors were independently associated with acquisition of an 'under age' puppy.

Owners who visited their puppy at least once before taking it home were more likely to acquire the animal before it was 8 weeks old. This might be because they couldn't bear to leave without taking the puppy home, or because they felt the puppy was old enough, suggest the researchers, by way of an explanation.

Owners who intended to use their puppy as a working dog, such as for herding animals, pest control, work in the police or military, as a search and rescue, or guard dog were also more likely to acquire their puppy before it was 8 weeks old. This might be because they wanted to start training the puppy as soon as possible, say the researchers.

The analysis also revealed that the odds of early acquisition increased in tandem with the number of dogs already in the household and if the dog was a mix of unknown breeds.

"Mixed breed puppies may be more likely to have been bred by a hobby breeder than a licensed breeder, or be a result of accidental mating," suggest the researchers. "Hobby breeders do not need to conform to the same selling restrictions as licensed breeders."

At the other end of the spectrum, the likelihood of acquiring a puppy under the recommended age fell as the level of annual household income rose.

Similarly, owners who visited their puppy before taking it home, or bought a puppy registered with the Kennel Club, or who viewed the puppy's father and/or collected the puppy from the breeder's home, had lower odds of acquiring a puppy without viewing the mother.

The researchers suggest that prospective owners may be more aware of the recommendations to view the puppy with its mother than those around the recommended minimum age.

Their findings might help target specific owners, "with educational or media campaigns that could decrease the proportion of puppies acquired in this way in the future," they conclude.

In a linked research comment, vet Dr Federica Pirrone, University of Milan, Italy, emphasised the importance of the guidance and regulations.

"Early separation of a puppy from its mother and littermates is a husbandry strategy that may increase the animal's chances of exhibiting potentially problematic behaviours as an adult," she warns.

"The occurrence of problematic behaviours is the most common reason why dogs are relinquished, abandoned or, in countries where it is allowed, even euthanased."

Early separation impairs early brain development which restricts the ability of puppies to adapt to new stimuli and to develop good social skills as adults. They are highly likely to exhibit fear and anxiety-related behaviours as adults, which are then often perceived by owners as problematic, she explains.

Similarly, she emphasises: "Seeing the mother before buying a puppy enables the prospective owner to ascertain that she is unstressed and free from behavioural problems, which in turn helps predict that the puppy will not develop behavioural problems later in life."

"It is, therefore, essential to encourage prospective owners to be well informed regarding dog behaviour and to be aware of the importance of correct socialisation," she says.

Daniella Dos Santos, British Veterinary Association President, commented: "There are very good reasons why puppies shouldn't leave their mother before they're eight weeks old. Rehoming from this age means puppies are fully and correctly weaned, and staying with their mother in early development plays a vital role in social and behavioural development.

"Prospective puppy buyers should always ask to view them alongside their mother first and we strongly recommend using the free Puppy Contract to make sure that they're getting a happy, healthy and well-socialised animal from a reputable breeder or rehoming centre."