Culture

Convergent origins of new mechanisms to supply oxygen to the retina were directly linked to concurrent enhancements in the functional anatomy of the eye.

In his "On the Origin of Species", Darwin used the complexity of the eye to argue his theory of natural selection and the eye has continued to fascinate and trouble evolutionary biologists ever since.

In a paper published today in eLife, researchers from Aarhus University teamed up with scientists from eight international institutions to explore the physiological requirements for the evolution of improved eyesight.

They argue that the evolution of high-acuity vision in ancestral animals was constrained by the ability to deliver sufficient amounts of oxygen to cells in the retina. Their study uncovered a fascinating pattern of mechanisms to improve retinal oxygen supply capacity that evolved in concert with enhanced retinal morphology to improve vision. The model fits across all bony vertebrates from fish through to birds and mammals. These findings add an additional component to our understanding of the evolution eye, which has fascinated and troubled evolutionary biologists for centuries.

The rises and falls of retinal oxygen supply

The study took advantage of the diversity in the physiology and anatomy among eyes from 87 animal species, including fishes, amphibians and mammals. By placing these species on the tree of life, the authors unravelled the evolutionary history of the eye from a 425 million-year-old extinct ancestor of modern vertebrates to current day animals. They identified three distinct physiological mechanisms for retinal oxygen supply that are always associated with improved vision. Thus, in fishes, mutations in haemoglobin were associated with the ability to deliver oxygen to the retina at exceptional high oxygen partial pressures to overcome the significant diffusion distance to the retinal cells.

The authors show that the origin of this mechanism around 280 million years ago was associated with a dramatic increase in eye size and retinal thickness that directly links to improved light sensitivity and spatial resolution. This mechanism in hemoglobin was subsequently lost several times, possibly to avoid oxidative damage and gas bubble formation in the eye.

Warm blooded dinosaurs shaped the vision of mammals

The authors show that increased reliance on vision in mammals was associated with the evolution of capillary beds inside the retina despite the potential trade-off to visual acuity imposed by the bending of light by red blood cells.

Retinal capillaries in mammals originated around 100 million years ago when dinosaurs evolved endothermy. Endothermy allowed these Mesozoic dinosaurs to hunt at night, which forced the previously nocturnal mammals into a diurnal lifestyle with an increased reliance of vision.

The new model on eye evolution shows that the evolution of intra-retinal capillaries coincided precisely with the improvements in vision around 100 million years ago. Further, it shows that some mammals lost retinal capillaries when they became less reliant on vision (e.g., echolocating bat).

Oxygen and vision go hand in hand

Overall, this analysis shows that the functional morphology of the eye has changed dynamically throughout animal evolution. It shows that eye morphology goes hand in hand with parallel changes in retinal oxygen supply, and they are likely driven by different tradeoffs to retinal oxygen supply. These tradeoffs appear acceptable in place of the improved visual acuity available when the thickness of the retina was allowed to increase.

Overall, this study shows that adaptations to ensure oxygen delivery to the retina was a physiological prerequisite for the functional evolution of the eye.

Normally, bird flu viruses do not spread easily from person to person. But if this does happen, it could trigger a pandemic. Researchers from the MDC and RKI have now explained in the journal Nature Communications what makes the leap from animals to humans less likely.

Whenever people suddenly become infected with a bird flu virus such as H5N1, H7N9, and H5N6, the World Health Organization (WHO) has to assess the risk: Are these the first signs of a pandemic? Or is it just a few dozen or hundred cases that have only arisen through close contact with infected poultry? Researchers led by Professor Matthias Selbach from the Max Delbrueck Center for Molecular Medicine (MDC) have now found another piece of the puzzle that may be important in this initial assessment. In a paper published in Nature Communications, the researchers explain that avian influenza A viruses (IAVs) are unable to transform infected human cells into effective virus factories, because they do not produce enough of the matrix protein M1 following infection. The virus requires this protein, however, to export its many copies of its genetic material from the cell nucleus - a prerequisite for building new viruses.

Not all flu is the same - the name refers to a large family of viruses. Each member of this family is named after two prickly growths on the virus's surface: hemagglutinin (H), which enables the virus to infect human and animal cells where it can multiply, and neuraminidase (N), which helps the virus's offspring to extract themselves from the infected cell. In waterfowl, there are 16 known hemagglutinin subtypes and nine known neuraminidase subtypes. That results in at least 144 possible combinations that are constantly changing and adapting to new hosts - like chickens, for example, but also mammals including horses, pigs, and humans.

Such new virus variants are often more dangerous than seasonal flu, because the human immune system has never encountered them before. Some people find themselves defenseless, while the immune system of others reacts so violently that the person's own resistance damages the body. In the worst case scenario, a pandemic could cost millions of lives. The Spanish flu of 1918, for example, claimed more than 50 million victims. Researchers around the world are therefore trying to understand the rules that determine when there is the possibility of a pandemic, and when there is not.

Why are human cells bad virus factories for bird flu?

"Hemagglutinin in humans and birds has a slightly different chemical structure, for example, which makes it more difficult for an avian influenza virus to infiltrate a human cell than a bird's cell," explains Selbach. Boris Bogdanow, a PhD student in Selbach's research group and the lead author of the current study, focused his research specifically on what other natural species barriers exist in flu viruses.

Matthias Selbach's group analyses proteins using quantitative mass spectrometry. In collaboration with the Robert Koch Institute (RKI), Boris Bogdanow and his colleagues infected human pulmonary epithelial cells separately with a bird flu virus and a human flu virus. They then measured the quantity of all newly produced proteins in the mass spectrometer. Postdoctoral researcher Dr. Katrin Eichelbaum had also developed a method that enables the precise differentiation of new and old proteins. "In the first analysis, we did not find any major differences between the two strains," reports Boris Bogdanow. "At first glance, the avian flu virus and the human virus displayed little difference with regard to protein production, which was quite surprising."

But the devil is in the detail, so Bogdanow performed more in-depth analyses to take a closer look at the protein distribution. In doing so, he came across the matrix protein M1, much larger quantities of which were produced in the lung cells infected with the human virus. The M1 protein is responsible, among other things, for exporting the replicated viral RNA from the nucleus of the infected cells and then assembling it with other newly produced viral proteins to form flu virus offspring. Could it be, therefore, that the viral RNA of bird flu viruses in human cells remains trapped in the cell nucleus because too little M1 protein is present?

Another piece of the puzzle

Fluorescence microscopic investigations confirmed these suspicions. The genetic material of the bird flu virus was far less capable of breaking out of the cell nucleus than the RNA of the human flu virus. But why? With the help of the MDC's sequencing platform and Professor Irmtraud Meyer, they discovered a small segment in the viral RNA of the avian flu virus that affects alternative splicing. "We call this a cis-regulatory element," says Bogdanow. "Alternative splicing regulates which proteins are ultimately made from a single gene, because many genes code for more than one protein. When human cells are attacked by bird flu, this element ensures that more M2 rather than M1 protein is produced."

In order to assess the relevance of this result, Professor Thorsten Wolff and his research team from the Robert Koch Institute transferred the cis-regulatory element from the bird virus to the human virus. This did indeed result in the human flu virus replicating less effectively in human lung cells. Selbach's team even conducted a similar experiment with Spanish flu viruses, whose genetic material was isolated in the nineties from graves in the permafrost soil of Alaska. However, they only used a small part of the viral RNA and not the entire virus for the experiment. Nevertheless, they were also able to confirm their theory on the cis-regulatory element for this virus.

"How pathogenic an avian flu virus is and whether or not it has pandemic potential depends, of course, on many factors," says Selbach. "A study on cell cultures cannot cover all these factors. Nevertheless, it might be useful in future to include an analysis of this RNA segment in the risk assessment of avian influenza viruses."

Results from a study conducted by St. Jude Children's Research Hospital and the Munich Leukemia Laboratory were presented today as a late-breaking abstract at the American Society of Hematology annual meeting. The study integrates genomic and transcriptomic sequencing to provide the most detailed classification of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) to date.

The researchers conducted whole genome sequencing and transcriptome sequencing (RNA-seq) on 598 adults with AML and 706 with MDS. The researchers found evidence to support several different biologic subgroups. They found sets of mutations that cooperate to drive the development of leukemia and predict poor outcomes as well as groups of mutations that indicate positive responses to treatment.

"These diseases have a complex genomic background that we cannot ignore if we want to treat these patients optimally," said first author and presenter Ilaria Iacobucci, Ph.D., of the St. Jude Department of Pathology. "Therapy for AML has changed little in the last five decades so we need to better understand the nature of genomic changes in order to offer new therapies to these patients."

Our understanding of the genetics of these diseases has advanced dramatically in the last decade due to intensive sequencing efforts. However, most of these studies used a targeted sequencing-based approach or were limited to specific subtypes. Now, by integrating whole genome and transcriptome sequencing, researchers can further unravel the biology of these diseases.

AML and MDS are similar since they both derive from aberrations occurring in hematopoietic stem cells and cause impaired differentiation. However, the diseases differ in immature white blood cell (blast) counts and cell morphology. The researchers wanted to learn more about how the diseases divide into genetic subgroups to inform treatments based on their biology. 

"This work lifts a veil on the constellations of mutations that come together to drive groups of cases that have similar or differing behavior," said co-senior author Charles Mullighan, M.D., MBBS, of the St. Jude Department of Pathology and deputy director of the Comprehensive Cancer Center. "It strongly supports the way the field is moving, that unbiased sequencing is needed to accurately diagnose and risk-stratify our patients."

"For all types of leukemia, we struggle with piecing together information from sequencing approaches to find the best predictors of outcome," Mullighan said. "There is data here that brings clarity to prognosis, which may ultimately help in identifying patients upfront in need of more or less therapy."

The findings demonstrate how different mutation patterns contribute to the growth of leukemia cells. For example, prognosis is generally considered quite good for patients whose disease has an NPM1 mutation. The researchers found that this subgroup can be further divided based on the presence of other mutations to indicate who is most likely to have a favorable response and thus might not require as stringent a treatment regimen.

The work also reveals a new finding regarding AML fueled by RUNX1 mutations. These mutations have only provisionally been considered a distinct subgroup by World Health Organization classification. Yet, the new results show that RUNX1 AML is a distinct subtype with a poor prognosis.

"We all feel the assessment is incomplete when you're just looking at the number of cancer cells under a microscope," said co-senior author Torsten Haferlach, M.D., of Munich Leukemia Laboratory. "We now have the options and ability to move forward, addressing all of the known targets and expression patterns that are present in these cases. Ours is the first study of this size showing this is feasible and applicable for routine clinical use."

New Orleans, LA - Research led by Nicolas Bazan, MD, Ph.D., Boyd Professor and Director of the Neuroscience Center of Excellence at LSU Health New Orleans School of Medicine, has discovered unique patterns of genetic activity that may lead to the development of blinding retinal diseases. The results are published online in the Federation of American Societies for Experimental Biology (FASEB) journal, BioAdvances.

"A central question to understand blinding retinal diseases is how key genes are expressed to sustain retinal function and how retina building blocks participate," notes Dr. Bazan, who also holds the Ernest C. and Yvette C. Villere Chair of Retinal Degenerative Diseases Research at LSU Health New Orleans.
Bazan's research team investigated retina structure and function using rodent models where two potentially strategic proteins were deleted. They used sensitive and specific molecular imaging to map the spatial arrangement of the building blocks where the retina cells that sense light (photoreceptors) are constructed. They used a multidisciplinary approach that includes Optical Coherence Tomography imaging (a procedure used clinically to see the integrity of retina noninvasively) and electroretinogram to decide about function.

They report the discovery of novel gene signatures leading to mutations in two proteins - MFRP, which participates in cell fate and development, and Adipor1, whose absence in the retina results in the inability to take up and incorporate the building block docosahexaenoic acid (DHA 22:6) and the onset of retinal degeneration. A single amino acid mutation of Adipor1 occurs in a high proportion of retinitis pigmentosa patients. Different forms of this receptor mutation have been found in age-related macular degeneration (AMD), as well as in other forms of retinal degeneration.

The researchers found that the absence of 22:6 leads to modifications, which then trigger an increase in proinflammatory genes and a decrease of genes that are critical for visual system function.

The study demonstrates that the MFRP mutation resembles the ADIPOR1 mutation on multiple levels. Deletion of these proteins leads to flecked retina and slow cell death onset. Functionally, the mutations express the same degree of functional attenuation. Both mutants clearly demonstrate the inability to take up and incorporate building blocks, which results in remarkable changes in the retina.

"Although the gene signature shows that both mutants are activated by signals involving proinflammatory cytokines, we found that each of these pathways has distinct features," Bazan says.

"Moreover, our results highlight the critical role of MFRP and ADIPOR1 in preserving retinal function. Our findings demonstrate that the maintenance of retinal function relies on two proteins MFRP and ADIPOR1, acting to ensure proper acquisition and distribution of key building blocks molecules necessary to sustain protection against age-related Macular degeneration and other retinal degenerative deceases."

A new clinical guideline from the American Society for Radiation Oncology (ASTRO) provides recommendations on the use of radiation therapy to treat patients diagnosed with the most common types of skin cancers. The guideline details when radiation treatments are appropriate as stand-alone therapy or following surgery for basal and cutaneous squamous cell carcinomas (BCC, cSCC), and it suggests dosing and fractionation for these treatments. The executive summary and full-text version of ASTRO's first guideline for skin cancer are published online in Practical Radiation Oncology.

Skin cancer is the most prevalent cancer in the United States, with more than 5 million cases diagnosed each year. More than 95% of these diagnoses are BCC or cSCC, which, in contrast to melanomas, respond well to radiation therapy if treated promptly and properly. Although surgery to remove the lesion is considered the primary approach for definitive/curative treatment of these non-melanoma skin cancers, radiation therapy can play an integral role in both the curative and post-operative settings.

ASTRO developed the new guideline to provide clarity about treatment options. "There is significant variation in practice about when and how radiation should be used for non-melanoma skin cancers, largely because few randomized studies have compared modern treatment options head-to-head," explained Phillip Devlin, MD, FASTRO, chair of the guideline task force and a radiation oncologist at Brigham and Women's Hospital in Boston.

"For this guideline, we drew on the consensus of a multidisciplinary group of leading experts, as well as a systematic review of the evidence, to help physicians understand when radiation is most likely to benefit their patients and to encourage informed discussion about treatment options," added Anna Likhacheva, MD, MPH, vice chair of the guideline task force and a radiation oncologist with Sutter Medical Group in Sacramento.

Recommendations for Radiation Therapy for BCC and cSCC

The guideline first defines appropriate indications for radiation therapy (1) as definitive/curative treatment for BCC and cSCC, (2) as adjuvant treatment following surgery and (3) as definitive or adjuvant treatment for disease that has spread to a patient's regional lymph nodes. Recommendations are as follows:

In the definitive/curative setting, radiation is strongly recommended for patients with BCC or cSCC who cannot undergo or decline surgical resection. It is conditionally recommended for patients with BCC or cSCC located in anatomically sensitive areas such as the nose or lips, where surgery could compromise function or cosmetic outcomes. Definitive radiation therapy is discouraged, however, for patients with genetic conditions that predispose them to be more sensitive to radiation.

In the adjuvant/post-operative setting, radiation following surgery is recommended for patients at high risk of cancer recurrence, including a strong recommendation when there is evidence that BCC or cSCC has spread to a patient's nerves. Post-operative radiation is also recommended for patients at high risk of recurrence following surgical resection, including strong recommendations for high-risk patients with cSCC and conditional recommendations for high-risk patients with the relatively less aggressive BCC. Recommendations also outline prognostic features that indicate which patients are at greater risk for recurrence and spread.

For patients with BCC or cSCC that has spread to regional lymph nodes, surgical removal of the affected lymph nodes followed by radiation is strongly recommended for both BCC and cSCC, although not for patients with one small involved lymph node without extracapsular spread. The guideline also strongly recommends definitive radiation for patients with regional cSCC spread who cannot undergo surgery.

Recommendations address technical aspects of radiation therapy, suggest dosing and fractionation schedules and include a brief discussion of the different types of radiation delivery methods. The task force concluded that the appropriate use of any of the major radiation modalities results in similar cancer control and cosmetic outcomes. The guideline also considers the use of drug therapies such as chemotherapy, biologic and immunotherapy agents in combination with radiation.

About the Guideline

The guideline was based on a systematic literature review which produced more than 1,500 articles, of which 143 (published from May 1988 through June 2018) were then carefully evaluated. The task force included a multidisciplinary team of radiation, medical and surgical oncologists, a radiation oncology resident, medical physicist, dermatologist and dermatopathologists. The guideline was developed in collaboration with the American Society of Clinical Oncology (ASCO) and the Society of Surgical Oncology (SSO), who provided representatives and peer reviewers.

ASTRO's clinical guidelines are intended as tools to promote appropriately individualized, shared decision-making between physicians and patients. None should be construed as strict or superseding the appropriately informed and considered judgments of individual physicians and patients.

ITHACA, N.Y. - Female grape berry moths are the biggest insect threat to wine grapes in the eastern U.S. The moths lay their eggs on grapes and, once hatched, the larvae penetrate the skin, then eat and damage the fruit. But no one is quite sure how the moths home in on berries from the wider landscape.

A new study, published Nov. 21 in the Journal of Chemical Ecology, investigates how these pests find their target amid a sea of other plants in the landscape.

The researchers originally hypothesized that grapes might have a unique profile of volatile compounds that the moths recognize, and perhaps other neighboring plants have volatile organic compound profiles that deter moths.

They created a study design that gauged the attraction of female grape berry moths to volatile organic compounds emitted from grape vines, the moths' natural host plant, as well as to nearby gray dogwood and apple trees.

"Chemical cues, signals, are used by almost all insects to locate resources in their habitat, such as mates or host plants," said Charles Linn, a senior research associate at Cornell, now retired, and the senior author on the paper.

"Grape plants produce maybe hundreds of compounds, but the insects are really only detecting a subset with their antennae," said Greg Loeb, professor of entomology at Cornell AgriTech and a co-author of the paper.

Michael Wolfin, Ph.D. '17, a postdoctoral researcher at Penn State, is the paper's first author.

The researchers ran gas chromatography, electro-antennal detection and mass spectrometry analyses coupled with behavioral tests in a wind tunnel and identified 11 volatile organic compounds emitted by grapes that the moths detected. Though these compounds appear in particular ratios in grapes, they are common and are shared by most plants, including gray dogwood and apples.

When the study's authors used the grape vine odors to lure the moths into traps, the method worked, but ineffectively.

In wind tunnel tests, the researchers found the moths flew upwind at the same rates toward both plant clippings and extracts of volatiles from grapes, dogwood or apples.

"The berry moth wasn't showing clear evidence of discrimination based on these compounds" over long distances, Loeb said. "We suggest that maybe plant-eating arthropods are using these common volatiles to find the correct habitat, and then using other cues to zero in on where they are going to lay their eggs."

"These results support a model that is in marked contrast to others in the literature and should provide a new hypothesis for future testing," Linn said.

More study is needed to determine what cues the moths use to find berries. A preliminary study using artificial wax grapes showed that berry moths would not lay eggs on bare wax, but when a grape skin was laid over the wax, the females did lay eggs, suggesting there is something on the skin's surface they recognize.

Though no deterring volatiles were found, the research offers clues for breeders to perhaps develop varieties with tweaked ratios of volatiles to throw insects off scent.

Researchers at the University of São Paulo (USP) in Brazil have described a system present in a species of opportunistic bacterium found in hospital environments that injects a cocktail of toxins into competing bacteria and completely eliminates them. This discovery can be used in the future development of new antimicrobial compounds.

The study was supported by São Paulo Research Foundation - FAPESP and published in PLOS Pathogens by researchers affiliated with USP's Chemistry Institute (IQ) and Biomedical Sciences Institute (ICB).

The researchers discovered that Stenotrophomonas maltophilia uses a secretion system that produces a cocktail of toxins and injects them into other microorganisms with which it competes for space and food. In addition, the researchers characterized one of 12 proteins in the cocktail - Smlt3024 - and observed that this molecule alone can considerably reduce the rate at which other bacteria replicate.

"We believe these toxins can be explored as a form of treatment in the future. Just as antibiotics can come from other bacteria, we are exploring this arsenal used by bacteria themselves to kill other species of pathogen," said Ethel Bayer-Santos, a researcher at ICB-USP.

The study was part of her postdoctoral project at IQ-USP, which was also supported by FAPESP. She currently has a Young Investigator grant from FAPESP.

Bacterial secretion systems are protein complexes present on the cell membranes of bacteria for the secretion of substances. These systems are used by pathogenic bacteria to secrete virulence factors and invade host cells.

"The Type IV secretion system [T4SS], as it is known, secretes proteins and DNA into other cells or the extracellular medium. We recently showed that it is present in Xanthomonas citri, the pathogen that causes citrus canker. We have now found it in this bacterium [S. maltophilia], which is frequently isolated from water and soil but can become an opportunistic pathogen in hospital environments," said Shaker Chuck Farah, a professor in IQ-USP and principal investigator for the study.

The research is linked to two Thematic Projects funded by FAPESP: "Cyclic di-GMP signaling and the Type IV macromolecule secretion system in Xanthomonas citri" and "Structure and function of bacterial secretion systems".

The group's discovery of the secretion system in X. citri was reported in a paper published in Nature Communications. Another article by the same group, published in 2018 in Nature Microbiology, describes the atomic structure of much of the secretion system using cryogenic electron microscopy (cryo-EM), an imaging technique that enables scientists to observe the 3D structure of biomolecules as they move and interact.

Bacterial warfare

Competition between microorganisms determines which species will dominate or be eradicated from a specific habitat. Bacteria have several mechanisms that can reduce the multiplication of competitors or even kill them. One is T4SS, which itself consists of more than 100 components originating from 12 different proteins present on the surface of their cells.

The researchers found that the secretion systems in X. citri and S. maltophilia contain antidotes to the toxins they secrete. These antidotes are required to protect the microorganisms from their own weapons. On approaching another species of bacterium, the attackers inject the toxins into the competitor by mere contact or using a pilus, a microscopic filament that functions like a harpoon.

To test the action of the system, the researchers performed several experiments involving competition between bacteria. In one experiment, they placed specimens of S. maltophilia and Escherichia coli, a species widely used in the laboratory, in the same medium. E. coli had barely begun to multiply when S. maltophilia approached and eliminated its rivals. The same effect was observed against Klebsiella pneumoniae and Salmonella typhi, as well as Pseudomonas aeruginosa, a bacterium that infects cystic fibrosis patients.

Another experiment consisted of testing the effect of Smlt3024 alone. Specimens of E. coli that expressed the toxin in the cytoplasm exhibited no growth alterations. However, when, in addition to the gene for Smlt3024, they also had a signal sequence - a set of certain amino acids that changes the location of the protein - the toxin was directed to the periplasm (the space between the inner and outer membranes in bacteria), exactly as the original system does in S. maltophilia and X. citri. In this case, cell division in E. coli was considerably reduced, demonstrating the effect of the protein.

Although both S. maltophilia and X. citri have the same system, they can kill each other using T4SSs, as another experiment showed. Experiments also showed that key components of one system can be replaced by homologues from another and that the T4SS in one bacterium can secrete the toxins of another.

All this is evidence of similarities in the structures that can be studied in the future to explore similar T4SSs (homologues) identified in tens of other bacterial species.
New studies may allow other researchers to develop molecules that inhibit the action of this system for use in the discovery of new drugs.

"We can screen drugs capable of binding to this system and inhibiting some important stages in the transfer of toxins from one cell to another. This could reduce the survival of these bacteria in some environments," Farah said.

"The toxin itself could be used as an antimicrobial agent, but other studies need to be done to test this possibility," Bayer-Santos said.

The study also has three other authors supported by FAPESP, and all are affiliated with IQ-USP: Bruno Yasui Matsuyama, who has a postdoctoral scholarship from FAPESP; Gabriel Umaji Oka, who also has a postdoctoral scholarship from FAPESP; and William Cenens, whose postdoctoral scholarship ended in May 2019.

A team of researchers from the Georgia Institute of Technology and The Ohio State University has developed a soft polymer material, called magnetic shape memory polymer, that uses magnetic fields to transform into a variety of shapes. The material could enable a range of new applications from antennas that change frequencies on the fly to gripper arms for delicate or heavy objects.

The material is a mixture of three different ingredients, all with unique characteristics: two types of magnetic particles, one for inductive heat and one with strong magnetic attraction, and shape-memory polymers to help lock various shape changes into place.

"This is the first material that combines the strengths of all of these individual components into a single system capable of rapid and reprogrammable shape changes that are lockable and reversible," said Jerry Qi, a professor in the George W. Woodruff School of Mechanical Engineering at Georgia Tech.

The research, which was reported Dec. 9 in the journal Advanced Materials, was sponsored by the National Foundation of Science, the Air Force Office of Scientific Research, and the Department of Energy.

To make the material, the researchers began by distributing particles of neodymium iron boron (NdFeB) and iron oxide into a mixture of shape memory polymers. Once the particles were fully incorporated, the researchers then molded that mixture into various objects designed to evaluate how the material performed in a series of applications.

For example, the team made a gripper claw from a t-shaped mold of the magnetic shape memory polymer mixture. Applying a high-frequency, oscillating magnetic field to the object caused the iron oxide particles to heat up through induction and warm the entire gripper. That temperature rise, in turn, caused the shape memory polymer matrix to soften and become pliable. A second magnetic field was then applied to the gripper, causing its claws to open and close. Once the shape memory polymers cool back down, they remain locked in that position.

The shape-changing process takes only a few seconds from start to finish, and the strength of the material at its locked state allowed the gripper to lift objects up to 1,000 times its own weight.

"We envision this material being useful for situations where a robotic arm would need to lift a very delicate object without damaging it, such as in the food industry or for chemical or biomedical applications," Qi said.

The new material builds on earlier research that outlined actuation mechanisms for soft robotics and active materials and evaluated the limitations in current technologies.

"The degree of freedom is limited in conventional robotics" said Ruike (Renee) Zhao, an assistant professor in the Department of Mechanical and Aerospace Engineering at Ohio State. "With soft materials, that degree of freedom is unlimited."

The researchers also tested other applications, where coil-shaped objects made from the new material expanded and retracted - simulating how an antenna could potentially change frequencies when actuated by the magnetic fields.

"This process requires us to use of magnetic fields only during the actuation phase," Zhao said. "So, once an object has reached its new shape, it can be locked there without constantly consuming energy."

Federal disability benefits can lead to increases in other support for beneficiaries, such as in-kind assistance from adult children, according to a new RAND Corporation study.

Receipt of federal disability insurance also increases the likelihood that children are paid for their in-kind assistance and enables children who provide that assistance to reduce the amount that they work.

These findings, published online by the Journal of Health Economics, suggest that disability recipients are using disability benefits to provide financial compensation to their adult children caregivers.

"These findings provide new evidence that family shares in the burden of disability and that the impact of disability benefits extends beyond the beneficiary to the entire family," said Stephanie Rennane, the study's author and an associate economist at RAND, a nonprofit research organization. "Receipt of federal disability benefits allows a family to reoptimize how they support one another."

While prior work has studied the various sources of income and insurance for individuals who experience a disability, less research has examined how family support mechanisms interact and change over the evolution of a disability, and how they interact with federal disability benefits.

In order to examine trends in income, benefits and family assistance, Rennane used the Health and Retirement Study to analyze information about informal caregiving provided to survey respondents, and matched these details to disability benefit records from the Social Security Administration. The experiences of about 3,000 people were analyzed.

The study compared informal care provided to respondents who had received benefits through either the Social Security Disability Insurance program or Supplemental Security Income program with care to respondents who applied for the benefits, but were denied. The analysis adjusted for differences in health and income between accepted and denied applicants.

The analysis found that the receipt of federal disability payments leads to a 9 percentage point increase in the likelihood of receiving assistance from their children.

Receipt of federal disability payments also more than doubles the likelihood that children are paid for their help and leads to a 50% decline in the probability that the assisting children work full time.

The effects are particularly strong among lower income beneficiaries who receive Supplemental Security Income and among those who recently lost a spouse. Social Security Disability Insurance disability payments also decrease the likelihood that a spouse works.

"The benefits of federal disability payments are shared in complementary ways within the family, enabling a more-holistic network of both formal and informal caregiving," Rennane said. "The resources from disability insurance allow children to reallocate their time to care for their parents."

Cystic fibrosis is caused by an inherited mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Due to this mutation, the CFTR protein doesn't embed in cell membranes to form a channel for chlorine ions the way it should. As a result, mucus-producing cells secrete a thicker-than-normal mucus that can create blockages in the lungs and digestive system. In the lungs, this thicker mucus can help bacteria thrive, making lung infections a serious and chronic problem for many people living with cystic fibrosis.

Yet some people with cystic fibrosis don't develop lung infections as early or as frequently as others. Researchers at University of California San Diego School of Medicine recently discovered that genetic variations dampening expression of another gene, called RNF5, offer a likely explanation.

In the study, published December 10, 2019 in eLife, the team found that individuals with cystic fibrosis who carry specific genetic variants lowering expression of RNF5 have more mutant CFTR protein on their cell surfaces. Even if the CFTR protein isn't totally functional, it's likely better than having none at all, the researchers said.

Cystic fibrosis symptoms can be significantly improved with relatively new medications that boost CTFR function. But there are two caveats: The drugs are extremely expensive and they don't work for everyone.

"The cystic fibrosis field is trying to figure out what are the modifiers across the genome that increase or decrease the probability that an individual patient will respond to these expensive drugs," said senior author Kelly A. Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine at UC San Diego School of Medicine. "RNF5 may be one of these modifier genes."

The RNF5 gene is located in the Major Histocompatibility Complex (MHC). Genes in this region encode molecules that are displayed on the surface of most cells in the body. They play an important role in how the body responds to infections. Scientists have long known that everyone has their own set of MHC gene variations, and that they make people more or less susceptible to infections or autoimmune diseases. But because the genes present in the MHC region are so dense with variations, they have not been well-studied for their direct link to diseases.

Frazer and colleagues took a new approach to analyzing MHC gene variants by grouping them. That allowed the team to more easily identify associations between genetic variation, gene expression levels and their effects on complex diseases. The researchers applied this approach with whole genome sequencing of induced pluripotent stem cells derived from 419 people. That translated into investigating more than 4,000 traits, from which they identified 180 associated with variants in the MHC region.

"We've known there's an association between MHC genes and bacterial colonization in patients with cystic fibrosis, but no one knew why," Frazer said. "We assumed it was due to MHC's involvement in the immune system. But now we know that's likely not the only mechanism -- different expression levels of RNF5 may also play an important role."

"This study uncovered a new aspect of cystic fibrosis -- one that could lead to new drug design and development, and allow clinicians to better tailor treatments," said first author Matteo D'Antonio, PhD, a project scientist in Frazer's lab. "But that's just one example of how we might employ this new genetic analysis technique. Now we have a road map, and we can apply it to other diseases and cell types."

Dec. 11, 2019 - A decision aid developed to support patients undergoing genomic sequencing can reduce the amount of time patients spend speaking with overburdened genetic counselors while helping them were more knowledgeable about the benefits of sequencing, suggests a study from St. Michael's Hospital.

Published in Genetics in Medicine, the official journal of the American College of Medical Genetics and Genomics (ACMG), the study evaluated the effectiveness of the Genomics ADvISER, an interactive online decision aid designed to guide patients who have had their genome sequenced and are being offered additional medical information revealed by the sequencing.

Generally, patients undergo genomic sequencing to learn about a particular condition they may have -- but the test also reveals secondary or incidental findings, a slew of other data that may or may not present troubling news about a person's risk to develop additional health issues.

For example, a person could have their genome sequenced to evaluate heart disease and uncover that they have a neuromuscular disease as well as a high risk for heart issues. Another might have their genome sequenced as part of a study on Cystic Fibrosis - a genetic lung disease - and find out they also have alterations in a gene that influences cancer.

"When you start to open the Pandora's box to find one thing you did want to know about your genome, you might find more than you bargained for," said Dr. Yvonne Bombard, a scientist at the Li Ka Shing Knowledge Institute of St. Michael's Hospital, who has led the creation of the Genomics ADvISER.

"Clinical guidelines recommend that clinicians engage in shared decision-making with patients about receiving secondary findings before sequencing. With existing constraints on genetic counselors' time, there is a need for less resource-intense ways to provide education and decision-making support."

Dr. Bombard's study found that patients who used the Genomics ADvISER needed to spend 24 minutes less speaking with a genetic counselor than those who did not access the tool. Those who used the Genomics ADvISER also said they were more knowledgeable about the benefits of sequencing.

This is the first known randomized controlled trial to evaluate a decision aid that guides adult patients' selection of secondary findings from genomic sequencing. One hundred and thirty three patients were randomized. The intervention arm used the Genomics ADvISER to select the categories of secondary findings they wished to receive, whereas control participants spoke to a genetic counselor to make their selection.

While the decision aid did not decrease decisional conflict compared with genetic counseling alone, it did result in shorter conversations with counselors and a higher knowledge of sequencing benefits.

"With this study, we have evidence that our decision aid has the potential to address a critical gap that exists in genomic sequencing," Dr. Bombard said.

"As genomic sequencing becomes more popular in a variety of specialties, achieving improved genomics knowledge with fewer resources and significantly less time spent with genetic counselors is a crucial benefit the Genomics ADvISER provides."

Dr. Bombard and her team have started to look at ways to develop tailored methods to support patient needs during and after genomic sequencing. They are working on the 2.0 version of the Genomics ADvISER, which will transform aid into an adaptable, interactive, patient-centered digital decision support tool using artificial intelligence to customize it based on patient preferences, values, health literacy and experiences.

Diseases of the gut are often notoriously difficult to diagnose, nevermind understand, which is where a network-based approach comes in. Rather than trying to understand individual symptoms, or the role of individual genes, we can use computational methods to get that deeper understanding - looking at how genes work together in complex systems, and how these fail in a disease.

The Korcsmaros Group at EI and QIB have therefore pioneered a combined experimental and computational pipeline that tells us what genes are the important 'master regulators' in the gut, and which of these genes overlap with those associated with IBD, suggesting new angles to research in the future.

Much of this requires us to look at the cells in the gut. Paneth cells release antimicrobial peptides to protect the gut from pathogens and goblet cells release mucus to create a protective barrier. Dysregulation of their function is implicated in diseases such as IBD.

A promising method of understanding the role of these cells has recently been introduced. Known as organoids, stem cells can be cultured from mice models or from patients to make a small model of a human gut, and the effects of different treatments can then be explored, opening avenues for precision medicine, among others.

These organoids can also be modified to study the relative importance of different cell types within the system, and to explore interactions between different genes in healthy or diseased cells. One question that scientists have had is whether this 'enrichment' of organoids, to give us more Paneth cells or goblet cells for example, gives us a realistic model.

The good news, according to PhD student Agatha Treveil of EI, who first authored the paper, is that: "Based on our transcriptomics analysis, we see clear increases in targeted cell types as we expected from using the organoid enrichment methods."

The pipeline, published in Molecular Omics, allows us to compare gene expression in organoids that are enriched for Paneth cells or goblet cells with those that are not. These can then be compared with a growing database of known gene interactions.

Essentially, we can tag the genes which regulate others - highlighting in particular those that regulate lots of processes and are important for goblet and Paneth cell function. The finding that many of these genes overlap with inflammatory processes and IBD both confirms the important role of Paneth cells in IBD, and opens another route to understanding this range of costly illnesses.

Agatha Treveil continues, "this is a pioneering step forward in establishing a pipeline to better understand the gene networks at play in the gut. It enables us to design new experiments to explore IBD-related processes further."

Dr Tamas Korcsmaros, the leader of the project, said, "This project nicely represents the collaborative environment we have at the Norwich Research Park, with UEA, EI and QIB focusing on new experimental models, transcriptomics and computational approaches, and then applying them in translational projects with clinical researchers of the Norfolk and Norwich University Hospital. Now, we have a pipeline that we can use to investigate organoids generated from IBD patients, and analyse drug compound or probiotic effects on these key cell types."

Aging adults are more likely to have - and die from - cardiovascular disease than their younger counterparts. New basic science research finds reason to link biological aging to the development of narrowed, hardened arteries, independent of other risk factors like high cholesterol.

Senior author Daniel Goldstein, M.D., of Michigan Medicine's Frankel Cardiovascular Center, says his team's new Circulation Research paper is the first to dissect the biological effect of aging from hyperlipidemia on atherogenesis.

"We identify a novel pathway within the aorta by which mitochondrial dysfunction and the pro inflammatory cytokine IL-6 co-exist in a positive feedback loop with aging to promote atherosclerosis," Goldstein says of the team's work using mouse models of cardiovascular disease and aging.

The researchers report aged mice had more severe atherogenesis than young mice, even when both groups had similar cholesterol levels for the same time period.

Future research, then, might investigate therapies to mitigate against the effects of vascular aging before high cholesterol becomes a problem, with the goal of reducing the development of atherogenesis in the first place, Goldstein and colleagues say.

LA JOLLA--(December 10, 2019) In mouse models of Alzheimer's disease, the investigational drug candidates known as CMS121 and J147 improve memory and slow the degeneration of brain cells. Now, Salk researchers have shown how these compounds can also slow aging in healthy older mice, blocking the damage to brain cells that normally occurs during aging and restoring the levels of specific molecules to those seen in younger brains.

The research, published last month in the journal eLife, suggests that the drug candidates may be useful for treating a broader array of conditions and points out a new pathway that links normal aging to Alzheimer's disease.

"This study further validated these two compounds not only as Alzheimer's drug candidates but also as potentially more widely useful for their anti-aging effects," says Pamela Maher, a senior staff scientist at Salk and a co-corresponding author of the new paper.

Old age is the biggest risk factor for Alzheimer's disease--above the age of 65, a person's risk of developing the disease doubles about every five years. However, at a molecular level, scientists aren't sure what occurs in the brain with aging that contributes to Alzheimer's.

"The contribution of old age-associated detrimental processes to the disease has been largely neglected in Alzheimer's disease drug discovery," says Antonio Currais, a Salk staff scientist and first author of the new paper.

Maher and David Schubert, the head of Salk's Cellular Neurobiology Lab, previously developed CMS121 and J147, variants of plant compounds with medicinal properties. Both compounds tested positive for their ability to keep neurons alive when exposed to cellular forms of stress related to aging and Alzheimer's disease. Since then, the researchers have used the drug candidates to treat Alzheimer's in animal models of the disease. But experiments revealing exactly how the compounds work suggested that they were targeting molecular pathways also known to be important in longevity and aging.

In the new research, Maher, Currais and their colleagues turned to a strain of mice that ages unusually fast. A subset of these mice was given CMS121 or J147 beginning at nine months old--the equivalent of late middle age in humans. After four months, the team tested the memory and behavior of the animals and analyzed genetic and molecular markers in their brains.

Not only did the animals given either of the drug candidates perform better on memory tests than mice that hadn't received any treatment, but their brains showed differences at the cellular and molecular levels. In particular, expression of genes associated with the cell's energy-generating structures called mitochondria was preserved by CMS121 and J147 with aging.

"The bottom line was that these two compounds prevent molecular changes that are associated with aging," says Maher.

More detailed experiments showed that both drugs affected mitochondria by increasing levels of the chemical acetyl-coenzyme A (acetyl-coA). In isolated brain cells, when the researchers blocked an enzyme that normally breaks down acetyl-CoA, or when they added extra amounts of an acetyl-coA precursor, they saw the same beneficial effect on mitochondria and energy generation. The brain cells became protected against the normal molecular changes associated with aging.

"There was already some data from human studies that the function of mitochondria is negatively impacted in aging and that it's worse in the context of Alzheimer's," says Maher. "This helps solidify that link."

Maher and Currais are planning future experiments to test the effects of CMS121 and J147 on how other organs age. They also hope to use the new results to inform the development of new Alzheimer's drugs; targeting other molecules in the acetyl-coA pathway may help treat the disease, they hypothesize.

"We are now using a variety of animal models to investigate how this neuroprotective pathway regulates specific molecular aspects of mitochondrial biology, and their effects on aging and Alzheimer's," says Currais.

Using a targeted gene epigenome editing approach in the developing mouse brain, Johns Hopkins Medicine researchers reversed one gene mutation that leads to the genetic disorder WAGR syndrome, which causes intellectual disability and obesity in people. This specific editing was unique in that it changed the epigenome -- how the genes are regulated -- without changing the actual genetic code of the gene being regulated.

The researchers found that this gene, C11orf46, is an important regulator during brain development. Specifically, it turns on and off the direction-sensing proteins that help guide the long fibers growing out of newly formed neurons responsible for sending electrical messages, helping them form into a bundle, which connects the two hemispheres of the brain. Failure to properly form this bundled structure, known as the corpus callosum, can lead to conditions such as intellectual disability, autism or other brain developmental disorders.

"Although this work is early, these findings suggest that we may be able to develop future epigenome editing therapies that could help reshape the neural connections in the brain, and perhaps prevent developmental disorders of the brain from occurring," says Atsushi Kamiya, M.D., Ph.D., associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine.

The study was published online in the September 11 issue of Nature Communications.

WAGR syndrome is also known as chromosome 11p13 deletion syndrome, which can result when some or all of the gene located in the region of chromosome 11p13 that includes C11orf46 is deleted by chance. The researchers used a genetic tool, short hairpin RNA, to cause less of the C11orf46 protein to be made in the brains of mice. The fibers of the neurons in the mouse brains with less of the C11orf46 protein failed to form the neuron bundled corpus callosum, as is found in WAGR syndrome.

The gene that makes Semaphorin 6a, a direction-sensing protein, was turned on higher in mice with lower C11orf46. By using a modified CRISPR genome editing system, the researchers were able to edit a portion of the regulatory region of the gene for Semaphorin. This editing of the epigenome allowed C11orf46 to bind and turn down the gene in the brains of these mice, which then restored the neuron fiber bundling to that found in normal brains.