Gene-editing offers hope for people with hereditary disorder

 A group of patients with a hereditary disorder have had their lives transformed by a single treatment of a breakthrough gene-editing therapy, according to the lead researcher.

The patients from New Zealand, the Netherlands and the UK have hereditary angioedema, a genetic disorder characterised by severe, painful and unpredictable swelling attacks.

These interfere with daily life and can affect airways and prove fatal.

Now researchers from the University of Auckland, Amsterdam University Medical Center and Cambridge University Hospitals have successfully treated more than ten patients with the CRISPR/Cas9 therapy, with interim results just published in a leading journal.

"It looks as if the single-dose treatment will provide a permanent cure for my hereditary angioedema patients' very disabling symptoms," says principal investigator Dr Hilary Longhurst, who is both a clinical immunologist at Auckland Hospital Te Toku Tumai and an honorary associate professor at the University of Auckland.

"Plus, of course, there is huge potential for development of similar CRISPR/Cas9 treatments for other genetic disorders."

Globally, it is estimated one in 50,000 people have hereditary angioedema, however, because it is rare, it is often not correctly diagnosed.

In the phase one study, there were no serious or lasting side-effects from the single infusion, which took place over two to four hours under clinical supervision from late 2021 and onwards.

The investigational therapy, called NTLA-2002, utilises in vivo CRISPR/Cas9 technology to target the KLKB1 gene, which is responsible for producing plasma prekallikrein.

By editing this gene, the therapy reduces the levels of total plasma kallikrein, effectively preventing angioedema (swelling) attacks.

The trial, published in the New England Journal of Medicine, demonstrated dose-dependent reduction in total plasma kallikrein protein with reductions of up to 95 percent achieved.

A mean reduction of 95 percent in angioedema attacks was observed across all patients through to the latest follow-up.

The patients from the initial study will be followed up for a further 15 years to continue to assess long-term safety and efficacy.

A larger and more robust, double-blinded, placebo-controlled phase two trial is under way and a Phase 3 trial is planned to start in the second half of 2024.

Dr Danny Cohn, from the Department of Vascular Medicine at the Amsterdam University Medical Center says these promising results are a step forward for this group of patients.

Source: ScienceDaily

Scientist shows focused ultrasound can reach deep into the brain to relieve pain

 You feel a pain, so you pop a couple of ibuprofen or acetaminophen. If the pain is severe or chronic, you might be prescribed something stronger -- an opioid pain killer that can be addictive under some circumstances.

But what if you could ease pain by non-invasively manipulating a spot inside your brain where pain is registered?

A new study by Wynn Legon, assistant professor at the Fralin Biomedical Research Institute at VTC, and his team points to that possibility.

The study, published in the journal PAIN today (Monday, Feb.

5), found soundwaves from low-intensity focused ultrasound aimed at a place deep in the brain called the insula can reduce both the perception of pain and other effects of pain, such as heart rate changes.

"This is a proof-of-principle study," Legon said. "Can we get the focused ultrasound energy to that part of the brain, and does it do anything? Does it change the body's reaction to a painful stimulus to reduce your perception of pain?"

Focused ultrasound uses the same technology used to view a baby in the womb, but it delivers a narrow band of sound waves to a tiny point.

At high intensity, ultrasound can ablate tissue. At low-intensity, it can cause gentler, transient biological effects, such as altering nerve cell electrical activity

Neuroscientists have long studied how non-surgical techniques, such as transcranial magnetic stimulation, might be used to treat depression and other issues.

Legon's study, however, is the first to target the insula and show that focused ultrasound can reach deep into the brain to ease pain.

The study involved 23 healthy human participants. Heat was applied to the backs of their hands to induce pain.

At the same time, they wore a device that delivered focused ultrasound waves to a spot in their brain guided by magnetic resonance imaging (MRI).

Participants rated their pain perception in each application on a scale of zero to nine.

Researchers also monitored each participant's heart rate and heart rate variability -- the irregularity of the time between heart beats -- as a means to discern how ultrasound to the brain also affects the body's reaction to a painful stimulus.

Participants reported an average reduction in pain of three-fourths of a point.

"That might seem like a small amount, but once you get to a full point, it verges on being clinically meaningful," said Legon, also an assistant professor in the School of Neuroscience in Virginia Tech's College of Science.

"It could make a significant difference in quality of life, or being able to manage chronic pain with over-the-counter medicines instead of prescription opioids."

The study also found the ultrasound application reduced physical responses to the stress of pain -- heart rate and heart rate variability, which are associated with better overall health.

"Your heart is not a metronome. The time between your heart beats is irregular, and that's a good thing," Legon said.

"Increasing the body's ability to deal with and respond to pain may be an important means of reducing disease burden."

The effect of focused ultrasound on those factors suggests a future direction for the Legon lab's research -- to explore the heart-brain axis, or how the heart and brain influence each other, and whether pain can be mitigated by reducing its cardiovascular stress effects.

Other authors on the paper include Andrew Strohman, an M.D.+Ph.D. student in the Virginia Tech Carilion School of Medicine and Virginia Tech's Translational Biology, Medicine, and Health program, and other Legon Lab members.

The study was supported by the Seale Innovation Fund, the Focused Ultrasound Foundation, and the National Institutes of Health.

Source: ScienceDaily

Clown anemonefish seem to be counting bars and laying down the law

 We often think of fish as carefree swimmers in the ocean, reacting to the world around them without much forethought. However, new research from the Okinawa Institute of Science and Technology (OIST) suggests that our marine cousins may be more cognizant than we credit them for.

By observing how a colony of clown anemonefish (Amphiprion ocellaris) -- the species of the titular character in Finding Nemo -- reacts to intruders in their sea anemone home, OIST researchers have found that the fish recognize different anemonefish species based on the number of white bars on their bodies.

"The frequency and duration of aggressive behaviors in clown anemonefish was highest toward fish with three bars like themselves," explains Dr. Kina Hayashi from the Marine Eco-Evo-Devo Unit at OIST, first author on the paper published in the Journal of Experimental Biology, "while they were lower with fish with one or two bars, and lowest toward those without vertical bars, which suggests that they are able to count the number of bars in order to recognize the species of the intruder."

The clown anemonefish is normally a gracious host, allowing many different species to visit their sea anemone.

However, should a member of their own species, and which is not part of the colony, enter their home, the largest fish of the colony, referred to as the alpha fish, will aggressively bite and chase out the intruder.

To figure out how these fish determine the species of their visitors, Dr. Hayashi and colleagues conducted two sets of experiments with immature clown anemonefish raised in the lab.

In the first set, they placed different species of anemonefish, with different numbers of white bars, in small cases inside a tank with a clown anemonefish colony and observed how often and for how long the fish would aggressively stare at and circle the case.

In the second set, the researchers presented a colony of clown anemonefish with different plastic discs painted with true-to-life anemonefish coloration and measured the level of aggression towards these models.

The clown anemonefish displayed the most aggressive behavior towards the intruders with three bars like themselves.

Fish and plastic models with two bars were attacked slightly less frequently, while the ones with one or zero bars received the least aggressive response.

Previous studies have shown that clown anemonefish react much stronger to models with vertical rather than horizontal bars, suggesting that the amount of white color or the general presence of white bars is not the deciding factor.

Combined with the observation that the plastic discs, which have no species defining traits other than the vertical bars, received the same response as the live fish, lead the researchers to suggest that the fish appear to be counting the number of vertical white bars to inform their level of aggression toward intruders.

Source: ScienceDaily

Automated method helps researchers quantify uncertainty in their predictions

 Pollsters trying to predict presidential election results and physicists searching for distant exoplanets have at least one thing in common: They often use a tried-and-true scientific technique called Bayesian inference.

Bayesian inference allows these scientists to effectively estimate some unknown parameter -- like the winner of an election -- from data such as poll results. But Bayesian inference can be slow, sometimes consuming weeks or even months of computation time or requiring a researcher to spend hours deriving tedious equations by hand.

Researchers from MIT and elsewhere have introduced an optimization technique that speeds things up without requiring a scientist to do a lot of additional work. Their method can achieve more accurate results faster than another popular approach for accelerating Bayesian inference.

Using this new automated technique, a scientist could simply input their model and then the optimization method does all the calculations under the hood to provide an approximation of some unknown parameter. The method also offers reliable uncertainty estimates that can help a researcher understand when to trust its predictions.

This versatile technique could be applied to a wide array of scientific quandaries that incorporate Bayesian inference. For instance, it could be used by economists studying the impact of microcredit loans in developing nations or sports analysts using a model to rank top tennis players.

"When you actually dig into what people are doing in the social sciences, physics, chemistry, or biology, they are often using a lot of the same tools under the hood. There are so many Bayesian analyses out there. If we can build a really great tool that makes these researchers lives easier, then we can really make a difference to a lot of people in many different research areas," says senior author Tamara Broderick, an associate professor in MIT's Department of Electrical Engineering and Computer Science (EECS) and a member of the Laboratory for Information and Decision Systems and the Institute for Data, Systems, and Society.

Broderick is joined on the paper by co-lead authors Ryan Giordano, an assistant professor of statistics at the University of California at Berkeley; and Martin Ingram, a data scientist at the AI company KONUX. The paper was recently published in the Journal of Machine Learning Research.

Faster results

When researchers seek a faster form of Bayesian inference, they often turn to a technique called automatic differentiation variational inference (ADVI), which is often both fast to run and easy to use.

But Broderick and her collaborators have found a number of practical issues with ADVI. It has to solve an optimization problem and can do so only approximately. So, ADVI can still require a lot of computation time and user effort to determine whether the approximate solution is good enough. And once it arrives at a solution, it tends to provide poor uncertainty estimates.

Source: ScienceDaily

First-ever sighting of a live newborn great white

 Great whites, the largest predatory sharks in the world with the most fatal attacks on humans, are tough to imagine as newborn babies. That is partially because no one has seen one in the wild, it seems, until now.

Wildlife filmmaker Carlos Gauna and UC Riverside biology doctoral student Phillip Sternes were scanning the waters for sharks on July 9, 2023, near Santa Barbara on California's central coast.

That day, something exciting appeared on the viewfinder of Gauna's drone camera.

It was a shark pup unlike any they'd ever seen.

Great whites, referred to only as white sharks by scientists, are gray on top and white on the bottom.

But this roughly 5-foot-long shark was pure white.

"We enlarged the images, put them in slow motion, and realized the white layer was being shed from the body as it was swimming," Sternes said.

"I believe it was a newborn white shark shedding its embryonic layer."

These observations are documented in a new paper in the Environmental Biology of Fishes journal.

The paper also details the significance of having seen a live newborn white shark.

Gauna is known online as The Malibu Artist. He has spent thousands of hours filming sharks around the world, and his videos of them swimming close to beachgoers have millions of views.

What he and Sternes observed could help solve the longstanding mystery of great white birthing habits.

"Where white sharks give birth is one of the holy grails of shark science. No one has ever been able to pinpoint where they are born, nor has anyone seen a newborn baby shark alive," Gauna said.

"There have been dead white sharks found inside deceased pregnant mothers. But nothing like this."

Though the paper authors acknowledge it is possible the white film the shark shed could have been a skin condition, the duo do not believe this to be the case.

"If that is what we saw, then that too is monumental because no such condition has ever been reported for these sharks," Gauna said.

For many reasons, the duo believes what they saw was in fact a newborn great white.

First, great white females give birth to live pups. While in utero, the embryonic sharks might feed on unfertilized eggs for protein.

The mothers offer additional nourishment to the growing shark pups with a 'milk' secreted in the uterus.

"I believe what we saw was the baby shedding the intrauterine milk," Sternes said.

A second reason is the presence of large, likely pregnant great whites in this location.

Source: ScienceDaily

'Old smokers' and 'squalling newborns' among hidden stars spotted for first time

 'Hidden' stars including a new type of elderly giant nicknamed an 'old smoker' have been spotted for the first time by astronomers.

The mystery objects exist at the heart of our Milky Way galaxy and can sit quietly for decades -- fading almost to invisibility -- before suddenly puffing out clouds of smoke, according to a new study published today in the Monthly Notices of the Royal Astronomical Society.

An international team of scientists led by Professor Philip Lucas, of the University of Hertfordshire, made their ground-breaking discovery after monitoring almost a billion stars in infrared light during a 10-year survey of the night sky.

They also detected dozens of rarely-seen newborn stars, known as protostars, which undergo extreme outbursts over a period of months, years or decades, as part of the formation of a new solar system.

Most of these newly-spotted stars are hidden from view in visible light by large amounts of dust and gas in the Milky Way -- but infrared light can get through, allowing scientists to see them for the first time.

Astronomers from the UK, Chile, South Korea, Brazil, Germany and Italy carried out their research with the help of the Visible and Infrared Survey Telescope (VISTA) -- a British-built telescope high in the Chilean Andes at Cerro Paranal Observatory, which is part of the European Southern Observatory (ESO).

The team kept a watchful eye on hundreds of millions of stars and analysed 222 that showed the largest changes in brightness.

Professor Lucas said: "About two-thirds of the stars were easy to classify as well-understood events of various types.

"The rest were a bit more difficult so we used ESO's Very Large Telescope to get spectra of many of them individually. A spectrum shows us how much light we can see at a spread of different wavelengths, giving a much clearer idea of what we are looking at."

The work was carried out as part of a long-term survey called 'VISTA Variables in the Via Lactea', or VVV.

Dr Zhen Guo, formerly of the University of Hertfordshire and now based at the University of Valparaiso in Chile, led the work on the spectra.

He said: "Our main aim was to find rarely-seen newborn stars, also called protostars, while they are undergoing a great outburst that can last for months, years, or even decades.

"These outbursts happen in the slowly spinning disc of matter that is forming a new solar system. They help the newborn star in the middle to grow, but make it harder for planets to form.

"We don't yet understand why the discs become unstable like this."

The team discovered 32 erupting protostars that increased in brightness at least 40-fold, and in some cases over 300-fold.

Most of the eruptions are still ongoing, allowing astronomers for the first time to analyse a large batch of these mysterious events throughout their evolution -- from the initial quiescent state, through the peak of brightness, and into the declining stage.

However, the study also threw up something completely unexpected.

There were 21 red stars near the centre of the Milky Way that showed ambiguous changes in brightness during the 10-year survey.

Professor Lucas explained: "We weren't sure if these stars were protostars starting an eruption, or recovering from a dip in brightness caused by a disc or shell of dust in front of the star -- or if they were older giant stars throwing off matter in the late stages of their life."

Analysis of the spectra for seven of these stars, compared with data from earlier surveys, concluded that they were in fact a new type of red giant star.

Professor Dante Minniti at Andrés Bello University, Chile, founder of the VVV survey, said: "These elderly stars sit quietly for years or decades and then puff out clouds of smoke in a totally unexpected way.

"They look very dim and red for several years, to the point that sometimes we can't see them at all."

A further clue about this new discovery lies in the location of these dwindling giant stars. They are heavily concentrated in the innermost part of the Milky Way, known as the Nuclear Disc, a region where stars tend to be richer in heavy elements than anywhere else.

This should make it easier for dust particles to condense out of gas in the relatively cool outer layers of red giant stars. However, how this leads to the ejection of puffs of dense smoke that the team observed remains a mystery.

The researchers said their discoveries could change what we know about the way that elements are distributed across space, as Professor Lucas explains.

"Matter ejected from old stars plays a key role in the life cycle of the elements, helping to form the next generation of stars and planets," he said.

Source: ScienceDaily

Neanderthals and humans lived side by side in Northern Europe 45,000 years ago

 A genetic analysis of bone fragments unearthed at an archaeological site in central Germany shows conclusively that modern humans -- Homo sapiens -- had already reached Northern Europe 45,000 years ago, overlapping with Neanderthals for several thousand years before the latter went extinct.

The findings establish that the site near Ranis, Germany, which is known for its finely flaked, leaf-shaped stone tool blades, is among the oldest confirmed sites of modern human Stone Age culture in north central and northwestern Europe.

The evidence that Homo sapiens and Homo neanderthalensis lived side by side is consistent with genomic evidence that the two species occasionally interbred. It also feeds the suspicion that the invasion of Europe and Asia by modern humans some 50,000 years ago helped drive Neanderthals, which had occupied the area for more than 500,000 years, to extinction.

The genetic analysis, along with an archaeological and isotopic analysis and radiocarbon dating of the Ranis site, are detailed in a trio of papers appearing today in the journals Nature and Nature Ecology and Evolution.

The stone blades at Ranis, referred to as leaf points, are similar to stone tools found at several sites in Moravia, Poland, Germany and the United Kingdom. These tools that are thought to have been produced by the same culture, referred to as the Lincombian-Ranisian-Jerzmanowician (LRJ) culture or technocomplex. Because of previous dating, the Ranis site was known to be 40,000 years old or older, but without recognizable bones to indicate who made the tools, it was unclear whether they were the product of Neanderthals or Homo sapiens.

The new findings demonstrate that "Homo sapiens made this technology, and that Homo sapiens were this far north at this time period, which is 45,000 years ago," said Elena Zavala, one of four first authors of the Nature paper and a Miller Research Fellow at the University of California, Berkeley. "So these are among the earliest Homo sapiens in Europe."

Zavala was a Ph.D. student at the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig in 2018 when she first began working on the project, which was a major effort spearheaded by Jean-Jacque Hublin, former director of the institute and a professor at the Collège de France in Paris.

"The Ranis cave site provides evidence for the first dispersal of Homo sapiens across the higher latitudes of Europe. It turns out that stone artifacts that were thought to be produced by Neanderthals were, in fact, part of the early Homo sapiens toolkit," Hublin said. "This fundamentally changes our previous knowledge about the period: Homo sapiens reached northwestern Europe long before Neanderthal disappearance in southwestern Europe."

Source: ScienceDaily