Culture

Newly identified gene reduces pollen number of plants

image: The plant species Arabidopsis thaliana is used as a model organism in research all over the world.

Image: 
Misako Yamazaki

Already in the 19th century Charles Darwin recognized that the number of male gametes - pollen for plants, sperm for animals - is highly variable among individuals and species. At first sight a high number of male gametes seems beneficial for the competition among males to produce more offspring. However, many domesticated species have a reduced number of male gametes. In theory it might be advantageous to reduce the cost of producing male gametes, for example when the rate of self-fertilization or inbreeding is high and fewer male gametes are necessary for successful reproduction.

Genome analysis of self-fertilizing plant

"So far there has been little evidence to support this idea, because the production of male gametes is a complex trait affected by many genes with small effects and its molecular basis remained unknown", says Kentaro Shimizu, Professor for Evolutionary Biology and Environmental Studies at the University of Zurich (UZH). An international study under his lead now provides such evidence and demonstrates that a reduction in pollen number is not necessarily deleterious but rather advantageous in a self-fertilizing species.

For their investigation the researchers used the well-characterized model plant Arabidopsis thaliana that is mainly self-fertilizing and has a reduced number of pollen grains compared to its relatives in the wild. They counted the pollen number of 144 plants with distinct genetic background and found variations from 2,000 to 8,000 pollen grains per flower. They then compared the entire genetic information of these variants, looking for differences between plants with higher and lower pollen numbers.

RDP1 gene controls pollen production

This computational analysis, a so-called genome-wide association study, revealed one gene that affects the number of pollen each plant produces, which was subsequently named REDUCED POLLEN NUMBER1 (RDP1) gene. Using the novel genome editing technology CRISPR-Cas9 the researchers created several mutant variants of the RDP1 gene, both in plants with high and low pollen number. They crossed the mutated plants with each other and counted the pollen the hybrid offspring produced. "These experiments confirmed the subtle but significant effect of the RDP1 gene", says co-author Misako Yamazaki, a technical staff of the Shimizu group. A comparison with other organisms revealed that the gene encodes a factor that promotes the building of ribosomes, the cellular factories for protein production.

Less pollen confers higher fitness

Next, the team investigated if the reduction in pollen number is positively selected for and did not happen incidentally. For this they used a statistical method to gain insight into the evolution of the RDP1 gene within model plants with different pollen production. The results showed that the trait for reduced pollen number has indeed been under positive selection.

Furthermore, the research team studied the evolution of the many genomic regions associated with pollen number. The selection on pollen number was very strong - in comparison to previous studies of more than 100 traits such as disease-resistance and environmental responses. This supports the importance of pollen number for reproductive success.

Optimizing fertilization in agriculture

"The evidence supports the theoretical prediction that reduced investment in male gametes is advantageous. This is not only important for evolutionary biology but also for the practice of plant breeding and domestication in general", explains Shimizu. "Many crop plants have a reduced number of pollen due to domestication. Lowering the cost of producing pollen may increase crop yield. On the other hand, too few pollen grains might be an obstacle to breeding and seed production. Our study opens the way for molecular breeding of the optimal pollen number."

Credit: 
University of Zurich

Protected areas worldwide at risk of invasive species

image: American mink (Neovison vison) was found in 1,251 protected areas such as Cairngorms National Park in the UK, where this photo was taken

Image: 
Professor Tim Blackburn, UCL

Protected areas across the globe are effectively keeping invasive animals at bay, but the large majority of them are at risk of invasions, finds a China-UK research team involving UCL.

The research, led by the Chinese Academy of Science and published in Nature Communications, show that for most protected areas, there is an invasive animal species living less than 10km away that is well suited to the protected area's environment.

Co-author Professor Tim Blackburn (UCL Genetics, Evolution & Environment and the Institute of Zoology, ZSL) said: "One of the most harmful ways that people are impacting the natural environment is through the introduction of 'aliens' - species that do not occur naturally in an area, but have been taken there by human activities.

"These species may kill or compete with native species, or destroy habitats, amongst other impacts. Invasions by alien species are regarded as one of the top five direct drivers of global biodiversity loss, and aliens are establishing themselves in new areas at ever increasing rates. Protected areas are a cornerstone of biodiversity conservation, but aliens don't know where their boundaries lie. It's important to know whether these areas might protect against the spread of invasive species."

The researchers investigated 894 terrestrial animal species (including mammals, birds, reptiles and invertebrates) that are known to have established alien populations somewhere in the world.

They then assessed whether these species occurred within, or near, the boundaries of 199,957 protected areas across the globe, as defined by the International Union for Conservation of Nature (IUCN), including wilderness areas, national parks, and natural monuments or features.

The team found that less than 10% of the protected areas are currently home to any of the invasive species surveyed, suggesting that protected areas are generally effective in protecting against invasive species.

But almost all of those areas may be at risk of invasion, as an invasive species was found within 100km of the boundaries of 99% of the protected areas. For 89% of the protected areas, there was an alien species resident within 10km of the boundaries.

More than 95% of the protected areas were deemed to be environmentally suitable for the establishment of at least some of the alien species under investigation.

The researchers also investigated common factors among the protected areas that are already home to alien species. They found that protected areas tend to have more alien animal species if they have a larger human footprint index, due to factors such as transport links and large human populations nearby.

The researchers also found that larger, and more recently established protected areas, tend to have more alien species. Older protected areas tend to be in more remote areas, so they are less exposed to human impacts.

Senior author Dr Li Yiming (Institute of Zoology, Chinese Academy of Sciences) said: "At the moment most protected areas are still free of most animal invaders, but this might not last. Areas readily accessible to large numbers of people are the most vulnerable."

"We need to increase efforts to monitor and record invasive alien species that people may bring into protected areas, deliberately or by accident, especially damaging species like the American bullfrog, brown rat and wild boar."

The findings do not suggest that the rich existing biodiversity in protected areas acts as a barrier to invasions, as they found mixed evidence on the relationships between existing native biodiversity and presence of invasive species.

Professor Blackburn concluded: "If alien species continue to spread - and we would expect many to do that - many more protected areas will have their boundaries reached, and potentially breached, by these alien species."

Credit: 
University College London

Advances in the production of minor ginsenosides using microorganisms and their enzymes

Advances in the Production of Minor Ginsenosides Using Microorganisms and Their Enzymes - BIO Integration

https://bio-integration.org/wp-content/uploads/2020/05/bioi20200007.pdf

Announcing a new article publication for BIO Integration journal. In this review article the author Almando Geraldi from the Universitas Airlangga, Indonesia considers the advances in the production of minor ginsenosides using microorganisms and their enzymes.

In this review, various minor ginsenosides production strategies, namely utilizing microorganisms and recombinant microbial enzymes, for biotransforming major ginsenosides into minor ginsenoside, as well as constructing synthetic minor ginsenosides production pathways in yeast cell factories, are described and discussed. The present challenges and future research direction for producing minor ginsenosides using those approaches are considered.

Minor ginsenodes are of great interest due to their diverse pharmacological activities such as their anti-cancer, anti-diabetic, neuroprotective, immunomodulator, and anti-inflammatory effects. The miniscule amount of minor ginsenosides in ginseng plants has driven the development of their mass production methods. Among the various production methods for minor ginsenosides, the utilization of microorganisms and their enzymes are considered as highly specific, safe, and environmentally friendly.

BIO Integration is fully open access journal which will allow for the rapid dissemination of multidisciplinary views driving the progress of modern medicine.

As part of its mandate to help bring interesting work and knowledge from around the world to a wider audience, BIOI will actively support authors through open access publishing and through waiving author fees in its first years. Also, publication support for authors whose first language is not English will be offered in areas such as manuscript development, English language editing and artwork assistance.

Credit: 
Compuscript Ltd

Super-cooled metallic ammonia gives clues about electron behavior

Buried deep within the varied properties of metals, there is a fundamental question up for grabs: What makes it a metal? In other words, which properties are inherent to a metal and which are incidental?

Scientists at USC Dornsife College of Letters, Arts and Sciences, collaborating with an international group of researchers, have helped further define what constitutes a metal. In the process, they open the door for organic chemists to improve the synthesis of useful compounds.

The study appears on the cover of the journal Science on June 5.

Going full metal

Intuition suggests that metals are dense, and while that bears true for some (think gold or lead), it fails to hold up for others. For example, lithium -- commonly used in batteries -- floats on water. Some metals are hard, such as titanium, yet others yield easily to pressure, including indium and aluminium. How about melting temperature? Platinum melts at more than 1,700 degrees Celsius (3,200 F), but mercury is a liquid well below zero.

Many other definitions of 'metal-hood' suffer similar contradictions, but British physicist and Nobel laureate Sir Nevill Mott provided one inherent property: "I've thought a lot about 'What is a metal?' and I think one can only answer the question at T = 0. There a metal conducts, and a non-metal doesn't."

Only metals are able to conduct electricity at absolute zero, the temperature at which even molecular motion all but stops. Conduction, unlike density or hardness, is an inherent property of metals.

Seeking to further understand the intrinsic properties of metals, the USC Dornsife scientists, led by Stephen Bradforth, professor of chemistry and divisional dean for natural sciences and mathematics, and their colleagues used a trick first noted by chemist Sir Humphry Davy in 1809. In essence, they made a metal from scratch.

The scientists cooled ammonia -- normally a gas at room temperature -- to minus 33 C to liquify it and then added, in separate experiments, the alkali metals lithium, sodium and potassium.

In these solutions, electrons from the alkali metal initially become trapped in the gaps between ammonia molecules. This creates what scientists call 'solvated electrons,' which are highly reactive but stabilized in the ammonia. These solutions have a characteristic blue color. Given enough solvated electrons (by adding about 1% alkali metal to the ammonia) the whole liquid turns bronze and, in essence, becomes a metal while remaining liquid.

Solvated electrons have proven to be extremely important to organic chemists. Through a reaction called the "Birch reduction," named after chemist Arthur Birch, they were key to synthesizing many important compounds and led to the manufacture of oral contraceptives in the 1950s.

Beaming in on electrons

The scientists next measured the amount of energy needed to bump the solvated electrons out of metallic ammonia using an X-ray beam. In a first-ever experiment, they forced different concentrations of the metallic ammonia through a microjet, which creates a stream about the width of a human hair that then passes through a hair-thin X-ray beam. Electrons interacting with the X-rays become dislodged.

The results show that, at low concentrations, solvated electrons are more easily dislodged from the solution by the interaction with the X-rays, giving a simple energy pattern. At higher concentrations, though, the energy pattern suddenly develops a sharp band edge, indicating the solution is behaving as a metal would.

Most important, however, the experiment presents a way for researchers to assess the behavior of solvated electrons in ammonia when other compounds are introduced to the mix. This opens a new window for chemists to synthesize important organic compounds, going well beyond Birch's experiments.

"This is the sort of things that goes in textbooks, or at least changes how textbooks are written," Bradforth said, noting the potentially historic importance of the work.

The work allows scientists to understand exactly how chemicals react with metallic ammonia, in essence giving the researchers a frame-by-frame view of what's happening in the test tube. Armed with this information, chemists can alter conditions to ensure they produce exactly the desired end product.

Credit: 
University of Southern California

First systematic report on the tug-of-war between DNA damage and repair

image: Example of base substitutions caused by the mutagen MMS (methyl-methan sulfonate) differ between WT (upper panel) and polk DNA repair defective strains (lower panel), T>A changes (indicted in gray) being increased >30 times.

Image: 
IBS

A collaborative project between the Center for Genome Integrity, within the Institute for Basic Science (IBS, South Korea), and the Dundee School of Life Sciences, the EMBL's European Bioinformatics Institute (EMBL-EBI), and the Wellcome Sanger Institute (UK) have screened almost 163,000 DNA mutations in 2,700 C. elegans roundworms to shed light on DNA damage. The results, published in Nature Communications, lead to the conclusion that mutation patterns seen in cancer are more complicated than we previously thought.

Our genetic material is constantly exposed to possible sources of mutations, including UV light, tobacco smoke and carcinogenic chemicals. These genetic alterations are usually corrected by an army of DNA repair proteins that patrol the DNA and fix its mistakes. However, what happens when the policemen themselves are malfunctioning? They can overlook some DNA alterations, or even generate some mutations while trying to correct them. In this study, researchers looked at mutational signatures - patterns of mutations occurring in the genome - caused by the combined action of 11 known DNA damaging agents and inaccurate DNA repair mechanisms using C. elegans worms as a model system.

"Our paper is the first to use experimental approaches to systematically test, at a genome-wide scale, how DNA damaging agents cause mutations, and how this is prevented by DNA repair proteins," says Anton Gartner, Associate Director of the IBS Center for Genomic Integrity and co-leading author of this study.

While mutagens were thought to generate unique mutational signatures, the results showed a more intricate picture. DNA repair pathways are highly redundant: up to four different repair pathways act together to prevent mutagenesis caused by the same cancer inducing agents. Using roundworms with 53 different DNA repair deficits, the researchers found out that a single mutagen may leave a variety of mutational signatures depending on the faulty repair system.

This study is particularly important because unmended mutations in specific parts of the DNA can lead to cancer. Since fundamental processes, such as DNA repair, are conserved throughout evolution, the team was able to use data derived from C. elegans to scan through thousands of human cancer genome sequences and find possible evidence for mutagenic events linked to faulty DNA repair systems.

Over the past years, mutational signatures of cancer have been deduced from computational analyses. Some of these signatures could be associated with suspected mutagenic causes, such as the exposure to UV light for melanomas, or exposure to aflatoxin for liver cancer. However, the cause of the majority of these mutational signatures observed in cancer is not known. In most cases, it is unclear if there is a direct one-to-one relationship between the mutational signatures and a single mutagen. This paper reports that mutational signatures are due to a combination of factors, 'offending' DNA damaging agents and cellular policemen that properly do their job most of the time, but in some cases allow culprits to escape.

Credit: 
Institute for Basic Science

Sex differences in participation in large-scale genetic studies may affect results

Genome-wide association studies (GWAS) analyse a genome-wide set of genetic variants in different individuals to see if any are associated with a trait or disease. Such studies are getting larger and larger and, in some cases, millions of participants are involved. This means that researchers can see smaller and smaller effects increasing the number of genes they can link to a disease or trait.

&laquoIt is good for us, because it allows us to understand much more about genetics influences our make-up, behaviour, and disease status, » says Dr Andrea Ganna, from the Institute for Molecular Medicine Finland, Helsinki, Finland, who will present his team's research to the 53rd annual conference of the European Society of Human Genetics, being held entirely on-line due to the Covid-19 pandemic, today [Monday]. &laquo But this good news comes with a downside. These large numbers mean that biases can creep in and affect our results. The most difficult of these to control is participation bias - when people who participate in a study are not from a random set but have something in common that is linked to their participation.

&laquoTo give an extreme example, if we were to use the participants in a professional basketball team to understand how tall or fit people are, the results would not be at all representative of the general population. But even low- level participation bias can skew results,» says Dr Ganna.

Recent studies looking at people who have participated more than once in a genetic study have shown a correlation with their level of educational attainment, for example. The researchers set out to characterise better what the consequences of this type of bias were. To do so, they needed a trait that they were certain was not determined genetically on the non-sexual chromosomes and about which they could be sure in advance that no association with those genes existed.
&laquoThe only area where we felt certain that genetics outside the sexual chromosomes was not involved was the genetic differences between males and females," commented co-author Dr Nicola Pirastu, from the University of Edinburgh, Edinburgh, United Kingdom. &laquoTherefore our analyses should have come out completely negative.»
The team carried out an association study of data from over three million individuals1 looking at which genetic variants showed differences in study participation frequencies between males and females. &laquoTo our surprise, we found over 150 loci with such differences. For example, we saw more body mass index-raising alleles2 among men than women, suggesting that genetically higher-weight women were less likely to participate in population studies than men. This can only have been related to differences in the characteristics that drive men and women to participate. And we saw a similar effect in different cohorts, which confirmed our hypothesis,» said Dr Pirastu.

These findings emphasise the importance of scientists' awareness of the necessity of careful study design and the meticulous choices of cases and controls when conducting genetic studies. In order to draw useful conclusions, the risk of participation bias should be minimised. If these kinds of bias exist in a study involving men and women, it will be far more difficult to distinguish between true results and those arising from biases when looking at disease. &laquoFor example, in the recent pandemic we know that those people who have been tested for Covid-19 were not chosen at random and share common characteristics, so making the right choice of controls to be used to understand if there are any genetic determinants involved is very important. I think our study shows what the risks are if this is not done,» says Dr Ganna.

At the moment, all the evidence is that participation biases are mild enough not to be a major problem. But it is important to take them into account when planning the collection of data from large cohorts and when data from participants is collected at multiple time points. Genotyping a random set of the population, for example, from the blood spots collected at birth, would be a good way of further verifying if these biases exist.
&laquoWe have shown that it would allow us to correct the statistical analyses. In addition, it would cost very little in comparison of what it has cost to date to create these studies. We really need to do this if we are to be able to draw the right conclusions from our analyses,» Dr Ganna will conclude.

Chair of the ESHG conference, Professor Joris Veltman, Dean of the Biosciences Institute at Newcastle University, Newcastle upon Tyne, UK, said: "This fascinating study shows us how important it is to be aware of unexpected biases in participation in genetic association studies as well as other large scale 'population' studies, as this can significantly impact results if not properly corrected for."

Credit: 
European Society of Human Genetics

Jodrell Bank leads international effort which reveals 157 day cycle in unusual cosmic radio bursts

image: Artist's impression of an orbital modulation model where the FRB progenitor (blue) is in an orbit with a companion astrophysical object (pink). The type of companion star is not know but models exist which suggest that it could be anything from a black hole to a massive star. Figure credits: Kristi Mickaliger."

Image: 
Kristi Mickaliger

An investigation into one of the current great mysteries of astronomy has come to the fore thanks to a four-year observing campaign conducted at the Jodrell Bank Observatory.

Using the long-term monitoring capabilities of the iconic Lovell Telescope, an international team led by Jodrell Bank astronomers has been studying an object known as a repeating Fast Radio Burst (FRB), which emits very short duration bright radio pulses.

Using the 32 bursts discovered during the campaign, in conjunction with data from previously published observations, the team has discovered that emission from the FRB known as 121102 follows a cyclic pattern, with radio bursts observed in a window lasting approximately 90 days followed by a silent period of 67 days. The same behaviour then repeats every 157 days.

This discovery provides an important clue to identifying the origin of these enigmatic fast radio bursts. The presence of a regular sequence in the burst activity could imply that the powerful bursts are linked to the orbital motion of a massive star, a neutron star or a black hole.

Dr Kaustubh Rajwade of The University of Manchester, who led the new research, said: "This is an exciting result as it is only the second system where we believe we see this modulation in burst activity. Detecting a periodicity provides an important constraint on the origin of the bursts and the activity cycles could argue against a precessing neutron star."

Repeating FRBs could be explained by the precession, like a wobbling top, of the magnetic axis of a highly magnetized neutron star but with current data scientists believe it may be hard to explain a 157-day precession period given the large magnetic fields expected in these stars.

The existence of FRBs was only discovered as recently as 2007 and they were initially thought to be one-off events related to a cataclysmic event such as an exploding star. This picture partly changed once FRB 121102, originally discovered with the Arecibo radio telescope on November 2 2012, was seen to repeat in 2016. However, until now, no one recognised that these bursts were in fact organised in a regular pattern.

Professor Benjamin Stappers, who leads the MeerTRAP project to hunt for FRBs using the MeerKAT telescope in South Africa said: "This result relied on the regular monitoring possible with the Lovell Telescope, and non-detections were just as important as the detections."

In a new paper published in Monthly Notices of the Royal Astronomical Society, the team confirm that FRB 121102 is only the second repeating source of FRBs to display such periodic activity. To their surprise, the timescale for this cycle is almost 10 times longer than the 16-day periodicity exhibited by the first repeating source, FRB 180916.J10158+56, which was recently discovered by the CHIME telescope in Canada.

"This exciting discovery highlights how little we know about the origin of FRBs," says Duncan Lorimer who serves as Associate Dean for Research at West Virginia University and, along with PhD student Devansh Agarwal, helped develop the data analysis technique that led to the discovery. "Further observations of a larger number of FRBs will be needed in order to obtain a clearer picture about these periodic sources and elucidate their origin," he added.

Credit: 
University of Manchester

Great white shark diet surprises scientists

image: GoPro image of a great white shark off east Australian coast at Evans Head, New South Wales.

Image: 
Richard Grainger/University of Sydney

The first-ever detailed study of the diets of great white sharks off the east Australian coast reveals this apex predator spends more time feeding close to the seabed than expected.

"Within the sharks' stomachs we found remains from a variety of fish species that typically live on the seafloor or buried in the sand. This indicates the sharks must spend a good portion of their time foraging just above the seabed," said lead author Richard Grainger, a PhD candidate at the Charles Perkins Centre and School of Life and Environmental Sciences at the University of Sydney.

"The stereotype of a shark's dorsal fin above the surface as it hunts is probably not a very accurate picture," he said.

The study, published today on World Oceans Day in the journal Frontiers in Marine Science, is an important contribution towards understanding the sharks' feeding and migratory habits.

Dr Vic Peddemors a co-author from the NSW Department of Primary Industries (Fisheries), said: "We discovered that although mid-water fish, especially eastern Australian salmon, were the predominant prey for juvenile white sharks in NSW, stomach contents highlighted that these sharks also feed at or near the seabed."

Mr Grainger said: "This evidence matches data we have from tagging white sharks that shows them spending a lot of time many metres below the surface."

The study examined the stomach contents of 40 juvenile white sharks (Carcharodon carcharias) caught in the NSW Shark Meshing Program. The scientists compared this with published data elsewhere in the world, mainly South Africa, to establish a nutritional framework for the species.

"Understanding the nutritional goals of these cryptic predators and how these relate to migration patterns will give insights into what drives human-shark conflict and how we can best protect this species," said Dr Gabriel Machovsky-Capuska, an adjunct Senior Research Fellow at the Charles Perkins Centre and a co-author of the study.

Mr Grainger said: "White sharks have a varied diet. As well as east Australian salmon, we found evidence of other bony fish including eels, whiting, mullet and wrasses. We found that rays were also an important dietary component, including small bottom-dwelling stingrays and electric rays.

"Eagle rays are also hunted, although this can be difficult for the sharks given how fast the rays can swim."

The study found that based on abundance, the sharks' diet relied mostly on:

- Pelagic, or mid-water ocean swimming fish, such as Australian salmon: 32.2%

- Bottom-dwelling fish, such as stargazers, sole or flathead: 17.4%

- Reef fish, such as eastern blue gropers: 5.0%

- Batoid fish, such as stingrays: 14.9%

The remainder was unidentified fish or less abundant prey. Mr Grainger said that marine mammals, other sharks and cephalopods (squid and cuttlefish) were eaten less frequently.

"The hunting of bigger prey, including other sharks and marine mammals such as dolphin, is not likely to happen until the sharks reach about 2.2 metres in length," Mr Grainger said.

The scientists also found that larger sharks tended to have a diet that was higher in fat, likely due to their high energy needs for migration.

"This fits with a lot of other research we've done showing that wild animals, including predators, select diets precisely balanced to meet their nutrient needs," said co-author Professor David Raubenheimer, Chair of Nutritional Ecology in the School of Life and Environmental Sciences.

Tracking of white sharks shows that they migrate seasonally along Australia's east coast from southern Queensland to northern Tasmania, and the range of movement increases with age.

Protecting this species and safely managing its interactions with humans is a priority for scientists and the NSW Department of Primary Industries.

"This study will give us a lot of information to assist in this management process," Dr Peddemors said.

Credit: 
University of Sydney

Hope for patients with primary hyperoxaluria type 1

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited disorder that begins in childhood and adolescence. Various defects in the enzyme alanine-glyoxylate aminotransferase cause an overproduction of oxalate in the liver, which is excreted in the urine (hyperoxaluria). It leads to the formation of recurrent kidney stones, renal calcification (nephrocalcinosis) and kidney injury, even kidney failure; many such patients require dialysis even before they reach adulthood. It can be managed prophylactically by drinking large amounts of fluids (2-3 litres), but this is not tolerated by smaller children, especially. Hardly any effective therapies have been available so far. In some patients, the administration of vitamin B6 (pyridoxine) can reduce oxalate excretion. Another basic therapy is to administer alkali citrate, as this improves the solubility of oxalate in urine, but no currently available treatment addresses the cause of the disease.

Lumasiran, a subcutaneously administered investigational RNAi therapeutic, could close that gap. RNA interference (RNAi) is a natural biological gene silencing mechanism. Lumasiran silences the HAO1 gene that encodes the liver enzyme GO, thereby inhibiting hepatic production of oxalate - the metabolite that directly contributes to the clinical manifestations of PH1.

At the ERA-EDTA Congress today, the results of a randomized, double-blind, placebo-controlled Phase 3 study were presented. 39 patients (age?6 years, 24hr urinary oxalate (UOx)?0.70 mmol/24hr/1.73 m2, confirmed PH1 diagnosis, eGFR?30 mL/min/1.73 m2) were randomized (2:1) and received either the investigational RNAi therapeutic or placebo once a month for 3 months followed by dosing once every 3 months. Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline after 6 months was -65.4% with lumasiran and -11.8% with placebo (LS mean difference: ?53.5%; p=1.7×10?14). Lumasiran treatment also resulted in a majority of patients achieving near-normalization (84%) or normalization (52%) of urinary oxalate (versus 0% of those treated with placebo), and reductions in mean plasma oxalate relative to placebo. The most common adverse events related to lumasiran were injection-site reactions, all of which were mild and transient; no severe or serious adverse events were reported.

"Lumasiran resulted in rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels and had an encouraging safety profile", concluded Sander Garrelfs from the Emma Children's Hospital, Amsterdam UMC, University of Amsterdam.

"We were very impressed by these results", added Maria Jose Soler Romeo, Chair of the Paper Selection Committee of the 2020 ERA-EDTA Congress. "It is now necessary to demonstrate that the drug not only reduces the overproduction of oxalate effectively, but can also prevent long-term injury to the kidneys. If that is the case, we will finally have a treatment for children and young people who are affected by this rare disease that prevents them from needing dialysis."

Credit: 
ERA – European Renal Association

Rethinking the US food system

The COVID-19 pandemic and resulting economic shutdowns have severely disrupted and spotlighted weaknesses in the U.S. food system. Farmers, food distributors and government agencies are working to reconfigure supply chains so that food can get to where it’s needed.

Ultrastable, selective catalyst for propane dehydrogenation developed

image: On the surface of the newly developed catalyst (PtGa-Pb/SiO2), Pt1 sites remain exposed to facilitate catalytic reaction while Pt3 sites (and Ga3 sites) shown with triangles are blocked by Pb. (Yuki Nakaya, et al., Nature Communications, June 5, 2020)

Image: 
Yuki Nakaya, et al., Nature Communications, June 5, 2020

A group of Japanese scientists has developed an ultrastable, selective catalyst to dehydrogenate propane - an essential process to produce the key petrochemical substance of propylene - without deactivation, even at temperatures of more than 600°C.

Propylene is an important raw material for plastics, synthetic rubber, surfactants, dyes and pharmaceuticals. In recent years, there has been an increased demand for propylene produced from cheaper, shale-originated propane. Reaction temperatures of more than 600°C are necessary to obtain sufficient propylene yields, but under these harsh conditions, severe catalyst deactivation is inevitable due to carbon deposition and/or sintering. Catalysts in practical use, therefore, must be regenerated either continuously or in short cycles, making the process inefficient and costly.

In the present study, the group, including a master's student Yuki Nakaya and Associate Professor Shinya Furukawa at Hokkaido University's Institute for Catalysis, focused on the intermetallics (PtGa) of platinum (Pt) and gallium (Ga), which have unique properties and structures. PtGa has a high thermal stability and its structure does not change even under high temperatures. It is also known to have two kinds of catalytic sites on its surface: a site with three Pt atoms (Pt3 site) and one with single-atom-like isolated Pt (Pt1 site).

The group hypothesized that if the Pt3 sites - which facilitates carbon deposition in addition to producing propylene - is disabled to allow only the Pt1 sites to function, the catalyst will be ultrastable and also able to prevent carbon deposition. The group tried various metals and catalyst synthesis methods to make only the Pt1 site function.

The newly developed catalyst (PtGa-Pb/SiO2), which is silica-supported and made by adding lead (Pb) to the surface of PtGa, exhibits no deactivation when dehydrogenating propane at 600°C. The catalyst maintained the initial conversion rate of 30 percent for 96 hours after the reaction started, which is significantly more stable than conventional catalysts. Propylene selectivity is as high as 99.6 percent with few side reactions, including carbon deposition. The results showed that this catalyst produces the world's best performance at temperatures of 580°C or higher. In particular, its life span is more than twice as long as the previous reported record longevity for such catalysts. Furthermore, the catalyst can be produced as cheaply as conventional catalysts. Their structural analysis confirmed Pt3 sites, not Pt1 sites, were covered and disabled by Pb, as they expected.

"Our finding could lead to a more efficient and cheaper industrial process to produce propylene from propane without the need for catalyst regeneration - which is far superior in selectivity and stability than conventional ones," says Furukawa. "Moreover, this method could be applicable to dehydrogenation of other lower alkanes such as ethane and isobutane, thus contributing to the petrochemical industry's development."

Credit: 
Hokkaido University

To think like a dinosaur

image: Three-dimensional virtual reconstruction of the braincase of the ankylosaur Bissektipelta archibaldi. Bones are semi-transparent and the internal contents of the endocranial cavity are seen. Pink - inner ear, yellow - nerves, red - major arteries, blue - veins and small arteries, light blue - endocranial cast.

Image: 
Image provided by the authors of the paper.

Palaeontologists from St Petersburg University have been the first to study in detail the structure of the brain and blood vessels in the skull of the ankylosaur Bissektipelta archibaldi. It was a herbivorous dinosaur somewhat similar in appearance to a modern armadillo. The first three-dimensional computer reconstruction of a dinosaur endocast made in Russia - a digital cast of its braincase - was of help to the scientists. It made it possible to find out that ankylosaurs, and Bissektipelta in particular, were capable of cooling their brains, had an extremely developed sense of smell, and heard low-frequency sounds. However, their brain was one and a half times smaller than that of modern animals of the same size.

Ankylosaurs appeared on Earth in the middle of the Jurassic - about 160 million years ago - and existed until the end of the dinosaur era, which ended 65 million years ago. These herbivorous animals were somewhat reminiscent of modern turtles or armadillos, were covered with thick armour, and sometimes even had a bony club on the tail. The researchers became interested in the uniquely-preserved remains of ankylosaurs from Uzbekistan. Although these fossils have been known for 20 years, only now have the scientists had a unique opportunity to study the specimens from the inside using cutting-edge methods.

During the study, the palaeontologists examined three fragments of fossil skulls of the ankylosaur Bissektipelta archibaldi. They were found during a series of international expeditions URBAC (Uzbek / Russian / British / American / Canadian Joint Paleontological Expeditions) in the late 1990s and early 2000s at the Dzharakuduk locality in the Central Kyzylkum Desert, Uzbekistan. The scientists emphasise that it is unique in that numerous remains of various representatives of the ancient fauna (about 90-million-year-old) can be found there. These include dinosaurs, pterosaurs, crocodiles, birds, mammals, and other vertebrates.

'This is really one of the richest locations in the world. The fauna of Dzharakuduk has now more than 100 species of ancient vertebrates,' said Pavel Skutschas, Associate Professor at St Petersburg University and an expert in Mesozoic vertebrates. 'Of course, such a diversity of life would not have been found without large-scale field studies. A series of nine URBAC expeditions, undertaken from 1997 to 2006, pooled together the efforts of palaeontologists from many countries in the search for the bones of ancient animals.'

The material that was collected at that time comprises dozens of fragments of skulls and skeletons, and hundreds of thousands of isolated bones. Scientists still use them in their research and say that it is enough for many years to come. At present, the three fragments of fossil ankylosaur braincases from Uzbekistan are stored at the Zoological Institute of the Russian Academy of Sciences. However, they have been temporarily transferred for research to the Department of Vertebrate Zoology at St Petersburg University.

Ankylosaurs lived on our planet for 100 million years

'Thanks to the development of computed tomography (CT) over the past 15-20 years, palaeontologists are able to learn more and more about the dinosaur brain and its structure,' said Ivan Kuzmin, the lead author of the article and a doctoral student at St Petersburg University. 'We decided to re-describe Bissektipelta archibaldi, and we managed to clarify its place on the phylogenetic tree of ankylosaurs. A 3D reconstruction of the endocast of its brain cavity was made using CT. It is important to understand that the digital 'cast' of the braincase is not the brain itself. It is necessary to study it carefully to understand how big the actual brain was, where its parts were, how the vessels and nerves were housed.'

After meticulous work that lasted for three years, the scientists managed to find out that a considerable part of the brain of Bissektipelta archibaldi was occupied by olfactory bulbs - about 60% of the size of the cerebral hemispheres. Bissektipelta could boast of an extremely developed sense of smell, which probably helped it to look for food, relatives of the opposite sex, and to feel the approach of predators in time. It was of vital importance to know about any danger in advance because ankylosaurs had such heavy armor and a clumsy figure. The olfaction of ankylosaurs can even be compared with the olfaction of the famous predator Tyrannosaurus rex. Its olfactory bulbs were even larger, as they occupied about 65-70% of the size of the large hemispheres.

'Another interesting skill of the ankylosaur that we learned about is the ability to cool its brains in the literal sense,' said Ivan Kuzmin. 'The network of veins and arteries in its braincase turned out to be very complicated: they did not go in a single direction, but constantly communicated with each other, like a system of railway tracks. The blood could have flown in different directions and been redistributed, while maintaining the optimal brain temperature of the animal. For example, if the top of an ankylosaur's head became warm, the vessels diverted quickly the warm blood and created a screening effect - as if a dinosaur put a sun hat on. Moreover, the endocranial vasculature of ankylosaurs turned out to be somewhat more like the vessels of present-day lizards than that of the closer extant relatives of dinosaurs - crocodiles or birds.'

Another important conclusion concerns the hearing of Bissektipelta archibaldi. The palaeontologists managed to examine the inner ear of the ancient animal. Its anatomy suggests the frequency of sounds that the ankylosaur could hear. The range turned out to have been from about 300 to 3,000 hertz - present-day crocodiles hear in the same range. These are quite low frequencies that correspond to the relatively large size of ankylosaurs. The larger the present-day animals are, the more low-frequency sounds they make and hear. The palaeontologists suggested that, during evolution, ankylosaurs increased in size, so later forms perceived sounds of even lower frequencies.

'Present-day animal species are characterized by a certain brain-body size relationship,' explained Ivan Kuzmin. 'If you look at dinosaurs, then ankylosaurs and their closest relatives (stegosaurs) were almost outsiders. The mass of their brain turned out to be at least half less than what we would expect, based on a comparison with present-day animals. It was about 26.5 grams for a three-meter Bissektipelta. Its brain size can be compared with two walnuts. Nevertheless, ankylosaurs existed on the planet for 100 million years. They were quite successful in terms of evolution. However, judging by the size of their olfactory bulbs, they sniffed a little faster than they thought.'

At the next stage of their research, the scientists would like to study the fossil braincases of other species of ankylosaurs in order to test the hypotheses expressed in the paper. Additionally, the palaeontologists continue to use computed tomography and are currently working with digital endocranial casts of hadrosaurs - duck-billed dinosaurs whose remains were found at the same locality in Uzbekistan.

In addition to Ivan Kuzmin and Pavel Skutschas, the study engaged: Ivan Petrov, a high school student and a trainee of the Krestovsky Ostrov Ecological and Biological Centre of the St Petersburg City Palace of Youth Creativity; Alexander Averianov, Head of the Laboratory of Theriology of the Zoological Institute of the Russian Academy of Sciences and Professor at St Petersburg University; Elizaveta Boitsova, a graduate of St Petersburg University, who was in charge of the visual part of the work; and Hans-Dieter Sues, a well-known palaeontologist from the National Museum of Natural History of the Smithsonian Institution. Also, Pavel Krasnov, a 3D printing specialist from St Petersburg, helped the researchers print a real-size three-dimensional model of the ankylosaur endocast. The academic paper features the current issue of Biological Communications. It is a renewed Vestnik of St Petersburg University. Series 3, Biology updated three years ago that has been published in Russian since 1946. Today it has been transformed into a journal in English on biology with a particular focus on communicating Russian scientific discoveries to the global academic community. After its renewal, the Editor-in-Chief was Yegor Malashichev, Associate Professor of the Department of Vertebrate Zoology at St Petersburg University, who passed away at the end of 2018. The palaeontologists from St Petersburg University have published this paper in Biological Communications in memory of their friend and talented scientist.

Credit: 
St. Petersburg State University

Chance of finding young Earth-like planets higher than previously thought

Research from the University of Sheffield has found that the chance of finding Earth-like planets in their early stages of formation is much higher than previously thought.

The team studied groups of young stars in the Milky Way to see if these groups were typical compared to theories and previous observations in other star-forming regions in space, and to study if the populations of stars in these groups affected the likelihood of finding forming Earth-like planets.

The research, published in The Astrophysical Journal, found that there are more stars like the Sun than expected in these groups, which would increase the chances of finding Earth-like planets in their early stages of formation.

In their early stages of formation these Earth-like planets, called magma ocean planets, are still being made from collisions with rocks and smaller planets, which causes them to heat up so much that their surfaces become molten rock.

The team, led by Dr Richard Parker, included undergraduate students from the University of Sheffield giving them the opportunity to apply the skills learnt on their course to leading published research in their field.

Dr Richard Parker, from the University of Sheffield's Department of Physics and Astronomy, said: "These magma ocean planets are easier to detect near stars like the Sun, which are twice as heavy as the average mass star. These planets emit so much heat that we will be able to observe the glow from them using the next generation of infra-red telescopes.

"The locations where we would find these planets are so-called 'young moving groups' which are groups of young stars that are less than 100 million years old - which is young for a star. However, they typically only contain a few tens of stars each and previously it was difficult to determine whether we had found all of the stars in each group because they blend into the background of the Milky Way galaxy.

"Observations from the Gaia telescope have helped us to find many more stars in these groups, which enabled us to carry out this study."

The findings from the research will help further understanding of whether star formation is universal and will be an important resource for studying how rocky, habitable planets like Earth form. The team now hopes to use computer simulations to explain the origin of these young moving groups of stars.

The research team included undergraduate students Amy Bottrill, Molly Haigh, Madeleine Hole and Sarah Theakston from the University of Sheffield's Department of Physics and Astronomy.

Molly Haigh said: "Being involved in this project was one of the highlights of our university experience and it was a great opportunity to work on an area of astronomy outside the typical course structure.

"It was rewarding to see a physical application of the computer coding we learnt in our degree by sampling the initial mass distribution of stars and how this can relate to the future of exoplanet detection."

The Department of Physics and Astronomy at the University of Sheffield explores the fundamental laws of the universe and develops pioneering technologies with real-world applications. Researchers are looking beyond our planet to map out distant galaxies, tackling global challenges including energy security, and exploring the opportunities presented by quantum computing and 2D materials.

Credit: 
University of Sheffield

Long term care faclities are where most COVID-19 deaths occur

BOSTON - Long-term care facilities (LTCFs) are a major driver of total COVID-19 deaths. Reported today in the Journal of the American Geriatrics Society, Boston Medical Center (BMC) and Boston University School of Medicine (BUSM) geriatricians Rossana Lau-Ng, Lisa Caruso and Thomas Perls studied the past month's case and death data reported by the Massachusetts Department of Health's COVID-19 daily Dashboard along with data provided by the Kaiser Family Foundation and other countries. As the pandemic drags on, the proportion of COVID-19 deaths in Massachusetts that occur in LTCFs (nursing homes and group homes) has climbed from 54 percent to 63 percent as of May 29t.

Some states have even higher proportions of COVID-19 deaths in LTCFs. According to Kaiser Family Foundation data, as of May 28, 81percent of COVID-19 deaths in Minnesota and Rhode Island had occurred in nursing homes. In Connecticut the proportion was 71 percent and in New Hampshire it was 70 percent. Another 22 states reported that 50 percent or more of their COVID-19 deaths occurred in LTCFs. Despite these lopsided figures, 11 states (Alabama, Alaska, Arizona, Arkansas, Hawaii, Michigan, Missouri, Montana, New Mexico, North and South Dakota) continue to not report the number of COVID-19 deaths occurring in LTCFs, which has contributed to a vast underestimation of the total number of COVID-19 deaths in the United States.

Other causes of under-reporting nursing home COVID-19 deaths include incomplete data collection by states and that up through mid-April, many states and the Centers for Disease Control did not accept a diagnosis of COVID-19 without substantiation by a positive test. Thus, many deaths were not reported because tests for COVID-19 were largely unavailable to nursing homes. Now, officials are going back to see if many deaths can be categorized as probable COVID-19 based upon the medical presentation and history of exposure. As of May 28, New York reported the lowest proportion of COVID-19 deaths in LTCFs at 21 percent, yet the rate is three-four times higher in other Northeastern states. "Once we get accurate counts of the COVID-19 deaths in all states, we will likely see a big increase in the total number of deaths in the United States," says Thomas Perls, MD, professor of medicine at BUSM and a study co-author.

Other countries are reporting that the majority of their COVID-19 deaths are also occurring in LTCFs. In early May, Canada indicated that 82 percent of its deaths are in LTCFs. The World Health Organization estimates that half of all COVID-19 deaths in Europe and the Baltics happen in nursing and care homes.

However, there are other countries and regions that are bucking the trend. Hong Kong reports no LTCF COVID-19 deaths and South Korea and Singapore each report fewer than 20 such deaths. New Zealand, because it closed its borders early and with its strict quarantining policy, also reports fewer than 20 LTCF COVID-19 deaths.

So why are most LTCFs so vulnerable to COVID-19? In Massachusetts, almost 90 percent of LTCFs have had at least one COVID-19 case. Lisa Caruso MD, assistant professor of medicine at BUSM and another author indicates, "the asymptomatic spread of this virus allows it to easily sneak in to these facilities where essential staff go from nursing home to nursing home, like x-ray technicians, phlebotomists, nurses and nursing assistants who have to work more than one job to make ends meet." Caruso, a geriatrician at BMC, goes on to say, "Checking temperatures of visitors and staff is obviously not enough. Everyone visiting or working in a LTCF needs to either be found to have immunity to the virus or to be regularly tested."

Beyond the untenable deaths, the pandemic is exacting a terrible psychological and social toll on families, residents and staff. Author Rossana Lau-Ng, MD, instructor of medicine at BUSM remarks, "Our residents are now isolated in their rooms and families who can't visit are terribly worried. We are doing all we can to maintain some semblance of the home-like environment that we had previously strived to achieve but that is now so very challenging." Just as the community at-large must adapt to a new norm during this pandemic, LTCFs have emerged as the front line and must be even more vigilant for the foreseeable future.

Credit: 
Boston University School of Medicine

New data show Abbott's FreeStyle® Libre 14 day system significantly reduces costs associated with diabetes management and complications

Cost model data published in U.S. Endocrinology show for commercially-insured people with diabetes on intensive insulin therapy, using FreeStyle Libre technology costs 60% less compared to traditional blood glucose monitoring

This cost-savings includes costs associated with severe hypoglycemia, including hospitalizations, which were approximately 50% less for FreeStyle Libre 14 day system users versus testing with traditional fingersticks

ABBOTT PARK, Ill., June 5, 2020 -- Abbott, the worldwide leader in continuous glucose monitoring (CGM), announced new cost comparison data published today in U.S. Endocrinology. The findings demonstrate significant savings for commercially-insured people with both type 1 and type 2 diabetes on intensive insulin therapy when using the FreeStyle Libre 14 day system compared to routine self-monitoring of blood glucose (SMBG), also known as traditional fingerstick testing.

The study, titled Cost Comparison of Flash Continuous Glucose Monitoring with Self-Monitoring of Blood Glucose in Adults with Type 1 or Type 2 Diabetes Using Intensive Insulin - From a U.S. Private Payer Perspective, highlighted:

Annual cost of using the FreeStyle Libre 14 day system for people with type 1 and type 2 diabetes was 61% and 63% lower, respectively, compared to testing with fingersticks on a per patient per year basis (PPPY). The data compared list prices and was modeled using the American Diabetes Association guidelines for testing, which are 6-10 or more times per day for people using intensive insulin therapy.

Using the FreeStyle Libre 14 day system is estimated to save roughly 50% in average costs associated with severe hypoglycemia (low blood sugar) in both type 1 and type 2 patients compared to SMBG, including from hospitalizations and emergency room visits.

"Approximately two in five Americans living with diabetes struggle to pay for care according to a recent study published in Circulation," said Mahmood Kazemi, M.D., divisional vice president, global medical and scientific affairs and chief medical officer, Diabetes Care, Abbott. "These new cost data published today in U.S. Endocrinology reinforce how use of Abbott's FreeStyle Libre technology, which was designed with affordability in mind, can transform how both patients and health systems improve health outcomes more cost-effectively compared to fingerstick testing."

As the #1 sensor-based glucose monitoring system used worldwide, Abbott's FreeStyle Libre portfolio has changed the lives of more than 2 million people across 46 countries by providing breakthrough technology that is accessible and affordable. It is priced at one-third of other continuous glucose monitoring systems available today. Abbott has also secured partial or full reimbursement for the FreeStyle Libre system in 36 countries, including Canada, Japan, the United Kingdom, and the U.S. For more information, please visit http://www.freestylelibre.us.

About the Study

The study in U.S. Endocrinology aimed to estimate the costs associated with the use of FreeStyle Libre 14 day system as a replacement for SMBG for people using intensive insulin to manage diabetes from a private insurance perspective. The study includes a hypothetical cohort of people using intensive insulin to assess the potential budget impact associated with the introduction of the FreeStyle Libre 14 day system as a replacement for routine SMBG. The costs of severe hypoglycemia were based on results obtained from recent studies , and utilization of ambulances, emergency rooms and hospital admissions from previous reports.

About Abbott

Abbott is a global healthcare leader that helps people live more fully at all stages of life. Our portfolio of life-changing technologies spans the spectrum of healthcare, with leading businesses and products in diagnostics, medical devices, nutritionals and branded generic medicines. Our 107,000 colleagues serve people in more than 160 countries.

Connect with us at http://www.abbott.com, on LinkedIn at http://www.linkedin.com/company/abbott-/, on Facebook at http://www.facebook.com/Abbott and on Twitter @AbbottNews and @AbbottGlobal.

INDICATIONS AND IMPORTANT SAFETY INFORMATION

The FreeStyle Libre 14 day Flash Glucose Monitoring system is a continuous glucose monitoring (CGM) device indicated for replacing blood glucose testing and detecting trends and tracking patterns aiding in the detection of episodes of hyperglycemia and hypoglycemia, facilitating both acute and long-term therapy adjustments in persons (age 18 and older) with diabetes. The system is intended for single patient use and requires a prescription.

CONTRAINDICATIONS: Remove the sensor before MRI, CT scan, X-ray, or diathermy treatment.

WARNINGS/LIMITATIONS: Do not ignore symptoms that may be due to low or high blood glucose, hypoglycemic unawareness, or dehydration. Check sensor glucose readings with a blood glucose meter when Check Blood Glucose symbol appears, when symptoms do not match system readings, or when readings are suspected to be inaccurate. The FreeStyle Libre 14 day system does not have alarms unless the sensor is scanned, and the system contains small parts that may be dangerous if swallowed. The FreeStyle Libre 14 day system is not approved for pregnant women, persons on dialysis, or critically-ill population. Sensor placement is not approved for sites other than the back of the arm and standard precautions for transmission of blood borne pathogens should be taken. The built-in blood glucose meter is not for use on dehydrated, hypotensive, in shock, hyperglycemic-hyperosmolar state, with or without ketosis, neonates, critically-ill patients, or for diagnosis or screening of diabetes. Review all product information before use or contact Abbott Toll Free (855-632-8658) or visit http://www.freestylelibre.us for detailed indications for use and safety information.

Journal

US Endocrinology

Credit: 
GCI Health NY