Culture

"Proteins are the workers in the cell, and it's important to know their shape," says Chris Sander, PhD, director of Dana-Farber's cBio Center in the Department of Data Sciences. Sander and his colleagues have now demonstrated a powerful "experimental evolution" method to discover details of protein shape and function, and the method may find uses across a very broad spectrum of biomedical research.

"This is a basic discovery in molecular evolutionary biology, with possible applications to cancer," says Sander, professor of cell biology at Harvard Medical School and co-senior-author on a paper describing the work in the journal Cell Systems.

Among its potential applications, the "3Dseq" technique may aid in determining the three-dimensional structure of cancer-related proteins that haven't been identified by alternative methods. The new technique also may help in understanding how oncogenes and tumor suppressor genes evolve in cancer, and in pinpointing which mutations in those genes contribute to disease progression.

For decades, molecular biologists have known that a protein's ability to function in a cell relies on its proper shape, which is dictated by the order of its constituent amino acids. Determining protein three-dimensional structure, however, requires complicated experimental techniques.

Back in 2011, working with Harvard associate professor Debora Marks and other colleagues, Sander took a big step forward on the challenge of predicting protein structure using a mathematical approach based on evolution. The "natural evolution" approach begins by analyzing how the genetic sequence of a particular protein changes over millions of years. To do this, the team examined the sequence of the protein across evolutionary time--from ancient species such as bacteria to more recently evolved species such as mice and humans.

The key insight in the earlier study came when the team used computational methods to identify which amino acids in the protein are interacting with each other, by looking at amino acids that change in lockstep across evolution. "We look at things that co-vary, where if one thing changes in the sequence, another thing changes," Sander says. "It's like a nut and a bolt--if you change one part, you have to change the other part so it still fits." He and his colleagues came up with a basic mathematical trick that can find changes in the amino acids that produce a direct effect on protein structure, providing key information that can be fed into existing algorithms from molecular physics to compute the structure.

However, not all proteins can be studied using sequences found in natural evolution. The latest innovation from the Sander group is to bring evolution into lab dishes, where the process can be tightly controlled and take weeks rather than millions of years.

Dana-Farber research scientists Michael Stiffler and Frank Poelwijk are co-lead authors, and Nicholas Gauthier is co-senior author, on the new paper about the project, which is the first-large scale demonstration of an experimental evolution method to determine protein structure.

The scientists started with a gene for an enzyme from E. coli bacteria that renders bacteria resistant to a common antibiotic. First they generated millions of copies of the original gene with mutations sprinkled in various positions, and then put these mutated genes into millions of bacteria. They then put an antibiotic into the lab dishes holding the bacteria, and harvested the bacteria that survive. These surviving bacteria have functional antibiotic resistance genes yet still contained selected mutations. This painstaking procedure was repeated many times to mimic evolutionary processes in analogy to natural evolution. "Out of tens of millions of proteins, we ended up with a few hundred thousand that actually work," Sander says.

Using the computational strategy pioneered in the 2011 study, they produced data that generated 3D protein structures for two very different antibiotic resistance proteins and got shapes very similar to the ones determined by X-ray crystallography.

3Dseq experimental evolution will join three existing technologies to reveal protein structure: X-ray crystallography, which shoots X -rays at a crystallized protein; nuclear magnetic resonance (NMR) spectroscopy, based on physics similar to that employed by magnetic resonance imaging (MRI) scanning; and cryo-electron microscopy, which scans frozen specimens with an electron microscope.

Once it is mature, the 3Dseq technology may bring two main advantages to protein structure determination, Sander says. First, the three existing methods do not always work for proteins. Second, 3Dseq provides details on the key interactions in the complicated protein shapes that are required for proteins to function. This capability eventually could prove to be very important for a number of applications in cell biology, ranging from understanding how pathogens evolve to accelerating the development of biotherapeutics, he says.

His group and its collaborators have begun efforts to improve the 3Dseq screening techniques and generalize the technologies for use with other proteins. Their paper was published along with its sequence data and software tools. "We will collaborate with other people to develop the assays to make it more generally applicable to proteins of interest," Sander says. "Whatever we develop, we'll make available publicly."

"This research shows the positive, open-minded scientific culture of Dana-Farber and Harvard Medical School, as an example of basic science that will spawn advances in cancer research," he adds. Lead funding for the work came from Dana-Farber and the National Institute of General Medical Sciences.

OAK BROOK, Ill. - Deep learning, a type of artificial intelligence, can boost the power of MRI in predicting attention deficit hyperactivity disorder (ADHD), according to a study published in Radiology: Artificial Intelligence. Researchers said the approach could also have applications for other neurological conditions.

The human brain is a complex set of networks. Advances in functional MRI, a type of imaging that measures brain activity by detecting changes in blood flow, have helped with the mapping of connections within and between brain networks. This comprehensive brain map is referred to as the connectome.

Increasingly, the connectome is regarded as key to understanding brain disorders like ADHD, a condition that makes it difficult for a person to pay attention and control restless behavior.

According to the National Survey of Children's Health, approximately 9.4% of U.S. children, ages 2 to 17 years (6.1 million) in 2016 have been diagnosed with ADHD. The disorder cannot yet be definitively diagnosed in an individual child with a single test or medical imaging exam. Instead, ADHD diagnosis is based on a series of symptoms and behavior-based tests.

Brain MRI has a potential role in diagnosis, as research suggests that ADHD results from some type of breakdown or disruption in the connectome. The connectome is constructed from spatial regions across the MR image known as parcellations. Brain parcellations can be defined based on anatomical criteria, functional criteria, or both. The brain can be studied at different scales based on different brain parcellations.

Prior studies have focused on the so-called single-scale approach, where the connectome is constructed based on only one parcellation. For the new study, researchers from the University of Cincinnati College of Medicine and Cincinnati Children's Hospital Medical Center took a more comprehensive view. They developed a multi-scale method, which used multiple connectome maps based on multiple parcellations.

To build the deep learning model, the researchers used data from the NeuroBureau ADHD-200 dataset. The model used the multi-scale brain connectome data from the project's 973 participants along with relevant personal characteristics, such as gender and IQ.

The multi-scale approach improved ADHD detection performance significantly over the use of a single-scale method.

"Our results emphasize the predictive power of the brain connectome," said study senior author Lili He, Ph.D., from the Cincinnati Children's Hospital Medical Center. "The constructed brain functional connectome that spans multiple scales provides supplementary information for the depicting of networks across the entire brain."

By improving diagnostic accuracy, deep-learning-aided MRI-based diagnosis could be critical in implementing early interventions for ADHD patients. Approximately 5% of American pre-school and school-aged children have been diagnosed with ADHD. These children and adolescents face a high risk of failing in academic study and building social relationships, which can result in financial hardship for families and create a tremendous burden on society.

The approach also has potential beyond ADHD, according to Dr. He.

"This model can be generalized to other neurological deficiencies," she said. "We already use it to predict cognitive deficiency in pre-term infants. We scan them soon after birth to predict neurodevelopmental outcomes at two years of age."

In the future, the researchers expect to see the deep learning model improve as it is exposed to larger neuroimaging datasets. They also hope to better understand the specific breakdowns or disruptions in the connectome identified by the model that are associated with ADHD.

NEW YORK (December 11, 2019) -- Nearly 1-in-10 patients admitted to a New York hospital with no symptoms of diarrhea were found to be carriers of Clostridioides difficile (C. diff), suggesting infections originate outside the hospital setting more often than thought, according to a study published today in Infection Control & Hospital Epidemiology, the journal of the Society for Healthcare Epidemiology of America.

The results suggest that hospitals and other healthcare facilities could consider identifying carriers of C. diff as a strategy to prevent the spread of the infection. According to a 2015 report, more than 400,000 cases of C. diff, resulting in nearly 30,000 deaths, are reported each year in the United States.

"It has generally been assumed that patients get the bacteria during their stay in the hospital," said Sarah Baron, MD, MS, the lead author of the study and the Director of Inpatient Quality Improvement in the Department of Medicine in Montefiore Health System and Assistant Professor of Medicine at Albert Einstein College of Medicine. "However, when we tested patients being admitted to the hospital, we found that many of them were carrying the bacteria that causes this diarrhea in their bodies already and often went on to develop the infection."

Researchers at Montefiore tested 220 patients who showed no symptoms of C. diff infection when they were admitted between July 2017 and March 2018. Perirectal swabs were completed within 24 hours of admission, and the patients were followed for six months. Upon admission, 21 patients were identified as carriers.

Within six months, 38 percent of the carriers progressed to symptomatic C. diff infection compared to just 2 percent of the non-carriers.

The study also suggests that there is a large pool of people who carry the organism that go unrecognized and may pass it on to others and/or develop an infection themselves, Baron said.

"These findings might mean that we can predict who will develop C. diff and try to stop it before it starts," Baron said. "More work is needed to determine how we can protect everyone, even the patients who already have the bacteria in their colons, from developing this dangerous form of diarrhea."

What The Study Did: Researchers compared opioid prescribing at discharge from the Mayo Clinic in Jacksonville, Florida, across 25 procedures before and after a Florida law that mandated changes to opioid prescribing went into effect in 2018.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

Authors: Steven B. Porter, M.D., of the Mayo Clinic in Jacksonville, Florida, is the corresponding author.

(doi:10.1001/jamasurg.2019.4913)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

The United States faces a crisis in providing complex care for high-need, high-cost individuals--people who often suffer economic, mental and physical challenges.

In 2014, Jefferson launched a pilot curriculum to build interdisciplinary teams to reach out to high-need patients and attempt to find low-cost, high-touch ways to reduce their recurrent difficulties. The results of the Jefferson-based pilot appear Dec. 10 in a new publication of the New England Journal of Medicine, NEJM Catalyst Innovations in Care Delivery.

The article, "Equipping the Workforce for Complex Care: How Jefferson University Trains Medical Students in Hotspotting," is co-authored by Jefferson's Dr. Lauren Collins, Dr. Stephen K. Klasko and Shoshana Sicks.

"We need healthcare teams that appreciate the diversity of our patients and understand how socioeconomic factors affect health outcomes," Dr. Collins said. "No one discipline can do this. We must develop collaborative teams among our students."

People with high needs and high use are the 5 percent of patients who account for 50 percent of the cost of America's healthcare, Dr. Klasko said. "It takes a new curriculum for all health professions to look beyond our specialties and integrate mental health as well as economic and social challenges in the care we provide. Technology can help, but the future belongs to the students who are joining Jefferson's initiative."

The project began in 2014, when the Camden Coalition, Primary Care Progress and the Association of American Medical Colleges created a curriculum to educate students attending 24 institutions across the country about hotspotting, with support from the Robert Wood Johnson Foundation. In 2016, Jefferson added elements to integrate it into the University's own curriculum within each discipline.

Through the Jefferson Student Interprofessional Hotspotting program, University students are assigned to interprofessional teams--each group tasked to help one patient navigate the complex world of health care over the academic year. Teams are also assigned interprofessional advisers who assist with patient recruitment and provide ongoing program mentorship.

For example, one team's patient deals with an array of health problems, including diabetes, partial blindness, rapidly declining kidneys and a resting heart rate of 130 beats per minute.

"This is a patient whose chart says, 'difficult, resistant, not willing to be on dialysis, not willing to have the surgery requested by the medical team,'" notes former hotspotter Sean O'Sullivan.

The student hotspotters found their patient's initial resistance came from a lack of understanding of basic medical terminology and a failure to trust healthcare providers. Gaining their patient's confidence became the biggest goal for O'Sullivan and his team.

"It's amazing to see how something small like baking low-carb cookies for them can really make a huge impact on your relationship with that person, particularly the behaviors you're trying to change," O'Sullivan says.

Altering Perceptions

The majority of the super-utilizer population struggles with health literacy. For instance, Anne Bono, a physical therapy alumnus of Jefferson and former hotspotter, says her patient's medical records vastly contrasted with the patient's own recount of prior doctor visits.

Similar to O'Sullivan, Bono and her team also understood that any change for their patient, who had a primary diagnosis of diabetes, only would come after they earned her trust.

"It took two or three home visits of talking and learning more about her for her to open up and feel comfortable," Bono says.

After building an authentic healing relationship, their time together went far beyond helping with health literacy issues, she says. Her team quickly realized their patient battled extreme social isolation.

"She said there were days when she hadn't left her house," says Bono, who with her team set up a tour of a nearby senior center for their patient. "She was very interested in the religious group and exercise classes. She definitely came out of her shell."

Both O'Sullivan and Bono say through this experience, it changed their perception of what a patient-provider relationship should look like.

"I think hotspotting is the future of medicine," O'Sullivan says. "It's how one can focus on the chronic diseases in the United States, which include metabolic syndrome, diabetes, hypertension and obesity, and change behaviors that allow us to treat them effectively. We've bridged the gap between our patient and the healthcare system and showed him, 'Your health is important. You're important.' That's very powerful."

Sharks play a critical role in keeping oceans healthy, balancing the food chain and ensuring species diversity. However, the demand for shark derivatives has led to their exploitation, often without appropriate management strategies in place. In an assessment of Pacific Panama fisheries published in Aquatic Conservation: Marine and Freshwater Ecosystems, scientists from the Smithsonian Tropical Research Institute and collaborating institutions provide a baseline to develop regulations for shark conservation.

Their field surveys, conducted over two years, revealed that artisanal and industrial fisheries of the Pacific coast of Panama regularly exploit at least 18 shark species from six families. A large number of these are caught while still immature. This is worrisome for endangered species, such as the scalloped hammerhead (Sphyrna lewini), for which immatures represented between 63 and 90 percent of the total catch. They were also among the most exploited species, alongside species from the Carcharhinid family, representing 80 percent of the catch.

"Conservation and management policies do not protect sharks as wildlife species," said Héctor M. Guzmán, STRI researcher and principal author of the study. "For example, although the jaguar and any shark species play similar roles in ecosystem functioning, only the treasured jaguar is protected in Panama as a wildlife species, while sharks are considered an exploitable resource."

Sharks are especially vulnerable to intensive fishing. They typically grow slowly, mature late and give birth to few offspring. So, poorly managed fisheries, such as those along Panama's Pacific coast, put considerable pressure on their survival. Despite working with incomplete data--independent studies estimate that 75 percent of shark catches are unreported--researchers verified this concern. They found that between 2001 and 2011, shark catches dropped over 90 percent in Panama.

"If a seasonal fishing ban prohibiting the use of nets and long-lines near the coast and inside critical nursery areas for at least six months during the migration of endangered species, is implemented, it may still be possible reverse this trend," Guzmán said.

If the current outlook prevails, recovering the populations of species that have been intensively exploited for decades will be a difficult task. Additionally, shark fisheries may start reporting economic losses and become unsustainable in the short or medium-term future.

"The study exposes the urgent need to obtain more scientific and fishery information in order to improve shark management and conservation strategies in Panama," said Jorge Morales, STRI researcher and co-author of the study.

Based on these conclusions, the researchers propose various strategies for the protection and exploitation of sharks in Pacific Panama. This includes the development of monitoring programs for the supervision of catches, protection of critical habitats, and the establishment of fishing exclusion zones for the reproduction and early growth of sharks. In this regard, the study identifies 11 potential nursery areas of locally common and migratory sharks, which could potentially support shark conservation efforts in Panama and the region.

"This research provides a baseline towards the management of artisanal and industrial shark fisheries that have been exploited in Panama under an open access scheme that significantly undermines the sustainability of such an important fishery," said Flor Torrijos, general administrator of the ARAP. "For the Panama Aquatic Resources Authority (ARAP), it will allow us to work on a comprehensive management plan that results in the sustainable fishing of this resource."

The microbial community populating the human body plays an important role in health and disease, but with few exceptions, how individual microbial species affect health and disease states remains poorly understood. A new study by Princeton researcher Mohamed Donia and colleagues, which appeared in the journal Science on December 13, 2019, gives scientists new tools to explore and understand the human microbiome.

The identity and balance of bacterial species on human skin and mucosal surfaces influences a variety of disease conditions, ranging from digestive ailments to halitosis, bacterial vaginosis, and eczema. The microbiome also aids immune development and the fight against pathogens. However, the human microbiome is incredibly diverse; the communities of bacteria, viruses, fungi and other tiny organisms differ according to the tissue where they live, and across human populations and individuals. It’s unclear what constitutes a normal, healthy microbiome, much less how one might go about bringing a sick one back into balance.

A common approach to solving this problem is to culture an individual microbe in the lab and explore how it contributes to health or disease states. Unfortunately, it can be difficult to identify and isolate very rare species, or find the conditions necessary to support their growth outside their natural niche. To do this with every species would be a daunting task. Alternatively, scientists can examine the microbiome in situ, with the aim of describing its individual components and how they interact. One way microbes communicate — and do battle – with each other and with human cells is through biologically active small molecules.

“Our long-term goal is to define the chemical space of the human microbiome,” explains Donia, an assistant professor in the Princeton Department of Molecular Biology. Donia’s group, led by co-first authors Yuki Sugimoto and Francine R. Camacho, set out to identify the set of genes that manufacture such chemicals (termed a biosynthetic gene cluster, or BGC) directly in clinical samples. This would allow scientists to listen in on the chemical conversation taking place, and discover who is speaking and when.

Sugimoto, Camacho et al. developed computer algorithms that can detect BGCs by analyzing and interpreting metagenomic sequencing data. Metagenomic sequencing data are composed of genetic sequences obtained from the tissues or excretions of hundreds of human subjects. Some metagenomic data sets are drawn from clinical samples taken from diverse populations, including persons in different states of health or disease, or people in different geographical locales. Intensive analysis is needed to make sense of the rich but often fragmentary information contained in these data sets.

The approach employed by Donia and colleagues begins by identifying genes essential for the synthesis of a particular molecule or chemical of interest, then using computational algorithms to sort through metagenomic data for similar (homologous) genetic sequences, and group these sequence fragments together. They then assess the prevalence of each group in the human population, and use the grouped sequences to piece together full-length BGCs. Importantly, this approach allows identification of novel BGCs even if they are extremely rare.

To validate this approach, the researchers investigated whether they could detect BGCs involved in the synthesis of type II polyketides. This class of chemicals, which includes the anti-cancer drug doxorubicin and several antibiotic drugs, was previously found in soil bacteria but had never before been found in bacteria of the human microbiome.

“To our surprise, we discovered 13 such gene clusters, which are widely distributed in the gut, oral, and skin microbiome of people all the way from the US to Fiji,” says Donia. To test if these newly identified BGCs actually make type II polyketides, Sugimoto, Camacho et al. selected two of the BGCs and inserted their genes into bacteria that can be easily grown in the lab, then used mass spectrometry to detect any new chemical products. These compounds were then purified and tested for antibiotic or anticancer activity.

“Two of the five new molecules we discovered are potent antibiotics, as potent as their clinically used relatives against neighboring microbes in the oral microbiome– revealing a potential mechanism for niche competition and defense against intruders and pathogens,” notes Donia. The identification of novel antibiotics is important because pathogens are evolving resistance to antibiotics currently in clinical use. More work will be needed to discover the biological activity of the other three molecules, and the role of all five in human health or disease. Such studies may uncover new pathways for interaction between microbes, or between the microbiome and its human host.

With this technology, it is now possible to mine our own microbiomes for drug discovery or novel biological interactions. What other treasures might this type of analysis reveal? As Donia observes, “This was only one clinically important class of molecules that we went after – there are dozens more to do, and we can’t even start to predict what we will discover!”

COLUMBUS, Ohio -- Country music songwriters must perform a careful dance when they work with famous singers who may be less talented at writing songs but bring the needed star power to attract fans - and, importantly, to get the song recorded in the first place, research suggests.

A study of 39 successful country-music songwriters found that they use two strategies to navigate creative collaboration with more famous artists.

"You have these recording artists who are being required to co-write their own songs, but maybe that's not their skill," said Rachel Skaggs, the study's author and an assistant professor of arts management at The Ohio State University.

"And then you have songwriters who are brought in to help, and to collaborate, and they have to balance this. There's the need to make money and make a living, and the need to not have their name on a 'bad' song."

The study, published in September in the journal Social Psychology Quarterly, identified the two strategies - what Skaggs has termed "bespoke facilitation" and "the manipulation dance" - that songwriters employ to co-write songs with someone who might be a famous performer, but who might not be a great songwriter.

"There are these strategies for when collaborators don't have the same idea of what they want to happen, particularly if one collaborator is much higher status - a more famous artist who is important to their label," Skaggs said.

"And if you're the songwriter in the room with them, you don't want to undermine that collaborator. You want to identify that they have something to bring to the table, and maybe it's their fame, but maybe it's not creativity. So what are the ways around that? How can you can still create something that is good, but not alienate or belittle your partner?"

Such collaborations, between famous artists and successful songwriters, are becoming more common, Skaggs said, because of economic pressures on the music industry.

"We often think about creativity as being this very personal, independent thing, like some kind of prodigy in a room by themselves and their creative juices just flowing, but really it's a socially constructed process," she said.

But that means that highly skilled songwriters might find themselves in a room with an artist who has a great deal of celebrity, but not much skill - or sometimes, interest - in writing a song. For the study, Skaggs interviewed songwriters who are, she said, highly successful in the country-music industry.

The songwriters' responses indicated that most either try to take a backseat to the singer - what Skaggs called "bespoke facilitation" - or they come in with the songs mostly written - "the manipulation dance."

"Bespoke facilitation is basically where the songwriter might say to the artist, 'Oh, you're from Ohio, so we're going to write a song called 'Ohio Girl,'" Skaggs said. "It's really kind of hitting on personal branding."

That personal branding is important in this age of social media, Skaggs said, where fans want to feel a connection to the artists they love.

But it could also mean that the songwriter, in writing a song that caters to the artist's personal brand, might lose reputation points among his or her songwriting community.

"It could be seen as fluff, right?" Skaggs said.

In the case of the manipulation dance, Skaggs said, songwriters might try to introduce ideas as though they were the more famous artist's own. In that case, Skaggs said, the songwriters generally pre-write a large portion of the song - one songwriter mentioned writing a chorus and several verses ahead of time - then casually suggest the ideas as if they originated with the artist.

"They'll get in the room and maybe it's hard to corral the artist, and so they'll say, 'oh, what was that you wrote a minute ago, artist, that was so good?' And they'll introduce something they have already written," she said. "And - it's kind of deceptive, right? But it seems to work."

That strategy - the "manipulation dance" - seems to be especially effective in cases when a songwriter wants to push the artist toward something with "more artistic merit," Skaggs said.

"Maybe that could be a Grammy-nominated song as opposed to only a chart-topper," she said.

Skaggs said her findings could also be applicable in other partnerships where collaborators are mismatched in some way - an office environment, for example, or a group project in a school or volunteer organization.

BUFFALO, N.Y. -- Participants who ate a diet high in red and processed meat, fried food, refined grains and high-fat dairy were three times more likely to develop an eye condition that damages the retina and affects a person's central vision, according to the results of a study from the University at Buffalo.

The condition is called late-stage age-related macular degeneration (AMD). AMD is an irreversible condition that affects a person's central vision, taking away their ability to drive, among other common daily activities.

"Treatment for late, neovascular AMD is invasive and expensive, and there is no treatment for geographic atrophy, the other form of late AMD that also causes vision loss. It is in our best interest to catch this condition early and prevent development of late AMD," said Shruti Dighe, who conducted the research as part of her master's in epidemiology at UB's School of Public Health and Health Professions.

And that's why the finding that diet plays a role in AMD is so intriguing, added Dighe, who is now pursuing her PhD in cancer sciences at Roswell Park Comprehensive Cancer Center.

It turns out that a Western dietary pattern, one defined as high in consumption of red and processed meat, fried food, refined grains and high-fat dairy, may be a risk factor for developing late AMD.

However, a Western diet was not associated with development of early AMD in the study, published this month in the British Journal of Ophthalmology.

The authors studied the occurrence of early and late AMD over approximately 18 years of follow-up among participants of the Atherosclerosis Risk in Communities (ARIC) Study.

Dighe and colleagues used data on 66 different foods that participants self-reported consuming between 1987 and 1995 and identified two diet patterns in this cohort -- Western and what researchers commonly refer to as "prudent" (healthy) -- that best explained the greatest variation between diets.

"What we observed in this study was that people who had no AMD or early AMD at the start of our study and reported frequently consuming unhealthy foods were more likely to develop vison-threatening, late stage disease approximately 18 years later," said study senior author Amy Millen, PhD, associate professor and associate chair of epidemiology and environmental health at UB.

This U.S.-based study is one of the first examining diet patterns and development of AMD over time. The other studies were conducted in European cohorts.

Early AMD is asymptomatic, meaning that people often don't know that they have it. To catch it, a physician would have to review a photo of the person's retina, looking for pigmentary changes and development of drusen, or yellow deposits made up of lipids. With early AMD, there could be either atrophy or a buildup of new blood vessels in the part of the eye known as the macula.

"When people start developing these changes they will begin to notice visual symptoms. Their vision will start diminishing," Dighe said. "This is advanced or late stage AMD."

But not everyone who has early AMD progresses to the more debilitating late stage.

To date, most research has been conducted on specific nutrients -- such as high-dose antioxidants -- that seem to have a protective effect. But, Dighe explains, people consume a variety of foods and nutrients, not just one or two, and that's why looking at diet patterns helps tell more of the story.

"Our work provides additional evidence that that diet matters," Millen added. "From a public health standpoint, we can tell people that if you have early AMD, it is likely in your best interest to limit your intake of processed meat, fried food, refined grains and high-fat dairy to preserve your vision over time."

The sweeping extent to which increasing 40Hz "gamma" rhythm power in the brain can affect the pathology and symptoms of Alzheimer's disease in mouse models has been surprising, even to the MIT neuroscientists who've pioneered the idea. So surprising, in fact, they can't yet explain why it happens.

In three papers, including two this year in Cell and Neuron, they've demonstrated that exposing mice to light flickering or sound buzzing at 40Hz, a method dubbed "GENUS" for Gamma ENtrainment Using Sensory stimuli, strengthens the rhythm across the brain and changes the gene expression and activity of multiple brain cell types. Pathological amyloid and tau protein buildups decline, neurons and their circuit connections are protected from degeneration and learning and memory endure significantly better than in disease model mice who do not receive GENUS.

In a new review article in Trends in Neurosciences two researchers leading those efforts lay out the few knowns and many unknowns that must be understood to determine how the widespread effects take place. It's a challenge they relish because the answers could both break new scientific ground and help them improve how GENUS could become a therapeutic or preventative approach for people.

"While we know it affects pathology in mice, we want to understand how because that will help us understand and refine potential treatment," said lead author Chinnakkaruppan Adaikkan, a postdoc in the lab of senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute for Learning and Memory.

Adaikkan has been interested in understanding how neural activity produces brain rhythms since his doctoral research. At MIT, he is channeling that passion into understanding how sensory stimulation can entrain oscillations.

"That's what drives me to come to the lab every day to study these mechanisms," Adaikkan said. "When we got the data from the first mouse where we recorded from the visual cortex, the hippocampus and the prefrontal cortex we were surprised to see that visual stimulation entrains in these brain regions. That was very exciting but we have a very long way to go to understand how this happens."

The new paper raises that question and many others for the field. What cells underlie the brain's response to GENUS? How do gamma rhythms engage non-neuronal cells such as astrocytes and microglia? How does it propagate beyond the brain regions responsible for perception? How extensively can enhancing gamma affect cognition? Does long-term stimulation affect brain circuit connections and how they change?

Cell roles

Studies of how groups of neurons engage in coherent oscillations of electrical activity have yielded two models to explain gamma rhythms. Both involve an interplay between excitatory and inhibitory neurons but differ on which type leads the interaction, Adaikkan and Tsai wrote. In his work, Adaikkan is attempting to dissect the roles of specific neuron types in GENUS and how closely those patterns mirror other sources of gamma, such as that invoked by cognitive tasks.

GENUS affects more than neurons. Tsai's lab has found that microglia change their gene expression, their physical form, their protein-consuming behavior and their inflammatory response depending on the Alzheimer's model involved. Work from another group showed that blocking vesicle release in astrocytes can hinder gamma power in mice and Tsai's group found that auditory GENUS recruits an increase reactive astrocytes, which are more inclined to consume pathological proteins.

The new paper offers three hypotheses about how such "glial" cells are involved: They might contribute directly to gamma entrainment by regulating the flow of ions that carry electrical charge; even if they don't contribute to rhythms, their ionic sensitivity may still make them responsive to gamma changes; they might instead be affected by changes in levels of neurotransmitters as a result of gamma.

Moreover, different glia may also become involved because of their proximity to electrical couplings between neurons called synapses, or because of how their activity is otherwise governed by neural activity.

The broader brain

That GENUS extends to the hippocampus, which is key for memory, and the prefrontal cortex, which is key for cognition, is likely a factor in how it preserves brain function. But again there are competing models for how increased gamma could facilitate multi-regional communication. In one, the authors write, coherence at the same frequency optimizes communication, while in the other model, one region's gamma activity directly drives activity in regions downstream. New experiments that directly manipulate inter-regional circuits, they argue, could help resolve which model better explains gamma entrainment's effects.

Finally, the effects of GENUS on brain function and behavior also aren't fully explained. The Tsai lab's has shown significant effects on spatial memory and some effects on other forms of memory, depending on the stimulation method. Other studies have shown that stimulating brain rhythms by other means, such as via genetic or optogenetic manipulations in mice, or via transcranial stimulation in humans, can also improve functions such as working memory. Adaikkan is interested in closing a gap between those studies and the Tsai lab's work: Most studies measure cognitive performance during stimulation, while the Tsai lab has done so after the conclusion of repeated stimulation. He said he'd like to also test how mice perform while GENUS is actively underway.

"Our lab is excited to tackle these many hypotheses and to see how the field tackles many more," Tsai said. "GENUS has created many intriguing new questions for neuroscience."

New research from anthropologists at McMaster University and California State University, San Bernardino (CSUSB), is shedding light on ancient dietary practices, the evolution of agricultural societies and ultimately, how plants have become an important element of the modern diet.

Researchers examined plant remains found on ceramic artifacts such as bowls, bottles and jars, and stone tools such as blades and drills, dating to the Early Formative period (2000-1000 BCE), which were excavated from the village site of La Consentida, located in the coastal region of Oaxaca in southwest Mexico.

They focused on remnants of starch grains, which are where plants store energy, and phytoliths, also known as 'microfossils,' a rigid, microscopic structure made of silica which is produced by plants and can survive the decay process. Both types of microbotanical remains are routinely recovered from artifacts to analyze ancient foodways.

A careful analysis found the remains of flowering plants, wild bean families and grasses, including maize. The findings support existing evidence that the village was transitioning from a broad, Archaic period (7000-2000 BCE) diet to one based on agriculture.

"This is an important piece of the puzzle. The work provides us with a better idea of how plants became cultivated and how they made their way to our plates," explains Éloi Bérubé, a graduate student in the Department of Anthropology at McMaster University, who conducted the work with advisor Shanti Morell-Hart, an assistant professor of anthropology.

"It gives us a more complete understanding of the daily activities that played a significant role in ancient societies," he says.

For example, researchers found maize microfossils pointing to the storage and processing of different parts of the plant, as well as indications of heat damage, likely caused by cooking. Evidence of maize and wild beans was also found in artifacts used for burial offerings.

"The Early Formative was a key moment of social transformation for native peoples of Mesoamerica," says Guy Hepp, director of the La Consentida Archaeological Project and assistant professor of anthropology at CSUSB. "La Consentida was among Mesoamerica's earliest villages, and these new dietary results help us better understand some of the changes the community was experiencing, including a shift toward permanent settlements and the beginnings of social complexity."

Combined with other evidence from the site, including variations in burial offerings and the diversity of human depictions in small-scale ceramic figurines, this study suggests that the community was in the early stages of establishing a complex social organization.

The artifacts considered for the study come from a variety of contexts at La Consentida, including mounded earthen architecture, the spaces around ancient houses, and even human burials.

Pottery from the site includes jars used in domestic and communal cooking events and likely also for storage. Some of the jars were later reused as offerings with human burials. Decorative bowls were likely used for serving foods at communal feasts. Ceramic bottles, also found in feasting refuse, likely held beverages brewed from maize and possibly even cacao.

Ethylene, or ethene, is a primary feedstock for the chemical industry, including as a starting material for the production of a wide variety of plastics. In the journal Angewandte Chemie, scientists have now introduced a new electrochemical technique for selective and energy-efficient production of ethylene from carbon monoxide, which can be obtained from renewable resources and waste.

From both economic and environmental points of view, the conversion of carbon monoxide (CO) into ethylene by energy-efficient methods is a key process for use of non-petrochemical raw materials. Today, ethylene is typically produced by steam cracking of naphtha derived from petroleum refineries. In this process, long-chain hydrocarbons are split into shorter chains at 800 to 900 °C. Alternatively, ethylene can be produced from synthesis gas--a mixture of CO and hydrogen obtained from coal gasification--though it can also be obtained from biogas, wood, and waste as carbon sources. The Fischer-Tropsch process can be used to convert synthesis gas into a mixture of hydrocarbons, including ethylene. The disadvantages of this method are the energy-intensive conditions of 200 to 250 °C, 5 to 50 bar of pressure, and the consumption of valuable hydrogen. In addition, a maximum of 30% of the products are the preferred C2 hydrocarbons (ethylene and ethane). Formation of longer chains cannot be prevented, the process for separating out ethylene is complex, and 30-50% CO(2) is also produced, which is an undesired emission and represents a waste of carbon.

Researchers working with Dehui Deng at Xiamen University and the Dalian Institute of Chemical Physics of the Chinese Academy of Sciences have now introduced a new approach for a direct electrocatalytic process for the highly selective production of ethylene. In this method, CO is reduced with water at room temperature and standard pressure, using a copper catalyst and electric current.

By optimizing the structure of their gas diffusion electrode, the researchers were able to achieve an unmatched Faradaic efficiency (charge-transfer efficiency within an electrochemical reaction) of 52.7% and they cracked the 30% limit for C2 selectivity. No CO(2) emission occurs. The success of the approach hinges on a microporous layer of carbon fibers with an optimally tuned hydrophobicity, which acts as a support for catalytically active copper particles, and an optimized potassium hydroxide concentration in the aqueous phase. This increases the CO concentration at the electrode and increases coupling between the carbon atoms. The side products of this reaction, ethanol, n-propanol, and acetic acid, are liquids, allowing for easy separation of gaseous ethylene.

For years, aquatic researchers have sought an easy way to determine when wild fish are under stress. Now University of Guelph researchers have shown for the first time that a key stress hormone, cortisol, accumulates in fish scales slowly and remains there for weeks.

The finding means measuring cortisol levels in scales could offer a simple, minimally invasive glimpse into fish well-being, allowing scientists to better understand how they are coping with agricultural, industrial or biodiversity changes.

Cortisol is a well-known stress indicator and appears readily in the blood. But blood tests are invasive and don't provide a good indication of long-term stress, because levels return to normal soon after a stressful event.

In new research published in the journal Conservation Physiology, professors Nicholas Bernier and Frédéric Laberge from U of G's Department of Integrative Biology demonstrate that cortisol accumulates in fish scales at a much slower rate than in blood and remains there for weeks.

"Recent research has found that cortisol can be measured in fish scales, but it wasn't able to demonstrate how long it took for the hormone to accumulate in the scales. This is important to know because the mere act of catching a fish will cause a cortisol spike. We are the first to show that cortisol increases slowly in scales and remains elevated for some time," said Laberge.

Much like human hair and fingernails, the scales of fish in the largest, most common fish group contain no live cells. But because scales grow within layers of the skin, they are in constant contact with the bodily fluids that keep them nourished, including circulating cortisol.

The research team wanted to better understand how long it took for cortisol to accumulate in scales after long-term stress and then dissipate after the stress ended. They conducted several experiments using goldfish in lab settings, exposing them to a variety of stressors over different time increments, and then allowing them to recover for one, two or three weeks. Blood and scale samples were taken throughout the stress and recovery periods.

The team found that blood levels of cortisol spiked within a half hour after exposure to a single stressor and then returned to normal within a few hours. While scale cortisol content did not change in response to a single incident of stress, repeated daily stress created a clear signature in the scales.

In fish that endured repeated stress over several weeks, their scale cortisol levels built up over time, taking at least 14 days to manifest in the scales, and then remained high, clearing from the scales slowly.

Even among the goldfish allowed to recover from their stress for more than three weeks, the cortisol levels in their scales were still high.

"One of the things we highlighted in our paper is that scales do not behave like hair and feathers," said Laberge. "With hair, cortisol is deposited as the hair grows and provides a retrospective look at stress levels. Scales are more dynamic. Hormones can accumulate and then dissipate in scales, but in a much slower way than in blood."

The team also learned that scales gathered from around the fish's horizontal midline showed the highest levels of cortisol, suggesting this area is best for sampling scales to measure this important hormone.

Although this research was conducted on goldfish in laboratory settings, the team has now begun similar research on wild fish in river settings to determine if adverse environmental conditions in natural settings increase scale cortisol levels.

The researchers expect scale cortisol accumulation and clearance will differ among fish species, just as the hormone accumulates differently in the hair of different mammal species.

"There is more work that needs to be done to understand these differences and also to make this testing method simpler, more precise and less invasive using as few scales as possible," said Bernier.

"This is still a new area of research, but there is a lot of excitement, both from ecological conservation researchers and from the animal welfare perspective, that scales have the potential to be a simple indicator of chronic stress."

The colour of our eyes or the straightness of our hair is linked to our DNA, but the development of Alzheimer's disease isn't exclusively linked to genetics, suggest recently published findings.

In the first study published about Alzheimer's disease among identical triplets, researchers found that despite sharing the same DNA, two of the triplets developed Alzheimer's while one did not, according to recently published results in the journal Brain. The two triplets that developed Alzheimer's were diagnosed in their mid-70s.

"These findings show that your genetic code doesn't dictate whether you are guaranteed to develop Alzheimer's," says Dr. Morris Freedman, a senior author on the paper, head of neurology at Baycrest and scientist at Baycrest's Rotman Research Institute. "There is hope for people who have a strong family history of dementia since there are other factors, whether it's the environment or lifestyle, we don't know what it is, which could either protect against or accelerate dementia."

All three, 85-year-old siblings had hypertension, but the two with Alzheimer's had long-standing, obsessive-compulsive behaviour.

The research team analyzed the gene sequence and the biological age of the body's cells from blood that was taken from each of the triplets, as well as the children of one of the triplet's with Alzheimer's. Among the children, one developed early onset Alzheimer's disease at age 50 and the other did not report signs of dementia.

Based on the team's analysis, the late onset of the Alzheimer's among the triplets is likely connected to a specific gene linked to a higher risk of Alzheimer's disease, apolipoprotein E4 (otherwise known as APOE4), that the triplets were carrying. But researchers couldn't explain the early onset of Alzheimer's in the child.

The research team also discovered that although the triplets were octogenarians at the time of the study, the biological age of their cells was six to ten years younger than their chronological age. In contrast, one of the triplet's children, who developed early onset Alzheimer's, had a biological age that was nine years older than the chronological age. The other child, who did not have dementia, of the same triplet showed a biological age that was close to their actual age.

"The latest genetics research is finding that the DNA we die with isn't necessarily what we received as a baby, which could relate to why two of the triplets developed Alzheimer's and one didn't," says Dr. Ekaterina Rogaeva, another senior author on the paper and researcher at the University of Toronto's Tanz Centre for Research in Neurodegenerative Diseases. "As we age, our DNA ages with us and as a result, some cells could mutate and change over time."

In addition, there are other chemical factors or environmental factors that don't necessarily change the gene itself, but affect how these genes are expressed, adds Dr. Freedman, who is also a professor in the Division of Neurology, Department of Medicine, at the University of Toronto.

As next steps, researchers are interested in looking at special brain imaging of each family member to determine if there is an abundance of amyloid plaques, protein fragments that are typical signs of Alzheimer's. They are also looking to conduct more in-depth studies into the biological age of individuals with Alzheimer's to determine whether biological age affects the age of onset of the disease.

This work was made possible with support from the Canadian Consortium on Neurodegeneration in Aging, Ontario Neurodegenerative Disease Research Initiative, the Alzheimer Society of London and Middlesex, the Saul A. Silverman Family Foundation, the Morris Kerzner Memorial Fund, the Shanghai Pujiang Program and the National Institutes of Health.

With additional funding, researchers could further explore the interaction between genetics and environment in the development of Alzheimer's disease and the impact of environmental factors in delaying the onset of this disorder.

WEST LAFAYETTE, Ind. - What if scientists could create more effective drugs to treat cancers and other diseases by better targeting specific sites on proteins in the body?

That's the primary question researchers in the Purdue University laboratory of Carol Post, a distinguished professor in Purdue's College of Pharmacy, are trying to answer. They have developed software called NmrLineGuru to move researchers closer to the answer. Their work is published in the Nov. 5 edition of Scientific Reports.

Chao Feng, a postdoctoral researcher in Post's lab, who helped lead the research team, said, "We created software for fast 1D nuclear magnetic resonance lineshape simulation and analysis with multistate equilibrium binding models. It enables researchers and scientists to study much more specific information about proteins that are linked to serious diseases to help in the drug discovery process."

Proteins play a crucial role in the growth of cancer in the body by stimulating molecules responsible for tumor growth. The graphical user interface software developed at Purdue can help researchers quickly understand, through simulated models, how certain proteins bind with other molecules in the body.

"Our work stems from a deep understanding of the need in the drug discovery field for better and faster solutions to understand biological functions of proteins and molecules in the body," Feng said.

The Purdue software supports the most common two-, three-, and four-state binding models used in the drug discovery industry to study such interactions between the proteins involved in a disease state and the molecules that bind to them. The software takes the information submitted by the user and creates specific model information about protein interactions.