How to see the Draconid meteor shower before it’s too late – CNET

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“Comet 21P” is the source of the Draconids.

NASA

The Draconid meteor shower peaked Wednesday evening right around sunset, but Thursday night still offers a chance to see shooting stars or even a fireball in the sky without having to put much effort or planning into the endeavor. 

Most similar showers require staying up late or getting up well before dawn to catch the best part of the show, but the Draconids are the rare bunch that tend to be out in force just after dinner. 

The Draconids are what the American Meteor Society considers a variable meteor shower, meaning they’re typically not that exciting, producing only a few shooting stars per hour at best. But they can produce strong activity on rare occasions. 

The Draconids occur when the Earth passes through trails of debris left behind by past visits from the comet 21P/Giacobini-Zinner. AMS reports that our planet is predicted to pass through two trails of dust and other detritus the space snowball left behind during its trips to the inner solar system all the way back in 1704 and 1711. 

It’s possible this will lead to an increase in activity and it especially favors the East Coast of the US, where the peak in activity will come as night falls and the constellation of Draco the dragon is high in the sky. The trails of the Draconids will appear to originate from around the head of the dragon, hence the shower’s name. 

The shower should be visible for sky watchers in other parts of the world, too. Astronomer Tony Phillips estimates that meteor fans should be able to see as many as 10 per hour in the northern hemisphere. Folks south of the equator won’t be totally cut out of the fun, but expect to see fewer shooting stars. 

To get a glimpse of the Draconids yourself, plan to head outside as soon as night falls. Get as far away from all light pollution as you can to a location with a wide, open view of the sky. Lay on your back, let your eyes adjust and just watch. If you can find Draco in the sky, great, but you should be able to see meteors without focusing on a particular part of the sky. 

Should you happen to capture a photo of anything spectacular in the sky, don’t forget to share it with me on Twitter @EricCMack.  

The best French press coffee makers for 2020: Frieling, Oxo, Bodum and more – CNET

As far as coffee makers go, French press brewers are relatively simple to operate. Even so, coffee made in this style is amazingly rich and complex. As a matter of fact this style of joe is almost as concentrated as cold-brew or espresso. And if made properly, a French press can produce pots to match what comes out of the best drip coffee makers.

These brewers also come in a myriad of shapes and designs, so choosing one is tricky. Fortunately for you, I’ve personally used and tested a group of top-selling models. And, after grinding pounds of beans and drinking scores of cups of coffee, here’s what I learned on my quest to find the best French press a coffee lover can buy. I update this periodically.

Brian Bennett/CNET

The Bodum Chambord has a classic French press design that hasn’t changed much from when it first hit the scene in the 1950s. Despite that, this model brews great coffee that’s strong, well-balanced and richly flavored. Its steel parts also come in various finishes. I especially like the vibrant red version shown here.

Brian Bennett/CNET

For just $15, the Bodum Brazil delivers hot coffee every bit as good as the company’s more expensive Chambord model. To cut down the price, Bodum uses plastic instead of steel for some of the coffee maker’s parts. Its carafe, however, is borosilicate glass. The coffee I brewed in the Brazil was satisfyingly strong, yet balanced.

Brian Bennett/CNET

The Veken French press is very well-equipped considering its reasonable price. Inside the kit you’ll find various tools you won’t see bundled with other French press models: a fancy wooden mixing spoon, a cleaning wand and a battery-powered milk frother for whipping up cafe-style drinks like lattes and cappuccinos.

I also like this French press’ elegant copper finish. It really sets it apart from other models I’ve seen. Most importantly, the Veken brews outstandingly delicious cups of coffee.

Brian Bennett/CNET

The most expensive model in this group, the Frieling French Press doesn’t come cheap. What you get for its steep price is a heavy stainless-steel press construction that’s designed to last. Out of all the French press coffee makers I used, it felt the most durable by far. Its metal body also has insulating dual walls that keep coffee hot for hours.

Coffee I brewed in the Frieling came out well-extracted yet strong. So if money is no barrier, this is the French press for you.

We put a bunch of French press coffee makers to the test to find out which is best.

Brian Bennett/CNET

Others we tested

Mueller French Press

Hamilton Beach French Press

Coffee Gator French Press

Kona Press

SterlingPro French Press

OXO Brew Venture French Press Coffee Maker

How we evaluated them

I test French press brewers much like I test standard drip coffee makers. I begin by hand-washing and hand-drying each product. Then I grind enough coffee beans to meet a specific brewing ratio. For a French press that’s 4 ounces of ground coffee to 32 ounces of water.

We test French press coffee makers the same way we test standard drip machines.

Brian Bennett/CNET

I then add hot water (203 F, 95 C) to the brewing chamber, stir the grounds and let them sit for 4 minutes. After that I drop the plunger for each press and pour a sample cup. Next I draw a sample of the brewed coffee and measure its percentage of total dissolved solids. I use a pocket reflectometer for this test. From there I can calculate the extraction percentage for each batch of coffee I brew.

Ideally, the extraction percentage of brewed coffee should be in the range of 19% to 22%. While this number alone doesn’t guarantee delicious joe, it’s a strong indicator of it. Ultimately the truth lies in a proper taste test.

Coffee extraction percentage

Bodum Chambord French Press

Bodum Brazil French Press

Mueller French Press

Hamilton Beach French Press

Coffee Gator French Press

Veken French Press

Frieling French Press

Kona Press

SterlingPro French Press

OXO Brew Venture French Press Coffee Maker

Note:

The ideal range is between 19 and 22%.

More for hot beverage enthusiasts

Now playing: Watch this: Oxo Brew 8-Cup Coffee Maker: Our new Editors’ Choice…


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Quality control mechanism closes the protein production ‘on-ramps’

Recent work led by Carnegie’s Kamena Kostova revealed a new quality control system in the protein production assembly line with possible implications for understanding neurogenerative disease.

The DNA that comprises the chromosomes housed in each cell’s nucleus encodes the recipes for how to make proteins, which are responsible for the majority of the physiological actions that sustain life. Individual recipes are transcribed using messenger RNA, which carries this piece of code to a piece of cellular machinery called the ribosome. The ribosome translates the message into amino acids — the building blocks of proteins.

But sometimes messages get garbled. The resulting incomplete protein products can be toxic to cells. So how do cells clean up in the aftermath of a botched translation?

Some quality assurance mechanisms were already known — including systems that degrade the half-finished protein product and the messenger RNA that led to its creation. But Kostova led a team that identified a new tool in the cell’s kit for preventing damage when protein assembly goes awry. Their work was published by Molecular Cell.

Using CRISPR-Cas9-based genetic screening, the researchers discovered a separate, and much needed, device by which the cell prevents that particular faulty message from being translated again. They found two factors, called GIGYF2 and 4EHP, which prevent translation from being initiated on problematic messenger RNA fragments.

“Imagine that the protein assembly process is a highway and the ribosomes are cars traveling on it,” Kostova explained. “If there’s a bad message producing incomplete protein products, it’s like having a stalled car or two on the road, clogging traffic. Think of GIGYF2 and 4EHP as closing the on-ramp, so that there is time to clear everything away and additional cars don’t get stalled, exacerbating the problem.”

Loss of GIGYF2 has previously been associated with neurodegenerative and neurodevelopmental problems. It is possible that these issues are caused by the buildup of defective proteins that occurs without the ability to prevent translation on faulty messenger RNAs.

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New method can pinpoint cracks in metal long before they cause catastrophes

When metallic components in airplanes, bridges and other structures crack, the results are often catastrophic. But Johns Hopkins University researchers have found a way to reliably predict the vulnerabilities earlier than current tests.

In a paper published today in Science, Johns Hopkins University researchers detail a new method for testing metals at a microscopic scale that allows them to rapidly inflict repetitive loads on materials while recording how ensuing damage evolves into cracks.

“We’re able now to have a more fundamental understanding about what leads up to cracks,” El-Awady said. “The practical implication is that it will allow us to understand and predict when or how the material is going to fail.”

Whether it is the pounding of vehicles on bridges or shifts in air pressure on airplanes, such continuous change called “cyclic loading” gradually induces slips in the internal molecular structure of the most durable metals until cracks occur that could have been anticipated long before their perilous appearance.

“Fatigue failure plagues all metals and mitigating it is of great importance,” El-Awady said. “It is the leading cause of cracks in metallic components of aircraft.”

That is why it is common practice in the airline industry to adhere to regular — and expensive — replacement schedules for many parts. But the life of those parts could be more accurately determined by better understanding the origins of crack initiation. French investigators just last month called for design reviews of the Airbus A380 to determine if they guard against metal fatigue risks.

“With the lack of understanding of the mechanisms that lead to crack initiation, it has been difficult to predict with any reasonable accuracy the remaining life of a cyclically loaded material,” El-Awady said. “The component could actually be fine and never fail but they throw it away anyway solely on the bases of statistical arguments. That’s a huge waste of money.”

Most current tests to understand the origins of crack initiation have focused on the moments just prior to or after cracking to assess what happened in the makeup of the metal. And many of those tests use far larger samples that preclude tracking the initiation of damage, which is a sub-micrometer scale feature. The new method narrows the lens as small as feasible and begins when metals are first exposed to loads that lead to localized damage that could become cracks.

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Drug delivery systems to treat connective tissue disorders

University of Delaware Professor Kristi Kiick is leading collaborative research to create new drug delivery systems with the potential to improve treatment for diseases that affect connective tissues, such as osteoarthritis or rheumatoid arthritis, which is an autoimmune disease.

The UD researchers have devised tiny cargo-carrying systems many times smaller than a human hair. These systems, or carriers, are made from molecules called peptides that help provide structure for cells and tissues.

The research team is working to program these nanoparticle carriers to selectively bind to degrading collagen in the body. Collagen is a protein that helps plump up or provide structure to connective tissue — everything from our skin to our bones, tendons and ligaments.

When collagen degrades, as a result of disease or injury, the nanoparticles designed by the Kiick lab can attach and remain at the injury site longer than many current treatment options. This allows for the possibility of delivering site-specific medicines over longer periods of time — from days to weeks.

In one collaborative project that involves this work, Kiick is trying to develop drug carriers that could be useful in treating osteoarthritis. Osteoarthritis is a degenerative joint disorder characterized by inflammation, pain and stiffness. According to the Centers for Disease Control and Prevention, it affects 32.5 million Americans.

Early studies with Christopher Price, an associate professor in biomedical engineering, suggests that these nanoparticles can be retained in tissue and knee joints. In other related studies, Kiick and her students have shown that drugs can be encapsulated and retained in the nanoparticles, until released by changes in temperature.

“We are interested in learning how to release drugs that can help not just with pain management, but also with slowing down disease progression,” said Kiick, Blue and Gold Distinguished Professor of Materials Science and Engineering. “It has been key that we have been able to collaborate with the Price laboratory in this type of work.”

For a long time, small molecule corticosteroids have been a standard of care for managing pain in osteoarthritic joints. Because the joint is full of thick, sticky fluid and is under constant mechanical stress and motion, these small-molecule drugs get expelled from the fluid around the knee pretty quickly, in minutes.

“We are hopeful that by controlling the nanoparticle composition and structure,” said Kiick, “we will be able to finely control, or tune, the drug delivery behavior to provide longer-lasting relief for people with inflammatory conditions, such as osteoarthritis.”

The paper’s key findings demonstrate the research team’s ability to control the shape of the nanoparticles, which will impact how well they can bind to tissue in the body and stay in a particular location. The research team also can precisely control the size of the nanoparticles, which has implications for how they might be retained at the injection site and also how they may be used by particular cells before being removed from the body. Finally, the paper describes some of the very fine details of how the specific building blocks inside these peptide molecules can affect the temperature at which those different shaped and sized nanoparticles can be disassembled to release a medicine.

The research builds on Kiick’s previous patented and patent-pending work in this area, but she said it is collaboration with others that is driving forward promising results. While the Kiick lab brings expertise in creating novel materials that can be used as delivery systems; Arthi Jayaraman, Centennial Term Professor for Excellence in Research and Education in the Department of Chemical and Biomolecular Engineering, is helping the team understand factors related to temperature sensitivity of the delivery vehicles and to develop computational tools that can help the research team characterize the vehicle’s shape.

Meanwhile, Price’s expertise in understanding post-traumatic osteoarthritis has been key to developing methods to use these nanoparticles to potentially treat disease. Price is exploring how particular drugs and cells interact, which may inform what specific classes of medicines are useful in treating osteoarthritis that develops following traumatic injury. The collaboration will help the Kiick lab tailor what types of nanoparticle devices can be used to deliver these different classes of medicines.

According to Kiick, thinking big, the team could imagine loading a custom cocktail of medicines into the drug-delivering nanoparticles capable of delivering relief over varying timescales and temperatures. The researchers already have the right material nanostructure that can allow this to happen; now they are exploring how to trigger the nanoparticles to release specific medications under particular conditions.

“You could imagine injecting these encapsulated medications at the knee,” she explained. “Then, when you want one medication to be released, the patient could ice their knee. If another drug is needed to provide relief over a longer time-period, heat could be applied.”

It could be a really simple way to help people manage chronic conditions that cause a lot of pain and reduce mobility. And because the treatment is local, it could reduce side effects that can occur when drugs have to be taken at high doses or over prolonged periods of time.

“If these delivery vehicles could reduce painful effects of osteoarthritis, or delay when osteoarthritis symptoms emerge, there could be important implications for improving quality of life for many people,” Kiick said.

New class of highly effective inhibitors protects against neurodegeneration

Neurobiologists at Heidelberg University have discovered how a special receptor at neuronal junctions that normally activates a protective genetic programme can lead to nerve cell death when located outside synapses. Their fundamental findings on neurodegenerative processes simultaneously led the researchers at the Interdisciplinary Center for Neurosciences (IZN) to a completely new principle for therapeutic agents. In their experiments on mouse models, they discovered a new class of highly effective inhibitors for protecting nerve cells. As Prof. Dr Hilmar Bading points out, this novel class of drugs opens up — for the first time — perspectives to combat currently untreatable diseases of the nervous system. The results of this research were published in Science.

The research by Prof. Bading and his team is focused on the so-called NMDA receptor. This receptor is an ion channel protein that is activated by a biochemical messenger: the neurotransmitter glutamate. It allows calcium to flow into the cell. The calcium signal sets in motion plasticity processes in the synapse but also propagates into the cell nucleus, where it activates a protective genetic programme. Glutamate-activated NMDA receptors located in the junctions of the nerve cells have a key function in the brain, contributing to learning and memory processes as well as neuroprotection. But the same receptors are also found outside of synapses. These extra-synaptic NMDA receptors pose a threat because their activation can lead to cell death. Normally, however, efficient cellular uptake systems for glutamate make sure that these receptors are not activated and nerve cells remain undamaged.

This situation can change dramatically in the presence of disease. If, for example, parts of the brain are not supplied with sufficient oxygen after a stroke, disruptions in circulation negate the glutamate uptake systems. The glutamate level outside synapses increases, thereby activating the extra-synaptic NMDA receptors. The result is nerve cell damage and death accompanied by restrictions in brain function. Increased glutamate levels outside the synapses occur not only during circulatory disturbances of the brain. “The evidence suggests that the toxic properties of extra-synaptic NMDA receptors play a central role in a number of neurodegenerative diseases,” explains Prof. Bading. According to the scientist, this applies, in particular, to Alzheimer’s disease and Amyotrophic Lateral Sclerosis with its resulting muscle weakness and muscle wasting as well as retinal degeneration, and possibly even brain damage after infections with viruses or parasites.

While glutamate-activated NMDA receptors inside neuronal junctions help build up a protective shield, outside synapses they change from Dr Jekyll into Mr Hyde. “Understanding why extra-synaptic NMDA receptors lead to nerve cell death is the key to developing neuroprotective therapies,” continues Prof. Bading. That is precisely where the Heidelberg researchers are focusing their efforts. In their experiments on mouse models, they were able to demonstrate that the NMDA receptors found outside synapses form a type of “death complex” with another ion channel protein. This protein, called TRPM4, has a variety of functions in the body, with roles in the cardiovascular system and immune responses. According to the latest findings by Hilmar Bading and his team of researchers, TRPM4 confers toxic properties on extra-synaptic NMDA receptors.

Using molecular and protein biochemical methods, the scientists identified the contact surfaces of the two interacting proteins. With this knowledge, they used a structure-based search to identify substances that might disrupt this very bond, thereby dismantling and inactivating the “death complex.” This new class of inhibitors — which the Heidelberg researchers call “interface inhibitors” because they disrupt the bond formed at the contact surfaces between the extra-synaptic NMDA receptors and TRPM4 — proved to be extremely effective protectors of nerve cells. “We’re working with a completely new principle for therapeutic agents here. The interface inhibitors give us a tool that can selectively remove the toxic properties of extra-synaptic NMDA receptors,” explains Prof. Bading.

Prof. Bading and his team were already able to demonstrate the efficacy of the new inhibitors in mouse models of stroke or retinal degeneration. According to the Heidelberg researcher, there is good reason to hope that such interface inhibitors — administered orally as broad-spectrum neuroprotectants — offer treatment options for currently untreatable neurodegenerative diseases. “However, their possible approval as pharmaceutical drugs for human use will take several more years because the new substances must first successfully pass through a number of preclinical and clinical testing phases.”

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Cannabis ads and store location influence youth marijuana use

Advertising and location of cannabis retailers influence adolescents’ intentions to use marijuana, according to a new study in the Journal of Health Communication by Washington State University researchers.

Stacey J.T. Hust, associate dean in the Murrow College of Communication, and Jessica Fitts Willoughby, associate professor of communication, conducted a survey of 13- to 17-year-olds in Washington State to find out how marijuana advertising and the location of marijuana retailers influence adolescents’ intentions to use the drug. The researchers also asked participants about their outcome beliefs — whether or not they thought using marijuana would be good for them personally and or socially.

Their research shows regular exposure to marijuana advertising on storefronts, billboards, retailer websites and other locations increased the likelihood of adolescents using marijuana.

“While there are restrictions against using advertising designed specifically to target youth, it does still appear to be having some influence,” Willoughby said. “Our research suggests a need to equip adolescents with the knowledge and skills to critically evaluate marijuana advertisements.”

Location of retail stores also played a role but the results of the survey were mixed.

While the actual density of marijuana retailers in an area was not associated with adolescents’ intentions to use, study participants who said they lived within five miles of a marijuana shop were more likely to report intentions to use the drug than those who perceived they lived farther away.

“This was especially the case when they also reported having positive beliefs about marijuana use,” Hust said. “The study participants who felt positively about marijuana and perceived living close to retailers were the most likely to report intentions to use marijuana.”

The results of the research team’s study could have significant policy implications as states that have legalized recreational marijuana use grapple with ways to adhere to the drug’s legal status while trying to prevent adolescent marijuana use.

For instance, most states with legalized marijuana restrict placing retailers and advertisements next to schools, but other locations, where adolescents live and spend a lot of their time, remain largely unregulated.

“Our findings are particularly relevant given that most states that have legalized recreational marijuana have not restricted their proximity to neighborhoods or living areas, which may be particularly challenging in large metropolitan areas,” Hust said. “States may want to consider using census data to identify the proportion of teens living in particular areas as they identify the location for marijuana retailers.”

The researchers are currently in the process of conducting a new experiment where they are testing different types of advertisements to see how young people interpret and respond to them.

“One of the things this research and other studies suggest is that these advertisements are pretty prolific in certain areas and we want to see what type of appeals are used in the advertisements and how those appeals affect viewers,” Hust said. “Our long-term goal is really to develop a better understanding of how adolescents can make heathy and informed decisions in an environment in which marijuana is legal.”

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Materials provided by Washington State University. Original written by Will Ferguson. Note: Content may be edited for style and length.

Vaporized metal in the air of an exoplanet

WASP-121b is an exoplanet located 850 light years from Earth, orbiting its star in less than two days — a process that takes Earth a year to complete. WASP-121b is very close to its star — about 40 times closer than Earth to the Sun. This close proximity is also the main reason for its immensely high temperature of around 2,500 to 3,000 degrees Celsius. This makes it an ideal object of study to learn more about ultra-hot worlds.

Researchers led by Jens Hoeijmakers, first author of the study and postdoctoral research fellow at the National Centre of Competence in Research PlanetS at the Universities of Bern and Geneva, examined data that had been collected by the high-resolution HARPS spectrograph. They were able to show that a total of at least seven gaseous metals occur in the atmosphere of WASP-121b. The results were recently published in the journal Astronomy & Astrophysics.

Unexpectedly much going on in the atmosphere of exoplanet WASP-121b

WASP-121b has been extensively studied since its discovery. “The earlier studies showed that there is a lot going on in its atmosphere,” explains Jens Hoeijmakers. And this despite the fact that astronomers had assumed that ultra-hot planets have rather simple atmospheres because not many complex chemical compounds can form in such blistering heat. So how did WASP-121b come to have this unexpected complexity?

“Previous studies tried to explain these complex observations with theories that did not seem plausible to me,” says Hoeijmakers. The studies had suspected that molecules containing the relatively rare metal vanadium were the main cause of the complex atmosphere in WASP-121b. According to Hoeijmakers, however, this would only make sense if a more common metal, titanium, were missing in the atmosphere. So Hoeijmakers and his colleagues set out to find another explanation. “But it turned out that they were right,” admits Hoeijmakers unequivocally. “To my surprise, we actually found strong signatures of vanadium in the observations.” At the same time, however, titanium was missing. This in turn confirmed Hoeijmakers’ assumption.

Vaporised metals

But the team made other, unexpected discoveries. In addition to vanadium, they newly discovered six other metals in the atmosphere of WASP-121b: Iron, chromium, calcium, sodium, magnesium and nickel. “All metals evaporated as a result of the high temperatures prevailing on WASP-121b,” explains Hoeijmakers, “thus ensuring that the air on the exoplanet consists of evaporated metals, among other things.”

A new era in exoplanet research

Such detailed results allow researchers to draw conclusions about the chemical processes that take place on such planets, for example. This is a crucial skill for the not too distant future, when larger, more sensitive telescopes and spectrographs will be developed. These will allow astronomers to study the properties of smaller, cooler rocky planets similar to Earth. “With the same techniques we use today, instead of just detecting signatures of gaseous iron or vanadium, we will be able to focus on biosignatures, signs of life such as the signatures of water, oxygen and methane,” says Hoeijmakers.

The extensive knowledge about the atmosphere of WASP- 121b not only confirms the ultra-hot character of the exoplanet, but also underlines the fact that this field of research is entering a new era, as Hoeijmakers puts it: “After years of cataloguing what is out there, we are now no longer just taking measurements,” explains the researcher, “but we are really beginning to understand what the data from the instruments show us. How planets resemble and differ from each other. In the same way, perhaps, that Charles Darwin began to develop the theory of evolution after characterizing countless species of animals, we are beginning to understand more about how these exoplanets were formed and how they work.”

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DNA test identifies genetic causes of severe fetal and newborn illness

A new study by University of California researchers shows the promise of high-throughput DNA-sequencing technologies to improve prenatal diagnosis and pregnancy outcomes for women who have experienced an abnormal prenatal ultrasound.

In the UCSF-led study, scientists used a technique called exome sequencing to identify genetic diseases as the underlying cause in 37 of 127 cases of nonimmune hydrops fetalis (NIHF), a life-threatening condition in which the fetus is overloaded with fluid. The study was published online Oct. 7, 2020, in The New England Journal of Medicine (NEJM).

Corresponding author Teresa Sparks, MD, MAS, a UCSF assistant professor in the Department of Obstetrics, Gynecology & Reproductive Sciences, led the study with senior study author Mary Norton, MD, a professor in the same department. “The cause of most cases of NIHF is not identified with standard testing, but when we apply exome sequencing, we find a genetic diagnosis in nearly 30 percent of cases of previously unknown cause,” Sparks said.

NIHF affects about one in every 1,700 to 3,000 pregnancies in the United States and is associated with high risks of stillbirth, preterm birth, neonatal death and other complications. Although NIHF often leads to death, identifying the precise genetic cause is critical, as associated outcomes vary widely in severity.

NIHF can be a manifestation of many genetic diseases, but evidence of abnormal fluid accumulation in the fetus detected through an ultrasound exam — whether it occurs under the skin, in the abdomen, or around the heart or lungs — does not pinpoint an underlying cause.

Participants in the NEJM study were referred from throughout the United States after NIHF was identified with prenatal ultrasound but no underlying genetic disease was found using long established methods for detecting genetic abnormalities. These traditional genetic tests — karyotype and chromosomal microarray analysis — detect large abnormalities in chromosomes, not disorders caused by a defect in a single gene as are identified with exome sequencing.

Exome sequencing is the complete spelling out of the genetic code for DNA segments within the genome that serves as the blueprints for proteins. This has become possible to perform quickly and accurately in recent years, thanks to the continual refinement of technology that can sequence DNA strands that are thousands of nucleotide building blocks long, often in a massively parallel manner that helps ensure accurate results. Exome sequencing can identify even the smallest mutations, such as a change in a single building-block nucleotide base pair.

Importantly, many of the disorders identified in the study have not previously been reported in association with NIHF, so the findings broaden knowledge of genetic diseases that can present with the condition. Among the most common of 37 genetic disorders identified in the NEJM study were 11 cases affecting a key intracellular signaling pathway called RAS-MAPK, four cases of inborn errors of metabolism, four cases of musculoskeletal disorders, and three cases each of lymphatic, neurodevelopmental, cardiovascular and blood disorders. Many of these diagnoses would also have been missed by commercial gene panels, Sparks said.

Most mutations identified in the study newly arose in the fetus, but several were inherited, with the potential to affect future pregnancies with the same biologic mother or father.

“There is a very wide range in genetic diagnoses underlying NIHF, and identifying the diagnosis is essential for families and healthcare providers,” Sparks said. “With advanced genetic testing, there is much more we can discover for families to help them understand the situation, for obstetricians and neonatologists to better take care of the pregnancy and anticipate the needs of the newborn, and ultimately to guide the development of novel prenatal management strategies such as in-utero therapies to improve health outcomes over the long term.”

For some of the genetic disorders identified in the study, prenatal interventions that can improve or save lives already have been identified. For example, genetic causes of anemia in the fetus may be closely monitored, and the fetus may receive a blood transfusion if needed.

Similarly, for some of the inborn errors of metabolism identified in the study, enzyme therapies already are available after birth. Early diagnosis and treatment of these metabolic disorders leads to better outcomes. A co-author of the NEJM study, Tippi MacKenzie, MD, a professor with the UCSF Department of Surgery, is investigating in utero treatments for specific genetic disorders underlying NIHF in a new clinical trial. Sparks, Norton, and co-authors are also pursuing further investigations to identify additional genomic abnormalities underlying NIHF for the cases that remain unsolved.

Moles: Intersexual and genetically doped

Moles are special creatures that roam in an extreme habitat. As mammals that burrow deep into the earth, they have forepaws with an extra finger and exceptionally strong muscles. What’s more, female moles are intersexual while retaining their fertility. Typical for mammals, they are equipped with two X chromosomes, but they simultaneously develop functional ovarian and testicular tissues. In female moles, both tissue types are united in one organ, the ovotestis — something that is unique among mammals.

A lot of testosterone in the female mole’s blood

The testicular tissue of the female mole does not produce sperm, but large amounts of the sex hormone testosterone, meaning the females have similarly high levels as the males. Presumably this natural “doping” makes the female moles aggressive and muscular, an advantage for life underground, where they have to dig burrows and fight for resources.

In a study in the journal Science, Berlin scientists are now reporting on the genetic peculiarities that lead to this characteristic sexual development in moles. According to the study, it is primarily changes in the structure of the genome that lead to altered control of genetic activity. In addition to the genetic program for testicular development, this also stimulates enzymes for male hormone production in the females.

The study was conducted by an international team co-led by Professor Stefan Mundlos, Research Group leader at the Max Planck Institute for Molecular Genetics (MPIMG) and Director at the Institute for Medical Genetics and Human Genetics at Charité — Universitätsmedizin Berlin and by Dr. Darío Lupiáñez, Research Group Leader at the Berlin Institute for Medical Systems Biology (BIMSB), which is part of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC).

Genomic mechanisms of evolution

“Since Darwin, it has been generally accepted that the different appearances of living organisms are the result of gradual changes in genetic makeup that have been passed onto subsequent generations,” says Mundlos. “But how are DNA changes and their manifestations in the appearance of an organism related in concrete terms, and how can we uncover such changes?”

To pursue this question, the researchers have completely sequenced the genome of the Iberian mole (Talpa occidentalis) for the first time. Moreover, they examined the three-dimensional structure of the genome within the cell. In the nucleus, genes and their associated control sequences form regulatory domains — relatively isolated “neighborhoods” consisting of large regions where DNA sections interact frequently with each other.

“We hypothesized that in moles, there are not only changes in the genes themselves, but particularly in the regulatory regions belonging to these genes,” says Mundlos.

In the course of the moles’ evolution, then not only would individual letters of the DNA have changed, also larger pieces of the genome would have shifted, says the researcher. If segments of DNA move from one location to another, completely new or reorganized regulatory domains can emerge and thus activate new genes and enhance or attenuate their expression.

Program for testicular development

“The sexual development of mammals is complex, although we have a reasonably good idea on how this process takes place,” says Darío Lupiáñez. “At a certain point, sexual development usually progresses in one direction or another, male or female. We wanted to know how evolution modulates this sequence of developmental events, enabling the intersexual features that we see in moles.”

In fact, when comparing the genome to that of other animals and humans, the team discovered an inversion — i.e., an inverted genomic segment — in a region known to be involved in testicular development. The inversion causes additional DNA segments to get included in the regulatory domain of the gene FGF9, which reorganizes the control and regulation of the gene. “This change is associated with the development of testicular tissue in addition to ovarian tissue in female moles,” explains Dr. Francisca Martinez Real, lead author of the study and scientist at the MPIMG as well as the Institute for Medical Genetics and Human Genetics at Charité.

The team also discovered a triplication of a genomic region responsible for the production of male sex hormones (androgens), more specifically the androgen production gene CYP17A1. “The triplication appends additional regulatory sequences to the gene — which ultimately leads to an increased production of male sex hormones in the ovotestes of female moles, especially more testosterone,” says Real.

Wild moles and transgenic mice

The highly territorial moles cannot be kept in the laboratory, which particularly challenged the work of the researchers. “We had to do all our research on wild moles,” says Lupiáñez. He and Real spent months in southern Spain collecting samples for their experiments. “However, this drawback also became a strength in our study. Our results are not limited to laboratory animals, but extend our knowledge to wild animals.”

The research group proved that the two genome mutations actually contribute to the special sexuality of female moles by creating a mouse model in which they mimic the genomic changes observed in moles. Of the altered animals, the female mice had androgen levels that were as high as in normal male mice. They were also significantly stronger than their unaltered conspecifics.

Evolution makes use of the genetic toolbox

With moles, the sexes are not that clearly delimited from one another; instead, females move on a spectrum between typically female and typically male phenotypes, i.e., they are intersexual.

“Our findings are a good example of how important the three-dimensional organization of the genome is for evolution,” says Lupiáñez. “Nature makes use of the existing toolbox of developmental genes and merely rearranges them to create a characteristic such as intersexuality. In the process, other organ systems and development are not affected.”

“Historically, the term intersexuality has caused considerable controversy,” says Mundlos. “There was and continues to be a tendency to characterize intersexual phenotypes as pathological conditions. Our study highlights the complexity of sexual development and how this process can result in a wide range of intermediate manifestations that are a representation of natural variation.”