Culture

London, UK: A prospective study recently published in the journal Cephalalgia, the official journal of the International Headache Society, extends the idea behind cluster headache chronicity. The study, entitled "Temporal changes of circadian rhythmicity in cluster headache", was first-authored by Dr. Mi Ji Lee, from the Department of Neurology, Neuroscience Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Cluster headache (CH) is known in the medical literature as the most intense pain experienceable by humans and is popularly known as "suicidal headache". CH consists of a primary headache disorder, classed as a Trigeminal Autonomic Cephalalgia by the 3rd Version of the International Classification of Headaches Disorders - ICHD-3. It is characterized by severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15-180 minutes, presenting with at least one of the following autonomic symptoms in the same side of the pain: conjunctival injection and/or lacrimation; nasal congestion and/or rhinorrhea; eyelid edema; forehead and facial sweating; miosis and/or ptosis; and a sense of restlessness or agitation.

Attacks occur with a frequency between one every other day and 8 per day. During part, but less than half, of the active time-course, attacks may be less severe and/or of shorter or longer duration. Attacks occur in series lasting for weeks or months (so-called cluster periods or bouts) separated by remission periods usually lasting months or years. Another hallmark feature of CH is its circadian, or even circannual pattern, with up to 82% of patients reporting CH attacks around the same time each day.

In this study, Dr. Lee's and colleagues investigated prospectively the pattern of circadian rhythmicity in relation to disease course in 175 patients in the active, within-bout period from 15 hospitals in Korea. The prevalence and characteristics of circadian rhythmicity were compared between- and within-patients with different numbers of total lifetime bouts. Patients with ≥ 2-lifetime bouts were categorized as stationary (no change between bouts), developing (becomes more prominent as disease progresses), decreasing (becomes less prominent as disease progresses), and variable (different from bout to bout), with regard the changes in the pattern of circadian rhythmicity during their disease progression.

Circadian rhythmicity was reported in 86 (49.1%) patients for the current bout. Seasonal rhythmicity was more prevalent in patients with circadian rhythmicity compared to patients with no seasonal rhythmicity (66.2 % vs 37.1 %, respectively). The prevalence of circadian rhythmicity was similar between groups (deciles groups) regarding the number of total lifetime bouts, while changes in circadian rhythmicity between bouts throughout the disease course were reported by 45.3% of patients. Patients without circadian rhythmicity showed a more variable pattern compared to patients with circadian rhythmicity (35.2% vs 8.8 %), whereas a stationary pattern was more common among patients with circadian rhythmicity in the current bout (64.7 % vs 40.9 %) compared to those without rhythmicity.

Regarding the time of CH attacks, 10 am and 3 pm, followed by 10 pm and 2 am, were the most common attack time recorded, and this was true either in the whole patients' sample as for patients with circadian rhythmicity. Concerning the time of day for cluster headache attacks in relation to the number of total lifetime bouts, with disease progression, a trend to a dichotomic distribution was observed for hypnic and midday occurrence in the current bout.

A greater variance was observed in the afternoon (1 pm to 6 pm) and hypnic (1 am to 6 am) groups, whereas the evening (7 pm to 12 am) group had the least variance, implicating that afternoon and hypnic attacks occur throughout the disease course, whereas evening attacks are prominent only during the earlier disease course.

The nighttime predilection was predominant in the earliest (1st to 2nd deciles) disease duration group, that is, those with ≤ 2 lifetime CH attacks, reduced as the disease progressed (up to the 7th decile), and increased again at the 8th and 10th deciles (mean of 44.1 total lifetime bouts in the 10th decile).

These data indicate that CH may not have fixed rhythmicity throughout the disease course, there is individual variability, and interpretations are as follows:

The suprachiasmatic nucleus may be additional, but not essential to in the pathophysiology of CH;

Internal/External homeostasis or treatment effects may influence as well;

Temporal evolution of CH rhythmicity should be further investigated;

Whether this circadian rhythmicity evolution is a marker of active disease progression merits additional research;

Many studies are needed indeed to clarify this new CH rhythmicity feature, as the authors conclude "This pattern may indicate a possible evolvement and regression of diurnal expression of CH, the biological implication of which has not yet been determined".

Arms control robots, a new national facility, and accelerating the drive to bring the fusion energy that powers the sun and stars to Earth. These far-reaching achievements at the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL) made 2019 another remarkable year. Research at the only national laboratory devoted to fusion and plasma physics -- the state of matter that makes up 99 percent of the visible universe -- broke new ground in varied fields as vast as astrophysics and as tiny as nanotechnology. Here in no particular order, in case you missed them, are 10 must-read stories that capture an example of the full range of research and development during the past year at the Laboratory -- plus three bonus stories highlighting a first-generation college student, an award-winning apprenticeship program, and creation of a supersonic plasma jet that could facilitate the study of stellar bodies light years away to help gain an understanding of our universe.

Find that nuclear warhead! PPPL develops and successfully tests the prototype for a swarm or robots that can detect neutrons, even when hidden, to help in arms control efforts.

High excitement for low-temperature plasma. The Laboratory teams with Princeton University to become home to a nationwide center to study a dynamic form of plasma in low temperatures, not the extremely high temperatures required for fusion reactions.

Artificial intelligence transforms scientific inquiry. The rapidly expanding branch of computer science speeds the development of fusion energy.

Spherical tokamaks as models for next-generation fusion facilities. A close look today at new options for tomorrow's power plants that will use fusion to provide energy.

Joining forces with private industry. The Laboratory houses a branch of a national program to enhance the harnessing of fusion energy, making a powerful public-private partnership.

A novel way to launch fusion reactions. PPPL scientists confirm a viable alternative to a widely used standard method.

All fired up and ready to go. The Laboratory powers up an upgrade of the Lithium Tokamak Experment (LTX) -- now called the LTX-β -- to test the ability of lithium metal to facilitate fusion reactions.

Streamlining designs of a different type of fusion device. PPPL physicist develops a technique to simplify development of complex stellarators -- the type of device created and envisioned by the Lab's founder, Lyman Spitzer -- to produce stable fusion plasmas.

Surprise! Researcher discovers turbulence is not all bad. Discovery demonstrates that eddies and currents that disturb the plasma that fuels fusion reactions may also be beneficial.

Smoothing the operation of fusion facilities. PPPL world-renowned expert is named co-leader of national program on the use of liquid metal components in future fusion devices.

Bonus 1. First-generation college student. Physics major Barbara Garcia pursues fresh ideas as a summer intern at PPPL.

Bonus 2. Apprentices alight. Award-winning program gives early career technicians the chance to learn high-tech skills.

Bonus 3. From the Lab to deep space. Development of plasma jets opens a new chapter in studying the stars.

Highlight

In a study of kidney transplant recipients, those with higher adherence to the Mediterranean diet were less likely to experience kidney function loss.

Washington, DC (January 2, 2020) -- A new study indicates that following the Mediterranean diet may help kidney transplant recipients maintain transplant kidney function. The findings appear in an upcoming issue of CJASN.

Despite improvements in the survival of transplanted kidneys in the early years after transplantation, loss of kidney function within 10 years still occurs in more than one-third of recipients. António Gomes-Neto, MD (University of Groningen, in the Netherlands) and his colleagues investigated whether adhering to the Mediterranean diet--which focuses on high intake of fish, fruit, vegetables, legumes, nuts, and olive oil together with lower intake of dairy and meat products--might help protect transplant recipients' kidney health.

For the study, 632 adult kidney transplant recipients with a functioning donor kidney for at least one year completed a food-related questionnaire, and adherence to the Mediterranean diet was assessed using a 9-point score.

During an average follow-up of 5.2 years, 119 recipients experienced kidney function decline (76 of whom developed kidney failure). The Mediterranean Diet Score was inversely associated with kidney function decline and kidney failure. Each 2-point higher score was associated with a 29% lower risk of kidney function decline and a 32% lower risk of kidney failure.

"Increasing scientific evidence has demonstrated health benefits of the Mediterranean Diet on cardiovascular and kidney health. In this study, we show that kidney transplant recipients with higher adherence to the Mediterranean Diet are less likely to experience function loss of their kidney transplant," said Dr. Gomes-Neto.

Malaria parasite mutations that inhibit the endocytoic appetite for a host’s red blood cells may render them resistant to artemisinin, a widely used frontline antimalarial drug, according to a new study, which reveals a key molecular mechanism of drug resistance. The results may help in the development of more effective antimalarial treatments. Malaria, a life-threatening mosquito-borne disease caused by the Plasmodium falciparum parasite, afflicts more than 200 million people worldwide each year. Artemisinin and its derivatives (ART) are among the most effective antimalarial drugs currently used. However, the emergence of Plasmodium parasites resistant to this and other widely used antimalarials puts their effectiveness at risk. Understanding how parasites develop and mediate ART resistance is critically important to combating malaria and preventing the spread of drug resistance. Previous research has linked ART resistance with mutations in the parasite’s Kelch13 protein, although the cellular function of Kelch13 and its role in resistance is poorly understood. Jakob Birnbaum and colleagues discovered that Kelch13 and its other associated proteins are essential for young ring-stage parasites to feed upon the host’s red blood cells; ART is activated by the parasite’s digestion of hemoglobin. However, Birnbaum et al. found that inactivation of all eight Ketch13 proteins decreased hemoglobin uptake, thus reducing ART activation resulting in parasite resistance to the drug. Similarly, reduced levels of Ketch13 proteins and hemoglobin uptake was also observed in wild P. falciparum carrying ART resistance. The results illustrate how mutations that alter Kelch13 protein stability can lead to ART resistance. In a related Perspective, Danushka Marapana and Alan Cowman discuss the study in greater detail.

Newly discovered action potentials in neuronal dendrites neurons uniquely amplify the computational power of the human brain, according to a new study. The results provide critical insights into the physiological circuits that underpin cortical network behavior. While it’s widely understood that the active electrical properties of dendrites play a critical role in neuronal signaling and are fundamental to brain function, much of what is known about active dendrites has been gleaned from the brains of rodents. Unlike rodent brains, however, the human brain’s cortical layers are thick – particularly layer 2 and 3 (L2/3), which contains numerous neurons with large and elaborate dendritic trees. Recent studies have shown a developmental program that drives the disproportionate thickening of L2/3 – a unique characteristic that may be fundamental to what makes us human. Albert Gidon and colleagues used somato-dendritic patch clamp and two-photon imaging to directly probe the active properties of L2/3 dendrites in slices of human brain tissue. The investigation revealed several previously unidentified electrical properties unique to L2/3 neurons unknown in all other neurons studied to date. Gidon et al. also identified a new class of dendritic calcium action potentials (dCaAPs). The findings make the activity of L2/3 dendrites far more complex than previously thought, according to the authors. By modeling their properties, the authors demonstrate the ability of single neurons to solve computational problems that were previously thought to require multi-layer neural networks.

When Lorna De Leoz invited laboratories to participate in her glycomics study, she hoped for 20 responses. Instead, she was deluged by emails from around the world.

De Leoz, at the time a research chemist at the National Institute for Standards and Technology, or NIST, was planning a study on how pharmaceutical and academic laboratories measure glycans, complex carbohydrate molecules that cells use to post-translationally modify various proteins. The project, the subject of a paper in this month's issue of Molecular & Cellular Proteomics, grew to include 76 participating labs.

The flood of responses, including from many well-known pharmaceutical companies, illustrates the industry's appetite for a better understanding of protein glycosylation. A growing number of drugs are made from proteins -- most often antibodies -- and this is a big variable in manufacturing them.

Glycans make up no more than 3% of the weight of an antibody-based drug, but they have an outsized impact. A change in glycosylation from one batch to the next can alter a drug's binding to its target or the likelihood that it will be attacked by the patient's immune system. To make sure patients receive the safest and most effective medicine, researchers must be able to keep track of the glycosylation status of antibody drugs.

Stephen Stein, a fellow at NIST's mass spectrometry data center, was the senior author of the study. "Glycosylation is one of the most important physical-chemical aspects of biology," he said, "but one of the most difficult to analyze."

Glycans' complex and heterogeneous structures make analysis difficult. Unlike macromolecules such as DNA and proteins, which are made of a linear chain of subunits, sugars can link in several places, building branched chains. Complicating matters, while those single-chain macromolecules are usually made by referring to a template, glycans are more free form. A scrum of enzymes, each making its signature modification, determines their final structure.

Measuring protein glycosylation is a challenge, even with a large amount of otherwise pure protein. Researchers have developed many methods, and their results can vary. That's where the NIST comes in: The institute is dedicated to establishing shared measurements. To help glycomics scientists get clear about what they're measuring, De Leoz sent each participating lab a sample of the same antibody, a failed drug candidate. It took almost a month to pack up samples and fill out dozens of customs forms.

There was enormous diversity of glycomics techniques among the participating labs. Some measurements, often used in manufacturing, are optimized to find the exact quantity of one or two glycan structures; others, more often used in academia, are better suited to showing the broad scope of glycan types that are present.

"There's a lot of variability in the labs themselves," Stein said. "There was no one method that was clearly better than all the others; they all have different advantages and disadvantages."

The researchers used a statistical approach to combine measurements from disparate labs into a list of consensus estimates of the concentration of certain glycan compositions. Stein said, "The glycosylation part is now characterized as fully as it can be by the different methods used."

The NIST will leave it up to the research community to figure out which measurement approach makes the most sense to use. MCP Editor-in-Chief Alma Burlingame said he hopes the paper will "point out to the biopharma industry and glycoanalytical community the urgent need to bring some methodological rigor to bear in the popular and important field of FDA-regulated antibodies."

Researchers provide predictive models that chart the likely effects of human-induced climate change and deforestation as individual and combined causes of habitat and species destruction.

The scientists employ a case study of two critically endangered lemurs using three decades of research throughout Madagascar to analyze threats to the country's eastern tropical rainforest.

The findings identified areas of intact forest that could be prioritized for protection in order to enable resilience and survival of threatened species.

NEW YORK, January 2, 2020 - A study in Nature Climate Change has found that, left unchecked, the combined effects of deforestation and human-induced climate change could eliminate Madagascar's entire eastern rainforest habitat by 2070, impacting thousands of plants, mammals, reptiles, and amphibians that are endemic to the island nation. However, the study's authors also found that protected areas will help to mitigate this devastation while environmentalists work toward long-term solutions for ending runaway greenhouse gas emissions and resulting climate change.

Madagascar--a biodiversity hotspot where 80 to 90% of its animal and plant species are exclusive to the area--has been devasted by decades of deforestation and overharvesting. The activities have destroyed much of the land cover that provides habitat for a variety of unique animals, including currently endangered varieties of lemurs. In particular, two species of ruffed lemurs are now critically endangered, and these animals play a central role in dispersing the seeds of a number of plant species that provide food and shelter for other animals across the rainforest.

"Because of their essential role as seed dispersers and their sensitivity to habitat degradation, ruffed lemurs serve as a critical indicator of the health of Madagascar's entire eastern rainforest," said Andrea Baden, a professor of anthropology at The Graduate Center, CUNY and Hunter College and the study's primary investigator. "When we projected the impact of deforestation and climate change, we found that deforestation alone and climate change alone could reduce ruffed lemur habitat by over 50%. Even more alarming, these two factors together are projected to essentially decimate suitable rainforest habitat by the end of the century."

The researchers' data suggest that the speed and intensity of destruction to Madagascar's eastern rainforest will be greatly determined by whether the country institutes strict protections against deforestation or a relaxed set of policies. Protecting forested areas that provide shelter to ruffed lemurs and serve as corridor links to their strongholds is particularly important to survival given their role as a keystone species that enables the survival of a large number of animal and plant species in one of the world's most biodiverse regions.

"The results from our study will be useful to nonprofit organizations, park management, and the broader conservation community," Baden said. "Our results indicate potential conservation opportunities for ruffed lemurs and any of the rainforest-dwellers that rely on forest cover and connectivity. Protected areas are vital to species persistence."

The News in Brief:

A new modeling framework showed that Hurricane Florence produced more extreme rainfall and was spatially larger due to human-induced climate change.

This new framework enables scientists to investigate the effect of climate change on individual extreme weather events in advance of their impact.

The research illustrates that climate change and its major impact on extreme storms is not a projection for the future but is a reality now.

STONY BROOK, January 2, 2020 -- A study led by Kevin Reed, PhD, Assistant Professor in the School of Marine and Atmospheric Sciences (SoMAS) at Stony Brook University, and published in Science Advances, found that Hurricane Florence produced more extreme rainfall and was spatially larger due to human-induced climate change.

Previous research has suggested that human influences such as emission of greenhouse gasses that alter climate does affect precipitation in extreme storms. The research in this study, however, is a first to use a "forecast attribution" framework that enables scientists to investigate the effect of climate change on individual storm events days in advance.

Reed explains the future tools of storm modeling including the approach by his team in this brief video.

Changes in extreme weather are one of the most serious ways society experiences the impact of climate change. Severe weather and natural disasters account for much damage and has a major economic impact on countries. Reed and colleagues nationally are investigating ways to better forecast extreme storms in the context of climate change.

In 2018, prior to the landfall of Hurricane Florence, Reed and colleagues made predictions based on simulations of the storm given climate change models. They predicted Hurricane Florence would be slightly more intense for a longer portion of the forecast period, rainfall amounts over the Carolinas would be increased by 50 percent due to climate change and warmer water temperatures, and the hurricane would be approximately 80 kilometers larger due to the effect of climate change on the large-scale environment around the storm.

"With our ability for additional 'hindsight' numerical modeling of the storm around climate change factors, we found predictions about increases in storm size and increased storm rainfall in certain areas to be accurate, even if the numbers and proportions are not exact," explains Reed. "More importantly, this post-storm modeling around climate change illustrates that the impact of climate change on storms is here now and is not something only projected for our future."

He said that while the post-storm analysis did show that the storm was slightly more intense during the forecast period due to climate change - as they predicted - as measured by minimum surface pressure and near-surface winds, the finding remains the most uncertain from the hindsight model.

One key finding of the post-storm model showed that Hurricane Florence was about nine kilometers larger in mean maximum diameter due to climate change. Additionally, rainfall amounts over large ranges were significantly increased. Mean total overland rainfall amounts associated with the forecasted storm's core were increased by 4.9 ± 4.6% with local maximum amounts experiencing increases of 3.8 ± 5.7% due to climate change.

Reed emphasizes that by attributing climate change effects to individual storms, as his team did with Hurricane Florence, scientists are better able to communicate the direct impacts of climate change on extreme weather to the public.

HOUSTON - (Jan. 2, 2020) - It turns out the coiled snakes often used to symbolize medical knowledge are more than apt. They also mimic a key to life itself.

Members of Rice's Center for Theoretical Biological Physics (CTBP) are taking a deep dive into the dynamics of essential proteins that help DNA fold into its compact, functional form in chromosomes. They found a key protein's "coiled coils" also braid around each other and writhe like snakes as they form bigger loops in the DNA.

The loops, in turn, bring together sites on DNA that regulate the transcription of genetic messages. While the loops and their functions are becoming better understood, until now nobody has been able to take a close look at the condensin and cohesin proteins that wrangle the DNA into shape.

The Rice team led by physicists José Onuchic and Peter Wolynes and postdoctoral fellow Dana Krepel report in the Proceedings of the National Academy of Sciences that structural maintenance of chromosomes (SMC) proteins may actively manage DNA through a novel mechanism.

They found these proteins have ring-shaped lassos that consist of two 35-nanometer long protein coiled coils. These terminate on one end in a pair of "head unit" motors that bind to DNA coils, and on the other in "hinges" thought to open and close to entrap the strands.

The lab's simulations showed these coiled coils are anything but limp lariats.

"We already knew the coiled coils have some sort of structural importance, but what we saw is that these long coils are quite active," Krepel said. "We're still investigating to what extent, but as we ran the simulations, we saw that the coils want to come together, kind of like headphones that get all twisted when you put them in your bag. We saw the twist right away."

"Braiding is the word we use," Wolynes added. "People thought the coiled coils were simply hanging out, but they didn't think they'd coil again on top of each other in an organized fashion.

"One of the key ideas of DNA physics is that DNA operates by changing its degree of coiling and its topology," he said. "Well, braiding is a topological feature. We think we see that the topology of the protein can interact with the topology of the DNA much as threads entwine with each other on a spinning wheel."

Krepel noted the SMC proteins are positively charged, and DNA is negatively charged. "We're looking at how these positive and negative charges potentially play together," she said.

"It seems clear the coils would almost certainly braid themselves around the DNA using these charge patterns," Wolynes said.

The project represents one of the largest challenges yet for the group's modeling techniques, which in this case combined direct coupling analysis (DCA) of the co-evolution of related protein sequences and the atomic forces within the proteins that determine their form and function.

To complete the structure in which there were fewer evolutionary clues, the group used the AWSEM algorithm developed by Wolynes and colleagues to determine complete folded, functional structures from a coarse subset of atomic forces within a protein.

For this study, the team looked at condensin and cohesin structures with between 1,100 to 1,300 residues. "These are huge compared to proteins we have previously studied," Wolynes said.

The size made it necessary to expand the tool set, Onuchic said. "An initial paper developed these tools but just for condensin in bacteria," he said. "Utilizing the same approach of DCA combined with structure-based simulations, we are now investigating condensin and cohesin as they appear in humans.

"Using this method, we are able to predict the structures, but to understand the details of their dynamics requires real force fields," Onuchic said. "So starting from the initially predicted structures, we ran AWSEM simulations. These simulations revealed the braiding."

The models further suggested that the ATPase motors that bind DNA can twirl the braids.

"We're still guessing at the details, but we think when the two motors are both twisting to extrude DNA into loops, one untwisting and the other uptwisting, the lassos could transfer twisting of the coils into twisting around the DNA," Wolynes said. "The coils aren't just passively hanging there. They're much more involved in the process than we thought."

The next step, he said, will be to test an even larger system with two strands of DNA, a more realistic representation, to see if the twisting action holds true. That effort will be part of a larger one at CTBP to extend its theories on protein folding to the much bigger problem of chromosome dynamics. The researchers pointed out this will be one of the main goals of the center's future work.

"This molecule and how it forms loops in DNA is a big part of many projects we have going on in chromosomes," Wolynes said. "There are quite a few diseases that arise from chromosome disorganization, and we want to have a better understanding of the mechanism of how chromosomes form."

Craft breweries aren't just a fun place to meet up with friends. They may be fueling an unprecedented geographic expansion of hop production across the U.S., according to researchers at Penn State and The University of Toledo. Their findings suggest that as more craft breweries emerge around the country, so may new opportunities for farmers.

Hops are a key ingredient in beer production, providing aroma and bittering characteristics. Before 2007, hop production in the U.S. was limited to only three Pacific Northwest states--Oregon, Washington, and Idaho--according to Claudia Schmidt, assistant professor of agricultural economics in Penn State's College of Agricultural Sciences. Citing a report released this year by the Hop Growers of America, she said that 29 states are now engaging in hop production.

"Our study is the first to systematically show that the number of hop farms in a state is related to the number of craft breweries," said Schmidt. "It suggests that in areas where hop production is possible and not cost-prohibitive, breweries are expanding markets for farmers and providing an opportunity to diversify farm income."

Using data from the U.S. Census of Agriculture and ReferenceUSA, the researchers found that from 2007 to 2017, the number of breweries in the U.S. more than quadrupled from 992 to more than 4,000, and that the number of breweries in a state is associated with more hop farms and hop acres five years later. The number of hop farms grew from 68 to 817, and hop acreage expanded from 31,145 to 59,429 acres.

"This growth has not only led to interesting changes in the locations of hop farms across the U.S., but it has positioned the U.S. as the largest producer of hops globally, both in terms of acreage and production," said Elizabeth Dobis, a postdoctoral scholar at the Penn State-based Northeast Regional Center for Rural Development, and lead author of the study.

Working with farm, brewery, and climate data, the researchers developed a statistical model to determine whether new craft breweries in a state between 2007 and 2017 resulted in a larger number of hop producers and hop acres planted, by both new and existing growers in that state. They built a time-lag into their model to identify the effect of new breweries over time. They also controlled for other variables that may influence

farmers to start growing hops, such as average farm size, average net farm income, and climate.

Their findings, which were published recently in the Journal of Wine Economics, are correlational and do not point to a clear cause-and-effect. However, the time-lag built into the model indicates that the growth in breweries preceded the growth in hop farms, said Dobis.

One possible explanation for the trend is that the growing consumer demand for locally sourced food and beverages encourages craft brewers to seek out locally grown ingredients, said Schmidt.

"While most craft breweries serve a local market, they haven't always sourced local ingredients for their beers," Schmidt said. "But if you're a brewer looking to differentiate yourself in an increasingly crowded market, sourcing ingredients locally is an approach that some brewers have found to be effective."

For example, in a project unrelated to this study, Penn State Extension's Kristy Borrelli and Maria Graziani conducted focus groups with Pennsylvania craft brewers, who reported that sourcing ingredients locally helps them connect with their customers' sense of place and preference for a flavor profile that is unique to the region.

If more brewers are looking for hops grown nearby, then more farmers may be willing to try growing them, even if only on a small scale. For instance, in Pennsylvania only 17 farms reported hop production in 2017, and their combined acreage is small--only 21 acres in all, according to the U.S. Census of Agriculture.

Looking forward, the researchers said that they will collaborate with Penn State Extension to identify the specific attributes and price points that Pennsylvania craft brewers are looking for in order to help inform farmers' production decisions.

Though scientist Richard Semon introduced the concept of the "engram" 115 years ago to posit a neural basis for memory, direct evidence for engrams has only begun to accumulate recently as sophisticated technologies and methods have become available. In a new review in Science, Professors Susumu Tonegawa of The Picower Institute for Learning and Memory at MIT and Sheena Josselyn of the Hospital for Sick Children (SickKids) and the University of Toronto describe the rapid progress they and colleagues have been making over the last dozen years in identifying, characterizing and even manipulating engrams, as well as the major outstanding questions of the field.

Experiments in rodents have revealed that engrams exist as multiscale networks of neurons. An experience becomes stored as a potentially retrievable memory in the brain when excited neurons in a brain region such as the hippocampus or amygdala become recruited into a local ensemble. These ensembles combine with others in other regions, such as the cortex, into an "engram complex." Crucial to this process of linking engram cells is the ability of neurons to forge new circuit connections, via processes known as "synaptic plasticity" and "dendritic spine formation." Importantly, experiments show that the memory initially stored across an engram complex can be retrieved by its reactivation but may also persist "silently" even when memories cannot be naturally recalled, for instance in mouse models used to study memory disorders such as early stage Alzheimer's disease.

"More than 100 years ago Semon put forth a law of engraphy," wrote Josselyn, Senior Scientist at SickKids, Professor of Psychology and Physiology at the University of Toronto and Senior Fellow in the Brain, Mind & Consciousness Program at the Canadian Institute for Advanced Research, (CIFAR) and Tonegawa, Picower Professor of Biology and Neuroscience at the RIKEN-MIT Laboratory for Neural Circuit Genetics at MIT and Investigator of the Howard Hughes Medical Institute. "Combining these theoretical ideas with the new tools that allow researchers to image and manipulate engrams at the level of cell ensembles facilitated many important insights into memory function."

"For instance, evidence indicates that both increased intrinsic excitability and synaptic plasticity work hand in hand to form engrams and that these processes may also be important in memory linking, memory retrieval, and memory consolidation."

For as much as the field has learned, Josselyn and Tonegawa wrote, there are still important unanswered questions and untapped potential applications: How do engrams change over time? How can engrams and memories be studied more directly in humans? And can applying knowledge about biological engrams inspire advances in artificial intelligence, which in turn could feedback new insights into the workings of engrams?

BIRMINGHAM, Ala. - People with drug-resistant epilepsy also can have deleterious neuropsychiatric symptoms like anxiety, depression, psychosis and impaired memory. These have negative impacts on quality of life, and there is an unmet need to improve therapy for such patients. Diagnosing and monitoring such neurobehavioral symptoms is challenging because their presentation can overlap with seizures.

Sandipan Pati, M.D., and colleagues at the University of Alabama at Birmingham now report cases of five patients who found better treatments for those symptoms using data collected -- while the patients were at home -- from implanted neurostimulators placed in their brains to control their epileptic seizures. This is an extra benefit from the implanted Responsive Neurostimulator Systems, due to the system's ability to record brain electrocorticography data initiated when a patient senses an anxiety or panic attack.

This data is key to showing whether the neuropsychiatric comorbidity began before, during or after an epileptic seizure. This guides medication or therapy changes that can reduce the negative symptoms caused by attacks that initiate outside of seizures, including psychogenic nonepileptic seizures. The only other way to get this useful information is video-electroencephalography in an inpatient clinic, with stays that typically last three to five days.

"Treating these patients can be challenging, and one reason for this is that sometime seizures can mimic anxiety and panic attacks, or psychosis," Pati said. "Seizure-induced anxiety or psychosis is treated with anti-seizure medications, while 'pure' psychosis is treated with anti-psychotic medications. This study will be attractive for patients, as anxiety or depression is a common problem in epilepsy, and patients get frustrated as they think we are always focused on treating seizures and not depression."

Pati, an associate professor in the UAB Department of Neurology, leads an epilepsy neuromodulation clinic at UAB to improve seizure control for drug-resistant epilepsy.

When a patient feels onset of a neuropsychiatric incident, he or she can use a magnet to initiate brain recording, with the prior minute of signals retained. They then can transfer the data to a password-protected laptop, and physicians can review the data to guide therapies.

Among 21 patients with implanted neurostimulators studied by Pati and colleagues, there were five patients with significant neurobehavioral comorbidities whose presentation overlapped with their seizures and, hence, could benefit from the use of the electrocorticography data stored by the neurostimulators. All saw improvements from changes in drug treatment, cognitive behavioral therapy or counseling to reduce symptoms such as panic-like attacks, psychosis and psychogenic nonepileptic seizures.

"The availability of ambulatory electrocorticography provides the opportunity to manage comorbidities in epilepsy that can mimic seizures and contribute to the overall poor quality of life," Pati said.

HIV patients lose immunity to smallpox even though they were vaccinated against the disease as children and have had much of their immune system restored with antiretroviral therapy, according to a study published in the Journal of Infectious Diseases.

Called HIV-associated immune amnesia, the finding could explain why people living with HIV still tend to have shorter lives on average than their HIV-negative counterparts despite being on antiretroviral therapy. The study follows other research recently published in the journals Science and Science Immunology that found the immune systems of children who contracted measles similarly "forgot" their immunity against other illnesses such as influenza.

Mark K. Slifka, Ph.D., a professor of molecular microbiology and immunology at the Oregon Health & Science University School of Medicine and Oregon National Primate Research Center, led the study. Slifka and his colleagues compared the T-cell and antibody responses of a total of 100 HIV-positive and HIV-negative women who were vaccinated against smallpox in their youth.

The research team chose smallpox because its last known U.S. case was in 1949, meaning study subjects haven't recently been exposed to its virus, which would have triggered new T-cell and antibody responses.

They found the immune systems of HIV-positive women who were on antiretroviral therapy had a limited response when their blood was exposed to the vaccina virus, which is used in the smallpox vaccine. Normally, those vaccinated against smallpox have CD4 T cells that remember the virus and respond in large numbers when they're exposed again. Previous research has shown smallpox virus-specific CD4 T cells are maintained for up to 75 years after vaccination.

This finding happened despite the fact that antiretroviral therapy works by boosting CD4 T cell counts in HIV-positive patients. This indicates that while antiretroviral therapy may boost total T cell counts overall, it can't recover virus-specific T cells generated from prior childhood vaccinations.

Slifka and his colleagues plan to evaluate whether the same phenomenon occurs in HIV-infected men, and if people living with HIV also lose immune memory to other diseases.

UNIVERSITY PARK, Pa.--Conventional measures of innovation suggest that only big cities foster new ideas, but a more comprehensive measure developed at Penn State shows that innovation is widespread even in rural places not typically thought of as innovative. This "hidden" innovation brings economic benefits to businesses and communities, according to researchers, whose findings will help decision makers think in new ways about innovation and how they can support it.

"The way we traditionally measure innovation is very narrow, and focuses primarily on new products or processes that result in a patent or involve R&D spending. This overlooks another kind of innovation--the incremental improvements that businesses make to their products and processes as a result of information they obtain from outside their firm," said Stephan Goetz, professor of agricultural and regional economics and director of the Northeast Regional Center for Rural Development (NERCRD). "Our measure shows that this latent, or hidden, innovation is at least as important to local income and employment growth as patent-level innovation."

The study, published this month in Research Policy, is based on well-documented evidence that businesses acquire innovation-promoting information through interactions with other businesses outside of their own industry. These can be both their suppliers and other firms to which they sell products.

"We know that inter-industry exchanges foster cross-fertilization of ideas, or knowledge spillovers, which in turn seeds innovation," said Goetz. "We wanted to explore these interactions more closely in order to better understand where the opportunities for innovation are greatest, including in rural and urbanized areas that are remote from cities."

To examine industry transactions, Goetz and his co-author, Yicheol Han, a former postdoctoral scholar at the NERCRD and now at the Korea Rural Economic Institute, used data from the national Input-Output (I/O) table. The I/O table documents annual sales and purchases both across and within U.S. industries. Focusing specifically on 381 intermediate industries, they applied a mathematical formula to measure the diversity of each industry's transactions with their customers and suppliers, both in terms of the number of different industries they interacted with, and how evenly their interactions were distributed across other industries.

They also incorporated geography into their measure in order to understand the effects that location has on innovation. They mapped the geographic location of the businesses within each of the 381 industries using county-level employment and business pattern data. Further, they included a measure

of each county's industrial makeup to capture the possibility of spillover-effects of inter-industry interactions that take place as a result of proximity.

This formula generated a "latent innovation index," which assigns a score to each U.S. county based on the degree to which opportunities for latent innovation exist. The researchers validated the index by correlating the county-level scores with county-level income and job growth while controlling for other factors that influence these variables, such as a county's starting employment, population density and share of the population with a college degree. They found that counties with higher innovation scores also had greater employment and income growth, even when they controlled for the number of patents held within a county. They also found that this type of innovation activity is present in both densely populated counties and sparsely populated, more rural counties.

"What these correlations suggest is that it's not just patent-based innovation that brings economic benefits to businesses and communities, and innovation is not restricted to urban centers with large populations," Goetz said. "This type of latent or hidden innovation is not recorded and tracked the way patents are, but it appears to be at least as important in terms of economic growth and it is happening in all types of places--rural and urban and in-between."

This has important implications, Goetz said, because it refutes conventional wisdom that only big cities enjoy innovation.

"We often see media articles touting big cities as innovation centers, and our research brings a different perspective to the conversation," he said. "Yes, places like Silicon Valley, Seattle and Boston are home to tech firms that are developing entirely new products and technologies. But at the same time many non-tech businesses also engage in innovative activity that is less obvious but nonetheless moving their industries forward and, more importantly, keeping them competitive."

Goetz said that by understanding where and how this type of innovation is already happening, community leaders can foster it by providing venues to support the exchange of ideas among a variety of businesses. For example, they can host trade shows that encourage business interactions. They also can think more strategically about targeting industries for recruitment that complement local innovation spillovers based on existing industries. The latent innovation index is available on the NERCRD website at: http://bit.ly/latent-innovation.

URBANA, Ill. - School test scores often show gaps in performance between white and non-white students. Understanding the complex reasons behind this can help reduce those gaps and promote social equality, explains Mary Paula Arends-Kuenning, associate professor of agricultural and consumer economics at the University of Illinois.

Arends-Kuenning is co-author of a study that analyzes math test scores for 9th-grade students in Brazil and breaks down the characteristics associated with performance gaps between different racial groups.

"The purpose of the study is to gain a better understanding of why there's a gap between black students and white students in Brazil, in order to inform policies to narrow that gap," she says.

Arends-Kuenning and co-author Kalinca Leia Becker, who served as a visiting Fulbright Junior Faculty Scholar at U of I, analyzed various factors that might influence the performance gap. This allowed them to estimate the effect of socio-economic characteristics such as parental education and standard of living and school characteristics such as quality of education. The gap still remaining after accounting for these factors may be due to racial discrimination and stereotypes, Arends-Kuenning says.

A unique contribution of this paper is to perform a decomposition (break-down) of factors that influence performance gaps at different test score levels rather than just looking at averages.

The researchers found that for students with test scores in the lower and middle range, the performance gaps can largely be associated with socio-economic factors; however, for higher-scoring students, structural factors that might be attributed to discrimination and stereotypes play a greater role.

Understanding the complexity of how various factors interact can help inform policy interventions, Arends-Kuenning explains.

"For example, we know that parents' education has a big effect on student performance in school. One reason blacks might do worse in school than whites is that the black students have parents who have lower levels of education than the parents of white students.

"But we can also look at how those characteristics are rewarded in the school. It might be the case that having a parent with a high school education has more of an impact on your achievement if you're white than it does if you're black. And that could be due to many factors, but one factor might be discrimination. Something is blunting the effect of the education on the students' performance for different racial groups."

The researchers used test data from the Brazilian National Evaluation System of Basic Education (SAEB), which is conducted biannually at public schools for 5th-, 9th-, and 11th-grade students. SAEB measures cognitive ability, and also collects information about student and family characteristics.

They analyzed math scores from 2015 for students in 9th grade, which is the last year of middle school in Brazil. They compared results from white, brown (mixed-race), black, and indigenous students. The racial distribution of the Brazilian population is 42% white, 48% brown, 9.3% black, and 0.5% indigenous.

The study looked at four groups of variables that might influence results. Those included characteristics of the student, such as age and gender; family characteristics, such as parental education level and standard of living; classroom characteristics, such as size, racial composition, and teacher attributes; and school characteristics, such as infrastructure and the principal's gender and race.

"This paper is innovative because it looks at differences in performance not just on average, but across the entire distribution, at the 10th, 50th and 90th percentile," Arends-Kuenning says.

The study showed that for scores in the lower and middle percentiles, student performance gaps can mostly be explained by differences in socio-economic and school characteristics, such as parents' educational level and education quality.

"However, when you get to the upper end of the distribution, we find that the performance gap is also influenced by other factors, which might include discrimination and stereotype threat; that is, how students are treated in school," Arends-Kuenning says.

The study's results indicate that it's important to invest in education, not just for the current generation of students. When those students grow up and raise families, it will affect their children too. That's especially important for students who are at the lower end of the performance distribution.

"For the high-performing students, other interventions are needed," Arends-Kuenning explains. "The first step is to being aware that there is discrimination, and help students understand that it might be affecting why they are not doing well on standardized tests. The next step is to establish a policy to help students confront stereotype threat."