Fruit, nectar, bugs and blood: How bat teeth and jaws evolved for a diverse dinnertime

They don't know it, but Darwin's finches changed the world. These closely related species -- native to the Galapagos Islands -- each sport a uniquely shaped beak that matches their preferred diet. Studying these birds helped Charles Darwin develop the theory of evolution by natural selection.

A group of bats has a similar -- and more expansive -- evolutionary story to tell. There are more than 200 species of noctilionoid bats, mostly in the American tropics. And despite being close relatives, their jaws evolved in wildly divergent shapes and sizes to exploit different food sources. A paper published Aug. 22 in Nature Communications shows those adaptations include dramatic, but also consistent, modifications to tooth number, size, shape and position. For example, bats with short snouts lack certain teeth, presumably due to a lack of space. Species with longer jaws have room for more teeth -- and, like humans, their total tooth complement is closer to what the ancestor of placental mammals had.

According to the research team behind this study, comparing noctilionoid species can reveal a lot about how mammalian faces evolved and developed, particularly jaws and teeth. And as a bonus, they can also answer some outstanding questions about how our own pearly whites form and grow.

"Bats have all four types of teeth -- incisors, canines, premolars and molars -- just like we do," said co-author Sharlene Santana, a University of Washington professor of biology and curator of mammals at the Burke Museum of Natural History & Culture. "And noctilionoid bats evolved a huge diversity of diets in as little as 25 million years, which is a very short amount of time for these adaptations to occur."

"There are noctilionoid species that have short faces like bulldogs with powerful jaws that can bite the tough exterior of the fruits that they eat. Other species have long snouts to help them drink nectar from flowers. How did this diversity evolve so quickly? What had to change in their jaws and teeth to make this possible?" said lead author Alexa Sadier, an incoming faculty member at the Institute of Evolutionary Science of Montpellier in France, who began this project as a postdoctoral researcher at the University California, Los Angeles.

Scientists don't know what triggered this frenzy of dietary adaptation in noctilionoid bats. But today different noctilionoid species feast on insects, fruit, nectar, fish and even blood -- since this group also includes the infamous vampire bats.

The team used CT scans and other methods to analyze the shapes and sizes of jaws, premolars and molars in more than 100 noctilionoid species. The bats included both museum specimens and a limited number of wild bats captured for study purposes. The researchers compared the relative sizes of teeth and other cranial features among species with different types of diets, and used mathematical modeling to determine how those differences are generated during development.

The team found that, in noctilionoid bats, certain "developmental rules" caused them to generate the right assortment of teeth to fit in their diet-formed grins. For example, bats with long jaws -- like nectar-feeders -- or intermediate jaws, like many insect-eaters, tended to have the usual complement of three premolars and three molars on each side of the jaw. But bats with short jaws, including most fruit-eating bats, tended to ditch the middle premolar or the back molar, if not both.

"When you have more space, you can have more teeth," said Sadier. "But for bats with a shorter space, even though they have a more powerful bite, you simply run out of room for all these teeth."

Having a shorter jaw may also explain why many short-faced bats also tended to have wider front molars.

"The first teeth to appear tend to grow bigger since there is not enough space for the next ones to emerge," said Sadier.

"This project is giving us the opportunity to actually test some of the assumptions that have been made about how tooth growth, shape and size are regulated in mammals," said Santana. "We know surprisingly little about how these very important structures develop!"

Many studies about mammalian tooth development were done in mice, which have only molars and heavily modified incisors. Scientists are not entirely sure if the genes and developmental patterns that control tooth development in mice also operate in mammals with more "ancestral" sets of chompers -- like bats and humans.

Sadier, Santana and their colleagues believe their project, which is ongoing, can start to answer these questions in bats -- along with many other outstanding questions about how evolution shapes mammalian features. They're expanding this study to include noctilionoid incisors and canines, and hope to uncover more of the genetic and developmental mechanisms that control tooth development in this diverse group of bats.

"We see such strong selective pressures in these bats: Shapes have to closely match their function," said Santana. "I think there are many more evolutionary secrets hidden in these species."

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Novel ultrasound uses microbubbles to open blood-brain barrier to treat glioblastoma in humans

A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can't permeate the blood-brain barrier to reach the aggressive brain tumor.

But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.

The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment.

This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.

Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances.

In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.

"This is potentially a huge advance for glioblastoma patients," said lead investigator Dr. Adam Sonabend, an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.

Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.

The paper will be published May 2 in The Lancet Oncology.

The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain.

In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.

Blood-brain barrier recloses after an hour

The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.

"There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream," Sonabend said.

Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.

In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.

Clinical trial for patients with recurrent glioblastoma

The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial -- in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique -- is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.

In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.

Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent die called fluorescein and by MRI obtained after ultrasound therapy.

"While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases," Sonabend said.

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Successful cure of HIV infection after stem cell transplantation, study suggests

Haematopoietic stem cell transplantation for the treatment of severe blood cancers is the only medical intervention that has cured two people living with HIV in the past. An international group of physicians and researchers from Germany, the Netherlands, France, Spain, and the United States has now identified another case in which HIV infection has been shown to be cured in the same way. In a study published this week in Nature Medicine, in which DZIF scientists from Hamburg and Cologne played a leading role, the successful healing process of this third patient was for the first time characterised in great detail virologically and immunologically over a time span of ten years.

An infection with the human immunodeficiency virus (HIV) was previously considered incurable. The reason for this is that the virus "sleeps" in the genome of infected cells for long periods of time, making it invisible and inaccessible to both the immune system and antiviral drugs. The "Düsseldorf patient," a 53-year-old man, is now the third person in the world to be completely cured of the HI virus by a stem cell transplant.

The patient, treated at the University Hospital Düsseldorf for his HIV infection, had received a stem cell transplant due to a blood cancer. As in the cases of the first two patients named "Berlin" and "London," the Düsseldorf patient received stem cells from a healthy donor whose genome contains a mutation in the gene for the HIV-1 co-receptor CCR5. This mutation makes it impossible for most HI viruses to enter human CD4+ T-lymphocytes, their major target cells.

Following transplantation, the patient was carefully monitored virologically and immunologically for almost ten years. Using a variety of sensitive techniques, the researchers analysed the patient's blood and tissue samples to closely monitor immune responses to HIV and the continued presence or even replication of the virus. Already shortly after transplantation and over the entire course of the study years, neither replicating virus nor antibodies or reactive immune cells against HIV were detected. More than four years ago, the antiviral therapy against HIV was discontinued. Ten years after transplantation and four years after the end of anti-HIV therapy, the Düsseldorf patient could be declared cured by the international research consortium.

"This case of curing a chronic HIV infection by stem cell transplantation shows that HIV can in principle be cured," says Prof. Julian Schulze zur Wiesch, DZIF scientist at the University Medical Center Hamburg-Eppendorf and one of the study leads. "In particular, the results of this study are also enormously important for further research into a cure for HIV for the vast majority of people living with HIV for whom stem cell transplantation is not an option."

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Ten-minute scan enables detection and cure of the commonest cause of high blood pressure

Doctors at Queen Mary University of London and Barts Hospital, and Cambridge University Hospital, have led research using a new type of CT scan to light up tiny nodules in a hormone gland and cure high blood pressure by their removal. The nodules are discovered in one-in-twenty people with high blood pressure.

Published today in Nature Medicine, the research solves a 60-year problem of how to detect the hormone producing nodules without a difficult catheter study that is available in only a handful of hospitals, and often fails. The research also found that, when combined with a urine test, the scan detects a group of patients who come off all their blood pressure medicines after treatment.

128 people participated in the study of a new scan after doctors found that their Hypertension (high blood pressure) was caused by a steroid hormone, aldosterone. The scan found that in two thirds of patients with elevated aldosterone secretion, this is coming from a benign nodule in just one of the adrenal glands, which can then be safely removed. The scan uses a very short-acting dose of metomidate, a radioactive dye that sticks only to the aldosterone-producing nodule. The scan was as accurate as the old catheter test, but quick, painless and technically successful in every patient. Until now, the catheter test was unable to predict which patients would be completely cured of hypertension by surgical removal of the gland. By contrast, the combination of a 'hot nodule' on the scan and urine steroid test detected 18 of the 24 patients who achieved a normal blood pressure off all their drugs.

The research, conducted on patients at Barts Hospital, Cambridge University Hospital, and Guy's and St Thomas's, and Universities of Glasgow and Birmingham, was funded by the National Institute for Health and Care Research (NIHR) and Medical Research Council (MRC) partnership, Barts Charity, and the British Heart Foundation.

Professor Morris Brown, co-senior author of the study and Professor of Endocrine Hypertension at Queen Mary University of London, said: "These aldosterone-producing nodules are very small and easily overlooked on a regular CT scan. When they glow for a few minutes after our injection, they are revealed as the obvious cause of Hypertension, which can often then be cured. Until now, 99% are never diagnosed because of the difficulty and unavailability of tests. Hopefully this is about to change."

Professor William Drake, co-senior author of the study and Professor of Clinical Endocrinology at Queen Mary University of London, said:"This study was the result of years of hard work and collaboration between centres across the UK. Much of the 'on the ground' energy and drive came from the talented research fellows who, in addition to doing this innovative work, gave selflessly of their time and energy during the national pandemic emergency. The future of research in this area is in very safe hands."

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How crocs can go hours without air: Crocodilian hemoglobin

It can pogo-stick along at 50-plus miles per hour, leaping 30-odd feet in a single bound. But that platinum-medal athleticism falls by the wayside at a sub-Saharan riverside, the source of life and death for the skittish impala stilling itself for a drink in 100-degree heat. A Nile crocodile has silently baptized itself in that same muddy river for the past hour. When the unseen apex predator lashes from the water to seize the impala, its infamous teeth latch onto a hindquarter, jaws clenching with 5,000 pounds of force. Yet it's the water itself that does the killing, with the deep-breathed reptile dragging its prey to the deep end to drown.

The success of the croc's ambush lies in the nanoscopic scuba tanks -- hemoglobins -- that course through its bloodstream, unloading oxygen from lungs to tissues at a slow but steady clip that allows it to go hours without air. The hyper-efficiency of that specialized hemoglobin has led some biologists to wonder why, of all the jawed vertebrates in all the world, crocodilians were the lone group to hit on such an optimal solution to making the most of a breath.

By statistically reconstructing and experimentally resurrecting the hemoglobin of an archosaur, the 240-million-year-old ancestor of all crocodilians and birds, the University of Nebraska-Lincoln's Jay Storz and colleagues have gleaned new insights into that why. Rather than requiring just a few key mutations, as earlier research suggested, the unique properties of crocodilian hemoglobin stemmed from 21 interconnected mutations that litter the intricate component of red blood cells.

That complexity, and the multiple knock-on effects that any one mutation can induce in hemoglobin, may have forged an evolutionary path so labyrinthine that nature failed to retrace it even over tens of millions of years, the researchers said.

"If it was such an easy trick -- if it was that easy to do, just making a few changes -- everyone would be doing it," said Storz, a senior author of the study and Willa Cather Professor of biological sciences at Nebraska.

All hemoglobin binds with oxygen in the lungs before swimming the bloodstream and eventually releasing that oxygen to the tissues that depend on it. In most vertebrates, hemoglobin's affinity for capturing and holding oxygen is dictated largely by molecules known as organic phosphates, which, by attaching themselves to the hemoglobin, can coax it into releasing its precious cargo.

But in crocodilians -- crocodiles, alligators and their kin -- the role of organic phosphates was supplanted by a molecule, bicarbonate, that is produced from the breakdown of carbon dioxide. Because hardworking tissues produce lots of carbon dioxide, they also indirectly generate lots of bicarbonate, which in turn encourages hemoglobin to dispense its oxygen to the tissues most in need of it.

"It's a super-efficient system that provides a kind of slow-release mechanism that allows crocodilians to efficiently exploit their onboard oxygen stores," Storz said. "It's part of the reason they're able to stay underwater for so long."

As postdoctoral researchers in Storz's lab, Chandrasekhar Natarajan, Tony Signore and Naim Bautista had already helped decipher the workings of the crocodilian hemoglobin. Alongside colleagues from Denmark, Canada, the United States and Japan, Storz's team decided to embark on a multidisciplinary study of how the oxygen-ferrying marvel came to be.

Prior efforts to understand its evolution involved incorporating known mutations into human hemoglobin and looking for any functional changes, which were usually scant. Recent findings from his own lab had convinced Storz that the approach was flawed. There were plenty of differences, after all, between human hemoglobin and that of the ancient reptilian creatures from which modern-day crocodilians evolved.

"What's important is to understand the effects of mutations on the genetic background in which they actually evolved, which means making vertical comparisons between ancestral and descendant proteins, rather than horizontal comparisons between proteins of contemporary species," Storz said. "By using that approach, you can figure out what actually happened."

So, with the help of biochemical principles and statistics, the team set out to reconstruct hemoglobin blueprints from three sources: the 240-million-year-old archosaur ancestor; the last common ancestor of all birds; and the 80-million-year-old shared ancestor of contemporary crocodilians. After putting all three of the resurrected hemoglobins through their paces in the lab, the team confirmed that only the hemoglobin of the direct crocodilian ancestor lacked phosphate binding and boasted bicarbonate sensitivity.

Comparing the hemoglobin blueprints of the archosaur and crocodilian ancestors also helped identify changes in amino acids -- essentially the joints of the hemoglobin skeleton -- that may have proved important. To test those mutations, Storz and his colleagues began introducing certain croc-specific mutations into the ancestral archosaur hemoglobin. By identifying the mutations that made archosaur hemoglobin behave more like that of a modern-day crocodilian, the team pieced together the changes responsible for those unique, croc-specific properties.

Counter to conventional wisdom, Storz and his colleagues discovered that evolved changes in hemoglobin's responsiveness to bicarbonate and phosphates were driven by different sets of mutations, so that the gain of one mechanism was not dependent on the loss of the other. Their comparison also revealed that, though a few mutations were enough to subtract the phosphate-binding sites, multiple others were needed to eliminate phosphate sensitivity all together. In much the same way, two mutations seemed to directly drive the emergence of bicarbonate sensitivity -- but only when combined with or preceded by other, easy-to-miss mutations in remote regions of the hemoglobin.

Storz said the findings speak to the fact that a combination of mutations might yield functional changes that transcend the sum of their individual effects. A mutation that produces no functional effect on its own might, in any number of ways, open a path to other mutations with clear, direct consequences. In the same vein, he said, those later mutations might influence little without the proper stage-setting predecessors already in place. And all of those factors can be supercharged or waylaid by the environment in which they unfold.

"When you have these complex interactions, it suggests that certain evolutionary solutions are only accessible from certain ancestral starting points," Storz said. "With the ancestral archosaur hemoglobin, you have a genetic background that makes it possible to evolve the unique properties that we see in hemoglobins of modern-day crocodilians. By contrast, with the ancestor of mammals as a starting point, it may be that there's some way that you could evolve the same property, but it would have to be through a completely different molecular mechanism, because you're working within a completely different structural context."

For better or worse, Storz said, the study also helps explain the difficulty of engineering a human hemoglobin that can mimic and approach the performance of the crocodilian.

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Neanderthals appear to have been carnivores

For the first time, zinc isotope ratios in tooth enamel have been analysed with the aim of identifying the diet of a Neanderthal. The Neanderthal to whom the tooth belonged was probably a carnivore. Other chemical tracers indicate that this individual did not consume the blood of their prey, but ate the bone marrow without consuming the bones.

A new study published on October 17th in the journal PNAS, led by a CNRS researcher, has for the first time used zinc isotope analysis to determine the position of Neanderthals in the food chain. Their findings suggest that they were in fact carnivores.

Were Neanderthals carnivores? Scientists have not yet settled the question. While some studies of the dental tartar of individuals from the Iberian Peninsula appear to show that they were major consumers of plants, other research carried out at sites outside Iberia seem to suggest that they consumed almost nothing but meat. Using new analytical techniques on a molar belonging to an individual of this species, researchers1 have shown that the Neanderthals at the Gabasa site in Spain appear to have been carnivores.

To determine an individual's position in the food chain, scientists have until now generally had to extract proteins and analyse the nitrogen isotopes present in the bone collagen. However, this method can often only be used in temperate environments, and only rarely on samples over 50,000 years old. When these conditions are not met, nitrogen isotope analysis is very complex, or even impossible. This was the case for the molar from the Gabasa site analysed in this study.

Given these constraints, Klevia Jaouen, a CNRS researcher, and her colleagues decided to analyse the zinc isotope ratios present in the tooth enamel, a mineral that is resistant to all forms of degradation. This is the first time this method has been used to attempt to identify a Neanderthal's diet. The lower the proportions of zinc isotopes in the bones, the more likely they are to belong to a carnivore. The analysis was also carried out on the bones of animals from the same time period and geographical area, including carnivores such as lynxes and wolves, and herbivores like rabbits and chamois. The results showed that the Neanderthal to whom this tooth from the Gabasa site belonged was probably a carnivore who did not consume the blood of their prey.

Broken bones found at the site, together with isotopic data, indicate that this individual also ate the bone marrow of their prey, without consuming the bones, while other chemical tracers show that they were weaned before the age of two. Analyses also show that this Neanderthal probably died in the same place they had lived in as a child.

Compared to previous techniques, this new zinc isotope analysis method makes it easier to distinguish between omnivores and carnivores. To confirm their conclusions, the scientists hope to repeat the experiment on individuals from other sites, especially from the Payre site in south-east France, where new research is under way.

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The benefits of exercise in a pill? Science is closer to that goal

Researchers at Baylor College of Medicine, Stanford School of Medicine and collaborating institutions report today in the journal Nature that they have identified a molecule in the blood that is produced during exercise and can effectively reduce food intake and obesity in mice. The findings improve our understanding of the physiological processes that underlie the interplay between exercise and hunger.

"Regular exercise has been proven to help weight loss, regulate appetite and improve the metabolic profile, especially for people who are overweight and obese," said co-corresponding author Dr. Yong Xu, professor of pediatrics- nutrition and molecular and cellular biology at Baylor. "If we can understand the mechanism by which exercise triggers these benefits, then we are closer to helping many people improve their health."

"We wanted to understand how exercise works at the molecular level to be able to capture some of its benefits," said co-corresponding author Jonathan Long, MD, assistant professor of pathology at Stanford Medicine and an Institute Scholar of Stanford ChEM-H (Chemistry, Engineering & Medicine for Human Health). "For example, older or frail people who cannot exercise enough, may one day benefit from taking a medication that can help slow down osteoporosis, heart disease or other conditions."

Xu, Long and their colleagues conducted comprehensive analyses of blood plasma compounds from mice following intense treadmill running. The most significantly induced molecule was a modified amino acid called Lac-Phe. It is synthesized from lactate (a byproduct of strenuous exercise that is responsible for the burning sensation in muscles) and phenylalanine (an amino acid that is one of the building blocks of proteins).

In mice with diet-induced obesity (fed a high-fat diet), a high dose of Lac-Phe suppressed food intake by about 50% compared to control mice over a period of 12 hours without affecting their movement or energy expenditure. When administered to the mice for 10 days, Lac-Phe reduced cumulative food intake and body weight (owing to loss of body fat) and improved glucose tolerance.

The researchers also identified an enzyme called CNDP2 that is involved in the production of Lac-Phe and showed that mice lacking this enzyme did not lose as much weight on an exercise regime as a control group on the same exercise plan.

Interestingly, the team also found robust elevations in plasma Lac-Phe levels following physical activity in racehorses and humans. Data from a human exercise cohort showed that sprint exercise induced the most dramatic increase in plasma Lac-Phe, followed by resistance training and then endurance training. "This suggests that Lac-Phe is an ancient and conserved system that regulates feeding and is associated with physical activity in many animal species," Long said.

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Why exercise gets harder the less you do

Doing less exercise could deactivate a vital protein in the body, causing further inactivity and making exercise more difficult, new research suggests.

University of Leeds scientists have discovered that deactivating the Piezo1 protein, a blood flow sensor, reduces the density of capillaries carrying blood to the muscles.

This restricted blood flow means activity becomes more difficult and can lead to a reduction in how much exercise is possible, the team found.

They say the results help to explain the biology of why exercise becomes harder the less you do.

The paper, Endothelial Piezo1 sustains muscle capillary density and contributes to physical activity, is published today in Journal of Clinical Investigation.

The experiments were carried out in mice, but the Piezo1 protein is found in humans, suggesting the same results could occur.

Lead author Fiona Bartoli, a Postdoctoral Researcher in the University of Leeds' School of Medicine, said: "Exercise protects against cardiovascular disease, diabetes, depression and cancer. Unfortunately, many people fail to exercise enough, for reasons such as injury and computer usage. This puts people at more risk of disease. The less people exercise, the less fit they become, often leading to a downward spiral.

"Although many responses to exercise are known, how the benefits of exercise are initially triggered at a molecular level is mysterious. Our study highlights the crucial link between physical activity and physical performance made at this level by Piezo1. Keeping our Piezo1s active by exercising may be crucial in our physical performance and health."

During the experiment, scientists compared two groups of mice -- a control group, and a group whose Piezo1 levels had been disrupted for 10 weeks. Walking, climbing and running wheel activity was observed, with the Piezo1 mice showing a striking reduction in activity levels. This suggests an important role for Piezo1 in sustaining normal physical activity.

The researchers considered whether the Piezo1 mice were less interested in exercise, but they found no differences in the amount or duration of activity between the two groups. Instead, there were fewer running wheel revolutions per exercise session, and slower running speed, suggesting a lowered ability to exercise, without a lesser desire.

Supervising author Professor David Beech, in the University of Leeds' School of Medicine, said: "Our work sheds new light on how Piezo1's role in blood vessels is connected to physical activity. A lot was already known about its role in blood vessel development, but far less was known about its contribution to vessel maintenance in adults.

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New model points to solution to global blood shortage

Blood transfusions save lives, yet the precious fluid is in desperately short supply, not just in the U.S. but around the globe. But what if transfusions don't always require blood?

A new mathematical model of the body's interacting physiological and biochemical processes -- including blood vessel expansion, blood thickening and flow-rate changes in response to the transfusion of red blood cells -- shows that patients with anemia, or blood with low oxygen levels, can be effectively treated with transfusions of blood substitutes that are more readily available.

The research, co-authored by scientists at Stanford University and the University of California, San Diego (UCSD), was published on Oct. 14 in the Journal of Applied Physiology.

Using a different fluid could also eliminate a harmful consequence of blood transfusion: Blood use has been observed to lower lifespan by 6 percent per unit transfused per decade because of its adverse side effects.

"Instead of real blood, we can use a substitute that can lower the costs and eliminate blood transfusion's negative effects," said lead study author Weiyu Li, a PhD student in energy resources engineering at Stanford's School of Earth, Energy & Environmental Sciences (Stanford Earth).

Transfusion is a common procedure for transferring blood components directly to anemic patients' circulation. Red blood cells are uniquely equipped to perform the function of carrying oxygen, which is why they are used for transfusions for patients experiencing anemia. But the process of obtaining, storing and delivering the correct, sanitary blood type for each patient is also intensive and costly. Moreover, the supply of blood that is available falls far short of the demand: The global deficit across all countries without enough supply totals about 100 million units of blood per year.

"You could deliver more goods, in this case, oxygen, with less -- that's actually the basic idea of sustainability," said senior study author Daniel Tartakovsky, a professor of energy resources engineering at Stanford Earth. "It's all about how to do more with less."

Transfusion of red blood cells is done to improve the likelihood that oxygen vital to organ and tissue function will be delivered. However, the process also thickens the blood, and that increased viscosity can be a problem, according to the research. The new model shows that during transfusion, some patients' blood vessels do not dilate and, since their blood has been thickened by additional red blood cells, it is more viscous and does not circulate as easily to deliver oxygen. For these patients, treating anemia with a 2-unit transfusion -- currently, the most frequently used transfusion quantity -- would reduce blood flow, regardless of the state of anemia, according to the model.

However, for many people, transfusion causes blood vessels to dilate, thereby increasing circulation and delivering more oxygen to the body. The findings reveal the advantage of anemic patients whose blood vessels dilate during transfusion. The model suggests that either abstaining from transfusion or transfusing alternative fluids known as plasma expanders, which prompt blood vessels to dilate, may be a more effective way to increase oxygen delivery. Plasma expanders consist of solutions of high-molecular-weight starch dissolved in normal saline; they have been in use in transfusion medicine for several decades and have proven to be effective in experimental studies.

"At present, blood transfusion is determined by addressing the wrong target, namely restoring oxygen-carrying capacity," said co-author Marcos Intaglietta, a professor and founder of the bioengineering discipline at UCSD. "But the logical target of a blood transfusion is restoring oxygen-delivery capacity."

Projections of the team's results show that safe and low-cost blood substitutes can decrease the overall cost of blood transfusion by 10 times, while significantly lowering the negative aspects of the process. Their model of the body's circulatory processes was derived from previously published experiments on how mammals react to transfusion.

"Our mathematical model identifies natural physiological processes that explain the conclusion of multiple observational studies: People can get the benefit of blood transfusion without using blood," Tartakovsky said. "But nothing really comes out of modeling alone -- it has to be grounded in observations, investigational studies and experience."

The co-authors hope their findings will lead to clinical trials that test the capacity for non-blood alternatives to increase oxygen delivery. To date, there have not been consistent results from rigorous medical trials that support the notion that small amounts of blood are more effective than just adding human plasma, according to the study authors.

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Researchers find warning signs for dementia in the blood

Researchers at the DZNE and the University Medical Center Göttingen (UMG) have identified molecules in the blood that can indicate impending dementia. Their findings, which are presented in the scientific journal EMBO Molecular Medicine, are based on human studies and laboratory experiments. Various university hospitals across Germany were also involved in the investigations. The biomarker described by the team led by Prof. André Fischer is based on measuring levels of so-called microRNAs. The technique is not yet suitable for practical use; the scientists therefore aim to develop a simple blood test that can be applied in routine medical care to assess dementia risk. According to the study data, microRNAs could potentially also be targets for dementia therapy.

"When symptoms of dementia manifest, the brain has already been massively damaged. Presently, diagnosis happens far too late to even have a chance for effective treatment. If dementia is detected early, the odds of positively influencing the course of the disease increase," says André Fischer, research group leader and spokesperson at the DZNE site in Göttingen and professor at the Department of Psychiatry and Psychotherapy at UMG. "We need tests that ideally respond before the onset of dementia and reliably estimate the risk of later disease. In other words, tests that give an early warning. We are confident that our current study results pave the way for such tests."

Molecular Signature

The biomarker that Fischer and his colleagues have found is based on measuring so-called microRNAs in the blood. MicroRNAs are molecules with regulatory properties: they influence the production of proteins and thus a key process in the metabolism of every living being. "There are many different microRNAs and each of them can regulate entire networks of interdependent proteins and thus influence complex processes in the organism. So, microRNAs have a broad impact. We wanted to find out whether there are specific microRNAs whose presence in the blood correlates with mental fitness," Fischer says.

Through extensive studies in humans, mice and cell cultures, the researchers ultimately identified three microRNAs whose levels were associated with mental performance. For this, they analyzed data from both young, cognitively normal individuals and from elderly people with mild cognitive impairment (MCI). For the data from healthy individuals, the Göttingen scientists cooperated with Munich University Hospital. The data from MCI patients came from a DZNE study that has been running for years and involves university clinics throughout Germany.

Omens of Dementia

In the end, the various findings came together like pieces of a puzzle: In healthy individuals, levels of microRNAs correlated with mental fitness. The lower the blood level, the better the subjects performed in cognition tests. In mice, in turn, this score increased even before the rodents started to show mental decline -- regardless of whether this was due to age or because they developed symptoms similar to those of Alzheimer's dementia. Further evidence came from patients with MCI: Of those in whom the blood marker was highly elevated, about 90 percent developed Alzheimer's disease within two years. "We therefore see an increased blood level of these three microRNAs as a harbinger of dementia," Fischer says. "We estimate that in humans this biomarker indicates a development that is about two to five years in the future."

Potential Targets for Therapy

In their studies on mice and cell cultures, the researchers also found that the three identified microRNAs influence inflammatory processes in the brain and "neuroplasticity" which includes the ability of neurons to establish connections with each other. This suggests that the three microRNAs are more than warning signals. "In our view, they are not only markers, but also have an active impact on pathological processes. This makes them potential targets for therapy," Fischer says. "Indeed, we see in mice that learning ability improves when these microRNAs are blocked with drugs. We've observed this in mice with age-related mental deficits, as well as in mice with brain damage similar to that occurring in Alzheimer's disease."

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Potential new treatment for deadly blood cancer

A drug used to treat certain advanced breast cancers may offer a new treatment option for a deadly blood cancer known as myelofibrosis, new research from UVA Cancer Center suggests.

The drug, palbociclib, may be able to prevent the scarring of bone marrow that existing treatments for myelofibrosis cannot. This scarring disrupts the marrow's production of blood cells and causes severe anemia that leaves patients weak and fatigued. The scarring also reduces the number of platelets in the blood, making clotting difficult, and often causes an enlarged spleen.

"Current therapies only provide symptomatic relief without offering significant improvement of bone marrow fibrosis. So, there is a critical need to develop more effective therapy for myelofibrosis," said senior researcher Golam Mohi, PhD, of the University of Virginia School of Medicine's Department of Biochemistry and Molecular Genetics. "We have identified CDK6, a regulator of cell cycle, as a new therapeutic target in myelofibrosis. We demonstrate that CDK4/6 inhibitor palbociclib in combination with ruxolitinib markedly inhibits myelofibrosis, suggesting this drug combination could be an effective therapeutic strategy against this devastating blood disorder."

Myelofibrosis: A Dangerous Cancer

Myelofibrosis is a form of leukemia. It occurs in approximately 1 to 1.5 of every 100,000 people, primarily those who are middle-aged or older. Patients with intermediate or high-risk cases typically survive only 16 to 35 months.

Existing treatments for myelofibrosis do not address the bone marrow scarring that is a hallmark of the disease. The drug ruxolitinib is used to relieve patients' symptoms, but Mohi's new research suggests that pairing the drug with palbociclib may make a far superior treatment.

Palbociclib, by itself, reduced bone marrow scarring in two different mouse models of myelofibrosis. It also decreased the abnormally high levels of white blood cells seen in myelofibrosis and shrank the mice's enlarged spleens.

Combining the drug with ruxolitinib offered even more benefits, restoring the bone marrow and white blood cell counts to normal and dramatically reducing the size of the mice's enlarged spleens.

Additional research is needed to determine if the findings will hold true in human patients. But Mohi and his team are hopeful. They note that palbociclib is known to quiet the activity of bone marrow in patients with metastatic breast cancer (cancer that has spread to other parts of the body), and they hope there will be beneficial effects in patients with myelofibrosis.

"A combinatorial therapeutic approach involving palbociclib and ruxolitinib will enable lowering the doses of each of the inhibitors and thus reducing toxicities while enhancing the therapeutic efficacy," they write in a new scientific paper outlining their findings.

New treatments for myelofibrosis are particularly needed because ruxolitinib treatment does not offer significant reduction in bone marrow fibrosis and often loses its effectiveness with prolonged use, the researchers note.

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New method could reveal what genes we might have inherited from Neanderthals

Thousands of years ago, archaic humans such as Neanderthals and Denisovans went extinct. But before that, they interbred with the ancestors of present-day humans, who still to this day carry genetic mutations from the extinct species.

Over 40 percent of the Neanderthal genome is thought to have survived in different present-day humans of non-African descent, but spread out so that any individual genome is only composed of up to two percent Neanderthal material. Some human populations also carry genetic material from Denisovans -- a mysterious group of archaic humans that may have lived in Eastern Eurasia and Oceania thousands of years ago.

The introduction of beneficial genetic material into our gene pool, a process known as adaptive introgression, often happened because it was advantageous to humans after they expanded across the globe. To name a few examples, scientists believe some of the mutations affected skin development and metabolism. But many mutations are yet still undiscovered.

Now, researchers from GLOBE Institute at the University of Copenhagen have developed a new method using deep learning techniques to search the human genome for undiscovered mutations.

"We developed a deep learning method called 'genomatnn' that jointly models introgression, which is the transfer of genetic information between species, and natural selection. The model was developed in order to identify regions in the human genome where this introgression could have happened," says Associate Professor Fernando Racimo, GLOBE Institute, corresponding author of the new study.

"Our method is highly accurate and outcompetes previous approaches in power. We applied it to various human genomic datasets and found several candidate beneficial gene variants that were introduced into the human gene pool," he says.

The new method is based on a so-called convolutional neural network (CNN), which is a type of deep learning framework commonly used in image and video recognition.

Using hundreds of thousands of simulations, the researchers at the University of Copenhagen trained the CNN to identify patterns in images of the genome that would be produced by adaptive introgression with archaic humans.

Besides confirming already suggested genetic mutations from adaptive introgression, the researchers also discovered possible mutations that were not known to be introgressed.

"We recovered previously identified candidates for adaptive introgression in modern humans, as well as several candidates which have not previously been described," says postdoc Graham Gower, first author of the new study.

Some of the previously undescribed mutations are involved in core pathways in human metabolism and immunity.

"In European genomes, we found two strong candidates for adaptive introgression from Neanderthals in regions of the genome that affect phenotypes related to blood, including blood cell counts. In Melanesian genomes, we found candidate variants introgressed from Denisovans that potentially affected a wide range of traits, such as blood-related diseases, tumor suppression, skin development, metabolism, and various neurological diseases. It's not clear how such traits are affected in present-day carriers of the archaic variants, e.g. neutrally, positively or negatively, although historically the introgressed genetic material is assumed to have had a positive effect on those individuals carrying them," he explains.

The next stage for the research team is to adapt the method to more complex demographic and selection scenarios to understand the overall fate of Neanderthal genetic material. Graham Gower points out that the team aims to follow up on the function of the candidate variants in the genome that they found in this study.

Looking forward, it remains a challenge to search the human genome for genetic material from as yet unsampled populations, so-called ghost populations. However, the researchers are hopeful that they can further train the neural network to recognize mutations from these unsampled populations.

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Proteins that predict future dementia, Alzheimer's risk, identified

The development of dementia, often from Alzheimer's disease, late in life is associated with abnormal blood levels of dozens of proteins up to five years earlier, according to a new study led by researchers at the Johns Hopkins Bloomberg School of Public Health. Most of these proteins were not known to be linked to dementia before, suggesting new targets for prevention therapies.

The findings are based on new analyses of blood samples of over ten thousand middle-aged and elderly people -- samples that were taken and stored during large-scale studies decades ago as part of an ongoing study. The researchers linked abnormal blood levels of 38 proteins to higher risks of developing Alzheimers within five years. Of those 38 proteins, 16 appeared to predict Alzheimer's risk two decades in advance.

Although most of these risk markers may be only incidental byproducts of the slow disease process that leads to Alzheimer's, the analysis pointed to high levels of one protein, SVEP1, as a likely causal contributor to that disease process.

The study was published May 14 in Nature Aging.

"This is the most comprehensive analysis of its kind to date, and it sheds light on multiple biological pathways that are connected to Alzheimer's," says study senior author Josef Coresh, MD, PhD, MHS, George W. Comstock Professor in the Department of Epidemiology at the Bloomberg School. "Some of these proteins we uncovered are just indicators that disease might occur, but a subset may be causally relevant, which is exciting because it raises the possibility of targeting these proteins with future treatments."

More than six million Americans are estimated to have Alzheimer's, the most common type of dementia, an irreversible fatal condition that leads to loss of cognitive and physical function. Despite decades of intensive study, there are no treatments that can slow the disease process, let alone stop or reverse it. Scientists widely assume that the best time to treat Alzheimer's is before dementia symptoms develop.

Efforts to gauge people's Alzheimer's risk before dementia arises have focused mainly on the two most obvious features of Alzheimer's brain pathology: clumps of amyloid beta protein known as plaques, and tangles of tau protein. Scientists have shown that brain imaging of plaques, and blood or cerebrospinal fluid levels of amyloid beta or tau, have some value in predicting Alzheimer's years in advance.

But humans have tens of thousands of other distinct proteins in their cells and blood, and techniques for measuring many of these from a single, small blood sample have advanced in recent years. Would a more comprehensive analysis using such techniques reveal other harbingers of Alzheimer's? That's the question Coresh and colleagues sought to answer in this new study.

The researchers' initial analysis covered blood samples taken during 2011-13 from more than 4,800 late-middle-aged participants in the Atherosclerosis Risk in Communities (ARIC) study, a large epidemiological study of heart disease-related risk factors and outcomes that has been running in four U.S. communities since 1985. Collaborating researchers at a laboratory technology company called SomaLogic used a technology they recently developed, SomaScan, to record levels of nearly 5,000 distinct proteins in the banked ARIC samples.

The researchers analyzed the results and found 38 proteins whose abnormal levels were significantly associated with a higher risk of developing Alzheimer's in the five years following the blood draw.

They then used SomaScan to measure protein levels from more than 11,000 blood samples taken from much younger ARIC participants in 1993-95. They found that abnormal levels of 16 of the 38 previously identified proteins were associated with the development of Alzheimer's in the nearly two decades between that blood draw and a follow-up clinical evaluation in 2011-13.

To verify these findings in a different patient population, the scientists reviewed the results of an earlier SomaScan of blood samples taken in 2002-06 during an Icelandic study. That study had assayed proteins including 13 of the 16 proteins identified in the ARIC analyses. Of those 13 proteins, six were again associated with Alzheimer's risk over a roughly 10-year follow-up period.

In a further statistical analysis, the researchers compared the identified proteins with data from past studies of genetic links to Alzheimer's. The comparison suggested strongly that one of the identified proteins, SVEP1, is not just an incidental marker of Alzheimer's risk but is involved in triggering or driving the disease.

SVEP1 is a protein whose normal functions remain somewhat mysterious, although in a study published earlier this year it was linked to the thickened artery condition, atherosclerosis, which underlies heart attacks and strokes.

Other proteins associated with Alzheimer's risk in the new study included several key immune proteins -- which is consistent with decades of findings linking Alzheimer's to abnormally intense immune activity in the brain.

The researchers plan to continue using techniques like SomaScan to analyze proteins in banked blood samples from long-term studies to identify potential Alzheimer's-triggering pathways -- a potential strategy to suggest new approaches for Alzheimer's treatments.

The scientists have also been studying how protein levels in the ARIC samples are linked to other diseases such as vascular (blood vessel-related) disease in the brain, heart and the kidney.

First author Keenan Walker, PhD, worked on this analysis while on faculty at the Johns Hopkins University School of Medicine and the Bloomberg School's Welch Center for Prevention, Epidemiology and Clinical Research. He is currently an investigator with the National Institute of Aging's Intramural Research Program.

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Scientists scour genes of 53,000+ people to better battle dangerous diseases

A new analysis of the entire genetic makeup of more than 53,000 people offers a bonanza of valuable insights into heart, lung, blood and sleep disorders, paving the way for new and better ways to treat and prevent some of the most common causes of disability and death.

The analysis from the Trans-Omics for Precision Medicine (TOPMed) program examines the complete genomes of 53,831 people of diverse backgrounds on different continents. Most are from minority groups, which have been historically underrepresented in genetic studies. The increased representation should translate into better understanding of how heart, lung, blood and sleep disorders affect minorities and should help reduce longstanding health disparities.

"The Human Genome Project has generated a lot of promises and opportunities for applying genomics to precision medicine, and the TOPMed program is a major step in this direction," said Stephen S. Rich, PhD, a genetics researcher at the University of Virginia School of Medicine who helped lead the project. "An important feature of TOPMed is not only publishing the genomic data on 53,000 people with massive amounts of data related to heart, lung, blood and sleep disorders but also the great diversity of the participants who donated their blood and data."

Historic Genome Analysis

The groundbreaking work identified 400 million genetic variants, of which more than 78% had never been described. Nearly 97% were extremely rare, occurring in less than 1% of people. This sheds light on both how genes mutate and on human evolution itself, the researchers say.

Of the groups studied, people of African descent had the greatest genetic variability, the researchers found. The resulting data is the best ever produced on people of African ancestry, the scientists report in the journal Nature.

The work also offers important new insights into certain gene variants that can reduce people's ability to benefit from prescription drugs. This can vary by race and ethnic group.

"TOPMed is an important and historic effort to include under-represented minority participants in genetic studies," said Rich, who served on the project's Executive Committee and chaired the Steering Committee. "The work of TOPMed should translate not only into better scientific knowledge but increase diversity at all levels -- scientists, trainees, participants -- in work to extend personalized medicine for everyone."

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Penguin hemoglobin evolved to meet oxygen demands of diving

 Call it the evolutionary march of the penguins.

More than 50 million years ago, the lovable tuxedoed birds began leaving their avian relatives at the shoreline by waddling to the water's edge and taking a dive in the pursuit of seafood.

Webbed feet, flipper-like wings and unique feathers all helped penguins adapt to their underwater excursions. But new research from the University of Nebraska-Lincoln has shown that the evolution of diving is also in their blood, which optimized its capture and release of oxygen to ensure that penguins wouldn't waste their breath while holding it.

Relative to land-dwelling birds, penguin blood is known to contain more hemoglobin: the protein that picks up oxygen from the lungs and transports it through the bloodstream before dropping it off at various tissues. That abundance could partly explain the underwater proficiency of, say, the emperor penguin, which dives deeper than any bird and has been documented holding its breath for more than 30 minutes while preying on krill, fish and squid.

Still, the particulars of their hemoglobin -- and how much it actually evolved to help penguins become fish-gobbling torpedoes that spend up to half of their lives underwater -- remained open questions. So Nebraska biologists Jay Storz and Anthony Signore, who often study the hemoglobin of birds that survive miles above sea level, decided to investigate the birds most adept at diving beneath it.

"There just wasn't a lot of comparative work on blood-oxygen transport as it relates to diving physiology in penguins and their non-diving relatives," said Signore, a postdoctoral researcher in Storz's lab.

Answering those questions meant sketching in the genetic blueprints of two ancient hemoglobins. One belonged to the common ancestor of all penguin species, which began branching from that ancestor about 20 million years ago. The other, dating back roughly 60 million years, resided in the common ancestor of penguins and their closest non-diving relatives -- albatrosses, shearwaters and other flying seabirds. The thinking was simple: Because one hemoglobin originated before the emergence of diving in the lineage, and the other after, any major differences between the two would implicate them as important to the evolution of diving in penguins.

Actually comparing the two was less simple. To start, the researchers literally resurrected both proteins by relying on models that factored in the gene sequences of modern hemoglobins to estimate the sequences of their two ancient counterparts. Signore spliced those resulting sequences into E. coli bacteria, which churned out the two ancient proteins. The researchers then ran experiments to evaluate the performance of each.

They found that the hemoglobin from the common ancestor of penguins captured oxygen more readily than did the version present in the blood of the older, non-diving ancestor. That stronger affinity for oxygen would mean less chance of leaving behind traces in the lungs, an especially vital issue among semi-aquatic birds needing to make the most of a single breath while hunting or traveling underwater.

Unfortunately, the very strength of that affinity can present difficulties when hemoglobin arrives at tissues starved for the oxygen it's carrying.

"Having a greater hemoglobin-oxygen affinity sort of acts like a stronger magnet to pull more oxygen from the lungs," Signore said. "It's great in that context. But then you're at a loss when it's time to let go."

Any breath-holding benefits gained by picking up extra oxygen, in other words, can be undone if the hemoglobin struggles to relax its iron-clad grip and release its prized cargo. The probability that it will is dictated in part by acidity and carbon dioxide in the blood. Higher levels of either make hemoglobins more likely to loosen up.

As Storz and Signore expected, the hemoglobin of the recent penguin ancestor was more sensitive to its surrounding pH, with its biochemical grip on oxygen loosening more in response to elevated acidity. And that, Signore said, made the hemoglobin more biochemically attuned to the exertion and oxygen needs of the tissues it served.

"It really is a beautiful system, because tissues that are working hard are becoming acidic," he said. "They need more oxygen, and hemoglobin's oxygen affinity is able to shift in response to that acidity to provide more oxygen.

"If pH drops by, say, 0.2 units, the oxygen affinity of penguin hemoglobin is going to decrease by more than would the hemoglobin of their non-diving relatives."

Together, the findings indicate that as penguins took to the seas, their hemoglobin evolved to maximize both the pick-up and drop-off of available oxygen -- especially when it was last inhaled five, or 10, or even 20 minutes earlier. They also illustrate the value of resurrecting proteins that last existed 20, or 40, or even 60 million years ago.

"These results demonstrate how the experimental analysis of ancestral proteins can reveal the mechanisms of biochemical adaptation," Storz said, "and also shed light on how organismal physiology evolved in response to new environmental challenges."

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Insulin rises before cells develop resistance, new diabetes research implies

 Researchers at the University of Gothenburg, Sweden, have now presented results that may change our basic view of how type 2 diabetes occurs. Their study indicates that free fatty acids (FFAs) in the blood trigger insulin release even at a normal blood-sugar level, without an overt uncompensated insulin resistance in fat cells. What is more, the researchers demonstrate the connection with obesity: the amount of FFAs largely depends on how many extra kilos of adipose tissue a person carries, but also on how the body adapt to the increased adiposity.

Worldwide, extensive research is underway to clarify exactly what happens in the body as type 2 diabetes progresses, and why obesity is such a huge risk factor for the disease. For almost 50 years, diabetes researchers have been discussing their version of the chicken-or-egg question: Which comes first -- insulin resistance or elevated insulin levels? The dominant hypothesis has long been that the pancreas steps up its insulin production because the cells have already become insulin-resistant, and blood sugar then rises. However, the results now published in the journal EBioMedicine support the opposing idea: that it is the insulin that increases first.

Detailed investigations

The study indicates that high FFA levels in the blood after the overnight fast raise insulin production in the morning. FFAs have long been part of the main research equation for type 2 diabetes, but it is now proposed that they also have another role: in progression of the disease.

For the study, researchers compared metabolism in adipose (fat-storing) tissue among 27 carefully selected research subjects (nine of normal weight, nine with obesity and normal blood sugar, and nine with both obesity and progressed type 2 diabetes). For several days, they underwent extensive examinations in which they had samples taken under varying conditions. The researchers analyzed metabolism and gene expression in the participants' subcutaneous fat, and the levels of blood sugar, insulin, and FFAs in their blood.

FFAs seem to trigger insulin production

The people with obesity but not diabetes proved to have the same, normal blood-sugar levels as the healthy individuals of normal weight.

"Interestingly, the nondiabetics with obesity had elevated levels of both free fatty acids and insulin in their blood, and those levels were similar to or higher than the levels we were able to measure in blood from the participants with both obesity and type 2 diabetes," says Emanuel Fryk, resident doctor specializing in general medicine and doctoral student at Sahlgrenska Academy, University of Gothenburg, who is one of the study's first authors.

In collaboration with researchers at Uppsala University, he observed the same pattern in a population study based on blood samples taken from 500 people after an overnight fast.

"The fact that we saw a link between free fatty acids and insulin there too suggests that the fatty acids are connected with the insulin release, and contribute to increased insulin production on an empty stomach, when blood sugar hasn't risen," says Fryk, who nevertheless points out that the finding needs to be confirmed with more research.

Ongoing research

Free fatty acids are found naturally in the bloodstream and, like glycerol, are a product of the body's fat metabolism. In the subjects, the amount of glycerol released proved to be broadly the same per kilo of body fat, regardless of whether they were of normal weight, had obesity alone, or also had type 2 diabetes.

"Our hypothesis is that the free fatty acids increase in the blood because the adipose tissue can't store the excess energy anymore. We believe, in that case, it could be an early sign of incipient type 2 diabetes. If our findings are confirmed when other research methods are used, there may be a chance that some specific fatty acids could be developed into biomarkers. But that's a long way off," Fryk says.

Lifestyle crucial

Diabetes is one of the most common diseases, with an estimated 500,000 people affected in Sweden. There are also a large number of undetected cases, since many with type 2 diabetes are not yet aware they are ill. Diabetics are at an increased risk for a number of serious conditions, such as cardiovascular disease (which may result in heart attacks and strokes).

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New blood test shows great promise in the diagnosis of Alzheimer's disease

Alzheimer's blood test, photo concept

A new blood test demonstrated remarkable promise in discriminating between persons with and without Alzheimer's disease and in persons at known genetic risk may be able to detect the disease as early as 20 years before the onset of cognitive impairment, according to a large international study published today in the Journal of the American Medical Association (JAMA) and simultaneously presented at the Alzheimer's Association International Conference.

For many years, the diagnosis of Alzheimer's has been based on the characterization of amyloid plaques and tau tangles in the brain, typically after a person dies. An inexpensive and widely available blood test for the presence of plaques and tangles would have a profound impact on Alzheimer's research and care. According to the new study, measurements of phospho-tau217 (p-tau217), one of the tau proteins found in tangles, could provide a relatively sensitive and accurate indicator of both plaques and tangles -- corresponding to the diagnosis of Alzheimer's -- in living people.

"The p-tau217 blood test has great promise in the diagnosis, early detection, and study of Alzheimer's," said Oskar Hansson, MD, PhD, Professor of Clinical Memory Research at Lund University, Sweden, who leads the Swedish BioFINDER Study and senior author on the study who spearheaded the international collaborative effort. "While more work is needed to optimize the assay and test it in other people before it becomes available in the clinic, the blood test might become especially useful to improve the recognition, diagnosis, and care of people in the primary care setting."

Researchers evaluated a new p-tau217 blood test in 1,402 cognitively impaired and unimpaired research participants from well-known studies in Arizona, Sweden, and Colombia. The study, which was coordinated from Lund University in Sweden, included 81 Arizona participants in Banner Sun Health Research Institute's Brain Donation program who had clinical assessments and provided blood samples in their last years of life and then had neuropathological assessments after they died; 699 participants in the Swedish BioFINDER Study who had clinical, brain imaging, cerebrospinal fluid (CSF), and blood-based biomarker assessments; and 522 Colombian autosomal dominant Alzheimer's disease (ADAD)-causing mutation carriers and non-carriers from the world's largest ADAD cohort.

• In the Arizona (Banner Sun Health Research Institute) Brain Donation Cohort, the plasma p-tau217 assay discriminated between Arizona Brain donors with and without the subsequent neuropathological diagnosis of "intermediate or high likelihood Alzheimer's" (i.e., characterized by plaques, as well as tangles that have at least spread to temporal lobe memory areas or beyond) with 89% accuracy; it distinguished between those with and without a diagnosis of "high likelihood Alzheimer's" with 98% accuracy; and higher ptau217 measurements were correlated with higher brain tangle counts only in those persons who also had amyloid plaques.
• In the Swedish BioFINDER Study, the assay discriminated between persons with the clinical diagnoses of Alzheimer's and other neurodegenerative diseases with 96% accuracy, similar to tau PET scans and CSF biomarkers and better than several other blood tests and MRI measurements; and it distinguished between those with and without an abnormal tau PET scan with 93% accuracy.
• In the Colombia Cohort, the assay began to distinguish between mutation carriers and non-carriers 20 years before their estimated age at the onset of mild cognitive impairment.

In each of these analyses, p-tau217 (a major component of Alzheimer's disease-related tau tangles) performed better than p-tau181 (another component of tau tangles and a blood test recently found to have promise in the diagnosis of Alzheimer's) and several other studied blood tests.

Other study leaders include Jeffrey Dage, PhD, from Eli Lilly and Company, who developed the p-tau217 assay, co-first authors Sebastian Palmqvist, MD, PhD, and Shorena Janelidz, PhD, from Lund University, and Eric Reiman, MD, Banner Alzheimer's Institute, who organized the analysis of Arizona and Colombian cohort data.

In the last two years, researchers have made great progress in the development of amyloid blood tests, providing valuable information about one of the two cardinal features of Alzheimer's. While more work is needed before the test is ready for use in the clinic, a p-tau217 blood test has the potential to provide information about both plaques and tangles, corresponding to the diagnosis of Alzheimer's. It has the potential to advance the disease's research and care in other important ways.

"Blood tests like p-tau217 have the potential to revolutionize Alzheimer's research, treatment and prevention trials, and clinical care," said Eric Reiman, MD, Executive Director of Banner Alzheimer's Institute in Phoenix and a senior author on the study.

"While there's more work to do, I anticipate that their impact in both the research and clinical setting will become readily apparent within the next two years."

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Study sheds light on how cancer spreads in blood

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

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

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

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

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

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

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

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

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Synthetic red blood cells mimic natural ones, and have new abilities

Illustration of red blood cells

Scientists have tried to develop synthetic red blood cells that mimic the favorable properties of natural ones, such as flexibility, oxygen transport and long circulation times. But so far, most artificial red blood cells have had one or a few, but not all, key features of the natural versions. Now, researchers reporting in ACS Nano have made synthetic red blood cells that have all of the cells' natural abilities, plus a few new ones.

Red blood cells (RBCs) take up oxygen from the lungs and deliver it to the body's tissues. These disk-shaped cells contain millions of molecules of hemoglobin -- an iron-containing protein that binds oxygen. RBCs are highly flexible, which allows them to squeeze through tiny capillaries and then bounce back to their former shape. The cells also contain proteins on their surface that allow them to circulate through blood vessels for a long time without being gobbled up by immune cells. Wei Zhu, C. Jeffrey Brinker and colleagues wanted to make artificial RBCs that had similar properties to natural ones, but that could also perform new jobs such as therapeutic drug delivery, magnetic targeting and toxin detection.

The researchers made the synthetic cells by first coating donated human RBCs with a thin layer of silica. They layered positively and negatively charged polymers over the silica-RBCs, and then etched away the silica, producing flexible replicas. Finally, the team coated the surface of the replicas with natural RBC membranes. The artificial cells were similar in size, shape, charge and surface proteins to natural cells, and they could squeeze through model capillaries without losing their shape. In mice, the synthetic RBCs lasted for more than 48 hours, with no observable toxicity. The researchers loaded the artificial cells with either hemoglobin, an anticancer drug, a toxin sensor or magnetic nanoparticles to demonstrate that they could carry cargoes. The team also showed that the new RBCs could act as decoys for a bacterial toxin. Future studies will explore the potential of the artificial cells in medical applications, such as cancer therapy and toxin biosensing, the researchers say.

The authors acknowledge funding from the Air Force Office of Scientific Research, the Laboratory Directed Research & Development Program at Sandia National Laboratories, the Department of Energy Office of Science, the National Institutes of Health and the National Natural Science Foundation of China.

From Science Daily

Scientists reliably predict people's age by measuring proteins in blood

The carnival worker who tries to guess your age relies on aspects of your appearance, such as your posture and whether any wrinkles emanate from the corners of your eyes and lips. If the carny's guess is more than a few years off, you win a stuffed koala.

But a team of Stanford University School of Medicine scientists doesn't need to know how you look to guess your age. Instead, it watches a kind of physiological clock: the levels of 373 proteins circulating in your blood. If the clock is off, you don't win a plush toy. But you may find out important things about your health.

"We've known for a long time that measuring certain proteins in the blood can give you information about a person's health status -- lipoproteins for cardiovascular health, for example," said Tony Wyss-Coray, PhD, professor of neurology and neurological sciences, the D. H. Chen Professor II and co-director of the Stanford Alzheimer's Disease Research Center. "But it hasn't been appreciated that so many different proteins' levels -- roughly a third of all the ones we looked at -- change markedly with advancing age."

Changes in the levels of numerous proteins that migrate from the body's tissues into circulating blood not only characterize, but quite possibly cause, the phenomenon of aging, Wyss-Coray said.

A paper describing the research will be published Dec. 5 in Nature Medicine. Wyss-Coray is the senior author. The lead author is neurology instructor Benoit Lehallier, PhD.

'Proteins are the workhorses'

The researchers analyzed plasma -- the cell-free, fluid fraction of blood -- from 4,263 people ages 18-95. "Proteins are the workhorses of the body's constituent cells, and when their relative levels undergo substantial changes, it means you've changed, too," Wyss-Coray said. "Looking at thousands of them in plasma gives you a snapshot of what's going on throughout the body."

The study's results suggest that physiological aging does not simply proceed at a perfectly even pace, but rather seems to chart a more herky-jerky trajectory, with three distinct inflection points in the human life cycle. Those three points, occurring on average at ages 34, 60 and 78, stand out as distinct times when the number of different blood-borne proteins that are exhibiting noticeable changes in abundance rises to a crest. This happens because instead of simply increasing or decreasing steadily or staying the same throughout life, the levels of many proteins remain constant for a while and then at one point or another undergo sudden upward or downward shifts. These shifts tend to bunch up at three separate points in a person's life: young adulthood, late middle age and old age.

The investigators built their clock by looking at composite levels of proteins within groups of people rather than in individuals. But the resulting formula proved able to predict individuals' ages within a range of three years most of the time. And when it didn't, there was an interesting upshot: People whose predicted age was substantially lower than their actual one turned out to be remarkably healthy for their age.

The researchers obtained their samples from two large studies. One of them, known as the LonGenity study, has assembled a registry of exceptionally long-lived Ashkenazi Jews. It was able to provide many blood samples from people as old as 95.

On measuring the levels of roughly 3,000 proteins in each individual's plasma, Wyss-Coray's team identified 1,379 proteins whose levels varied significantly with participants' age.

Divergence

A reduced set of 373 of those proteins was sufficient for predicting participants' ages with great accuracy, the study said. But there were cases of substantial divergence between participants' chronological and physiological age -- for example, among the subjects in the LonGenity study, with their genetic proclivity toward exceptionally good health in what for most of us is advanced old age.

"We had data on hand-grip strength and cognitive function for that group of people," Wyss-Coray. "Those with stronger hand grips and better measured cognition were estimated by our plasma-protein clock to be younger than they actually were."

The study also strengthened the case that men and women, who were about equally represented in the study, age differently. Of the proteins the analysis found to change with age, 895 -- nearly two-thirds -- were significantly more predictive for one sex than for the other.

"The differences were striking," Wyss-Coray said. He added that this finding strongly supports the rationale for the National Institutes of Health's policy, instituted in 2016, promoting increased inclusion of women in clinical trials and the demarcating of sex as a biological variable.

Any clinical applications of the technique are a good five to 10 years off, he said. With further validation, though, it could be used not only to identify individuals who appear to be aging rapidly -- and, therefore, at risk of age-linked conditions such as Alzheimer's disease or cardiovascular disease -- but also to find drugs or other therapeutic interventions, like leafy green vegetables, that slow the aging process, or conversely to flash an early warning of a drug's unanticipated tendency to accelerate aging.

"Ideally, you'd want to know how virtually anything you took or did affects your physiological age," Wyss-Coray said.

While the words "373 proteins" may conjure up the image of a transfusion-sized blood extraction, a drop is all it takes for a 373-protein readout.

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