Brain

Oak Brook, IL - April's edition of SLAS Discovery features the cover article, "Maximizing the Value of Cancer Drug Screening in Multicellular Tumor Spheroid Cultures: A Case Study in Five Head and Neck Squamous Cell Carcinoma Cell Lines." Stanton J. Kochanek, Ph.D., David A. Close, Ph.D., Daniel P. Camarco, Ph.D., and Paul A. Johnston, Ph.D., (University of Pittsburgh, PA, USA) disseminate their recent study that shows how incorporating morphology and dead cell readouts into cancer drug screening helps improve the drug selection rate.

Consistent with solid tumors, multicellular tumor spheroids (MCTS) develop gradients of nutrient distribution and oxygen concentration resulting in diverse microenvironments with differential proliferation and drug distribution zones. Kochanek, Close, Camarco and Johnston produced head and neck squamous cell carcinoma (HNSCC) MCTSs and used viability reagents and imaging methods to measure the effects of anti-cancer drug exposure. This step revealed that cell viability reagents under-estimate the impact of drug exposure in HNSCC MCTS cultures, but that incorporating morphology and dead cell readouts increased the number of drugs judged to have substantially impacted MCTS cultures.

A multi-parameter drug impact score provided a way to stratify MCTS drug responses and maximize the value of these more physiologically relevant tumor cultures.

Currently, cancer drug approval rates are less than 5%, while the overall probability of success in oncology clinical trials is 3.4%. Kochanek, Close, Camarco and Johnston continue to build on their current research to help improve these cancer drug discovery and development success rates through the use of more physiologically relevant and complex 3D models featured in this study.

The group's lead researcher, Paul A. Johnston, has 30 years of drug discovery experience in the pharmaceutical, biotechnology and academic sectors. As an innovator of cell-based lead generation, he pioneered the implementation of high-content imaging technology for drug discovery, and in 2005 helped create the University of Pittsburgh Molecular Library Screening Center (Pittsburgh, PA, USA). In 2011, Johnston established his own chemical biology laboratories within the University's Department of Pharmaceutical Sciences of the School of Pharmacy in order to conduct research on the application of novel drug discovery strategies to find new and effective drugs or drug combinations for prostate cancer, melanoma, head and neck cancer and hepatocellular carcinoma.

TROY, N.Y. -- Could there be a new kind of light in the universe? Since the late 19th century, scientists have understood that, when heated, all materials emit light in a predictable spectrum of wavelengths. Research published today in Nature Scientific Reports presents a material that emits light when heated that appears to exceed the limits set by that natural law.

In 1900, Max Planck first mathematically described a pattern of radiation and ushered in the quantum era with the assumption that energy can only exist in discrete values. Just as a fireplace poker glows red hot, increasing heat causes all materials to emit more intense radiation, with the peak of the emitted spectrum shifting to longer wavelengths as heat rises. In keeping with Planck's Law, nothing can emit more radiation than a hypothetical object that absorbs energy perfectly, a so-called "blackbody."

The new material discovered by Shawn Yu Lin, lead author and a professor of physics at Rensselaer Polytechnic Institute, defies the limits of Planck's law, emitting a coherent light similar to that produced by lasers or LEDs, but without the costly structure needed to produce the stimulated emission of those technologies. In addition to the spectroscopy study just published in Nature Scientific Reports, Lin previously published an imaging study in IEEE Photonics Journal. Both show a spike in radiation at about 1.7 microns, which is the near-infrared portion of the electromagnetic spectrum.

"These two papers offer the most convincing evidence of 'super-Planckian' radiation in the far-field," said Lin. "This doesn't violate Planck's law. It's a new way to generate thermal emission, a new underlying principle. This material, and the method that it represents, opens a new path to realize super-intense, tunable LED-like infrared emitters for thermophotovoltaics and efficient energy applications."

For his research, Lin built a three-dimensional tungsten photonic crystal -- a material that can control the properties of a photon -- with six offset layers, in a configuration similar to a diamond crystal, and topped with an optical cavity that further refines the light. The photonic crystal shrinks the spectrum of light that is emitted from the material to a span of about 1 micrometer. The cavity continues to squeeze the energy into a span of roughly 0.07 micrometers.

Lin has been working to establish this advance for 17 years, since he created the first all-metallic photonic crystal in 2002, and the two papers represent the most rigorous tests he has conducted.

"Experimentally, this is very solid, and as an experimentalist, I stand by my data. From a theoretical perspective, no one yet has a theory to fully explain my discovery," Lin said.

In both the imaging and spectroscopy study, Lin prepared his sample and a blackbody control -- a coating of vertically aligned nanotubes on top of the material -- side by side on a single piece of silicon substrate, eliminating the possibility of changes between testing the sample and control that could compromise the results. In an experimental vacuum chamber, the sample and control were heated to 600 degrees Kelvin, about 620 degrees Fahrenheit.

In Nature Scientific Reports, Lin presents spectral analysis taken in five positions as the aperture of an infrared spectrometer moves from a view filled with the blackbody to one of the material. Peak emission, with an intensity of 8 times greater than the blackbody reference, occurs at 1.7 micrometers.

The IEEE Photonics Journal paper presented images taken with a near-infrared conventional charge-coupled device, a camera that can capture the expected radiation emission of the material.

Recent unrelated research has shown a similar effect at a distance of less than 2 thermal wavelengths from the sample, but Lin's is the first material to display super-Planckian radiation when measured from 30 centimeters distance (about 200,000 wavelengths), a result showing the light has completely escaped from the surface of the material.

Although theory does not fully explain the effect, Lin hypothesizes that the offsets between the layers of photonic crystal allow light to emerge from within the many spaces inside the crystal. The emitted light bounces back and forth within the confines of the crystal structure, which alters the property of the light as it travels to the surface to meet the optical cavity.

"We believe the light is coming from within the crystal, but there are so many planes within the structure, so many surfaces acting as oscillators, so much excitation, that it behaves almost like an artificial laser material," Lin said. "It's just not a conventional surface."

The new material could be used in applications like energy harvesting, military infrared-based object tracking and identification, producing high efficiency optical sources in the infrared driven by waste heat or local heaters, research requiring environmental and atmospheric and chemical spectroscopy in the infrared, and in optical physics as a laser-like thermal emitter.

Nashville, Tennessee - New research finds that as education policy has shifted, post-No Child Left Behind and as a result of Race to the Top (RTTT), the rollout of statewide teacher evaluation systems have proven to phase out lower performing teachers and retain more effective teachers for longer periods of time - particularly in urban districts and low-performing schools.

"While we found that the rollout of a statewide evaluation system is associated with increased turnover, we saw it as a positive that most of the teachers departing schools - and sometimes the profession itself - were the low-performing instructors," said Luis A. Rodriguez, lead researcher and assistant professor of education leadership at NYU Steinhardt School of Culture, Education, and Human Development. "This research implies that states and districts can use evaluations as a way to increase exit rates of its least effective teachers and also highlights the need for concurrent policies to retain effective instructors while developing supports for a well-trained teacher labor force through programs like Teaching Fellows and high quality coaching."

Rodriguez's research, published today in the peer-reviewed academic research journal American Educational Research Journal (AERJ), is the first study to investigate statewide teacher evaluation reform and assess changes in mobility patterns for teachers of varying effectiveness levels.

Research Methodology and Further Findings

Along with his colleagues Walker A. Swain of the University of Georgia and Matthew G. Springer of the University of North Carolina at Chapel Hill, Rodriguez examined the state of Tennessee's teacher evaluation system. They looked at longitudinal administrative records made available through the partnership between the Tennessee Department of Education and the Tennessee Education Research Alliance as well as state test score data to match students to teachers to first quantify teaching effectiveness in math and English language arts in grades 4 through 8.

In the study, the researchers tracked teacher moves within districts, across districts, and out of the Tennessee public school system (before and after the implementation of statewide evaluation reform). The data allowed Rodriguez and his colleagues to track transfer and exit patterns for more than 100,000 teacher-year observations across a diverse set of school and district settings over a nine-year period.

"Ultimately, we conclude that the introduction of comprehensive evaluation systems can reshape the process by which school and district leaders determine who stays and leaves the teaching profession, opening the door to potential improvements in overall education quality," continued Rodriguez.

The researchers also looked at whether changes in turnover patterns differed across schools based on school-level performance and geographical urbanicity. "We found that increased turnover of low-performing teachers post-reform was, for the most part, concentrated in low-performing schools and schools in urban areas," explained Rodriguez. "We interpret these findings to suggest that changes in teacher turnover patterns associated with the reformed evaluation system are strongest in environments most influenced by accountability policies and that also benefit from a sizable, competitive pool of potential teaching candidates to replace low-performing teachers."

"These findings also have equity implications in that they indicate a well-constructed evaluation system can induce turnover of least effective teachers in some of the schools that are in most need of high-quality teaching. But in the end, guaranteeing that low-performing departing teachers are replaced by candidates who can perform better nevertheless remains a challenge to which schools and districts will have to be attentive."

Young children go on to achieve more academic success when their verbal skills are enhanced, a new study suggests.

The study, by researchers at the University of York, looked at why children from wealthier and well-educated family backgrounds tend to do better at school.

The researchers found that children from families of higher socioeconomic status had better language abilities at nursery school age and that these verbal skills boosted their later academic performance throughout school.

The researchers looked at data from nearly 700 British children. The children's pre-school ability was tested at four years-old and their educational outcomes were tracked throughout school up until the age of 16.

Differences in language skills between children explained around 50% of the effect of family background on children's achievement in the first year of school. This achievement gap widened over the course of their education, the study suggests.

Lead author of the study, Professor Sophie von Stumm from the Department of Education said: "Our findings show that a child's learning at home when they are under five is really important to their chances of later academic success.

"Children from more advantaged backgrounds are more familiar before starting school with the language patterns and linguistic codes that are used in formal educational settings and are expected by teachers.

"Not all children get the same start in life, but this study highlights the importance of helping parents of all backgrounds to engage with their children in activities which enhance verbal skills - such as reading bedtime stories and engaging the child in conversations.

"Activities designed to improve verbal skills boost cognitive, social and emotional development, in addition to benefitting parent-child bonding."

The research is the first major study to look at children's abilities in their early years and the extent to which it explains their later educational achievement.

The researchers also looked at non-verbal ability at nursey school age and found that it had a smaller, but never-the-less significant role in explaining the link between background inequalities and academic success.

Children from high socioeconomic backgrounds were at an advantage when it came to their non-verbal skills - such as solving puzzles, drawing shapes and copying actions - before they started school.

These skills were found to account for around a third of the link between family background and later educational achievement.

Preschool verbal and nonverbal ability mediate the association between socioeconomic status and school performance is published in Child Development.

The photoelectric effect, whereby photons impinging on matter cause the emission of electrons, is one of the quintessential effects of quantum mechanics. Einstein famously explained the key mechanism underlying the phenomenon in 1905, earning him the 1921 Nobel Prize in Physics. He built on a concept introduced merely five years earlier by Max Planck: electromagnetic energy is absorbed and emitted only in discrete packets --- that is, in quanta. The quantum concept revolutionised physics. The photoelectric effect, for its part, has been explored in ever greater detail, and is nowadays exploited in applications ranging from solar cells to night-vision goggles. A shift in our understanding of the effect came in the past decade or so. Laser experiments made it possible to look directly at the intricate quantum dynamics that unfold at the attosecond timescale as electrons are removed from their parent system when they interact with light. However, time-resolved measurements of the photoionization process in its arguably purest form --- the absorption and emission of single photons by a single unbound electron --- remained elusive. Until now.

Writing in the journal Optica, Jaco Fuchs and colleagues in the Ultrafast Laser Physics group of Prof. Ursula Keller at the Institute of Quantum Electronics, working with collaborators in the US, Austria and Spain, report an experiment in which they measured for the first time how the absorption and emission of single photons alters the dynamics of an electron that is not bound to an atomic nucleus, but still feels its Coulomb potential. Introducing a novel experimental protocol, they found that the dynamics depends on the angular momentum of the photoionized electron: they measured a delay of up to 12 attoseconds between outgoing s- and d-electrons in helium. This is a subtle yet unmistakable signature of underlying quantum-mechanical effects. And they observed fundamental phenomena of classical origin, too: they measured phase changes that reflect that in d-electrons the outward propagation is slower than in s-electrons. This can be explained by the larger fraction of rotational energy and hence a lower radial energy in d-electrons.

Extracting the contribution of single photons

These results mark several 'firsts'. The Keller group has pioneered various areas of attoscience, including the measurement of attosecond time delays in photoionsation, which arise as photoexcited electrons propagate in the potential of the parent ion, resulting in a measurable group delay. The measurement of these attosecond-scale time delays typically involves at least two photons, making it exceptionally difficult to extract the contribution of single photons. Fuchs et al. now found a way to do just that.

In their case two photons are involved too, one in the extreme ultraviolet (XUV) and the other in the infrared (IR) range. But they devised a fitting procedure that enabled them to extract from their high-quality data the amplitudes and relative phases of all the quantum pathways through which photoionsation proceeds in their system. In this way they were able to isolate the different contributions of the IR photons, which are the ones inducing transitions in an unbound electron (whereas the XUV photons ionise the atom, by transferring an electron from a bound state to the continuum).

Direct measurement of delays arising from Bremsstrahlung

Not only did the ETH physicists gain for the first time access to time delays from any one-photon transition. Theirs are also the first measurements of such time delays for the absorption and emission of photons by unbound electrons, a phenomenon known as (inverse) Bremsstrahlung. The experimental results are well reproduced by two independent theoretical methods Fuchs and colleagues employed. These simulations also provide evidence that some of the observed effects are universal, in the sense that they are independent of the atomic species of the parent ion.

This work illustrates that also 115 years after Einstein's seminal work, the photoelectric effect does not cease to inspire. The tools introduced by Fuchs and co-workers provide new experimental capabilities for studying photoionization dynamics, both in atoms and in small molecules. Such studies could in turn provide a fuller understanding of photoemission time delays, in particular in the presence of interactions in the intermediate-to-long range.

The current pace of climate change exceeds historical events by 1-2 orders of magnitude, which will make it hard for organisms and ecosystems to adapt. For a long time, it has been assumed that adaptation was only possible by changes in the genetic makeup - the DNA base sequence. Recently, another information level of the DNA, namely epigenetics, has come into focus.

Using a fish species from the Baltic Sea, the three-spined stickleback, an international team investigated whether and how epigenetics contributes to adaptation. "Our experiment shows that epigenetic modifications affect adaptation, but also that the changes from one generation to the next are smaller than previously assumed," says biologist Dr. Melanie Heckwolf from GEOMAR Helmholtz Centre for Ocean Research Kiel. She is one author of the study, which has now been published in Science Advances.

But what distinguishes changes in DNA from changes in epigenetics? "Individuals with certain heritable traits encoded in the DNA can cope with the prevailing environment better than others. On average, those individuals can cope better with their environment, hence survive longer and produce more offspring. In the long run, their characteristics encoded in the DNA will prevail. This process refers to natural selection," explains Dr. Britta Meyer from GEOMAR. However, selection requires time, and time is scarce in the face of rapid climate change.

In contrast, epigenetic processes chemically influence the structure of the DNA. They activate or deactivate areas of the genome that are responsible for certain traits or responses to environmental conditions. On the one hand, "stable" epigenetic markers, through natural selection, contribute to adaptation in a similar way as the DNA itself. On the other hand, "inducible" markers are those that can change during the life of an individual. In theory, if this happens in the gametes of the parents, their offspring are given an advantage to cope with their environment. Many scientists therefore expect that inducible markers will react particularly quickly and thus ensure the survival of organisms in the face of rapid changes.

The research groups of Prof. Dr. Thorsten Reusch (GEOMAR, Germany) and Dr. Christophe Eizaguirre (Queen Mary University of London, UK) have investigated whether and how these stable and inducible markers contribute to adaptation. They use the Baltic three-spined stickleback fish because it is currently adapted to different salinity conditions ranging from saltwater to freshwater. Further, the Baltic Sea is a natural laboratory for climate change research because the effects of climate change are already evident there.

"In order to understand how fish respond to the consequences of climate change, we collected stickleback populations from different regions of the North and Baltic Seas with different salinity levels," explains Dr. Meyer. The team found that the different populations differed in their genetic and epigenetic makeups and also had different tolerances to changes in salinity. In an experiment involving two generations of sticklebacks, the team was also able to show that inducible markers improve the response of the second generation to environmental change, albeit to a lesser extent than initially assumed.

Overall, the study shows that organisms will eventually reach their limits to respond to climate change, even with epigenetic modes of adaptation. "We have to be careful not to overinterpret this exciting but poorly understood field of research in epigenetics as a silver bullet against climate change for all species," says Melanie Heckwolf. "Climate change is one of the greatest challenges for species and ecosystems, and the natural mechanisms available to species to respond may not be sufficient if climate change remains so strong and rapid."

Water balloons may seem like a trivial matter. A toy for mischievous kids in summer. But for scientists, the behavior of balls of liquid wrapped in a thin elastic membrane is critical to everything from understanding blood cells to fighting fires.

Using custom-made air cannons and high-speed photography, Princeton researchers have established the definitive physical rules governing capsule impact, a research area that had gone virtually unexplored until now. The results, published March 16 in Nature Physics, reveal a surprising relationship between the behavior of capsules and water droplets. Where capsules are held together by the tension of a membrane, water droplets are held together by a force called surface tension. The researchers used that connection to adapt the well understood mathematics describing water droplets to engineering problems related to capsules.

"The most surprising thing is that the impact looks a lot like that of a drop," said Etienne Jambon-Puillet, a postdoctoral researcher and the study's first author. "Most people who study capsules resort to complex numerical simulations to model their deformation, where here we have derived a simple model, something that is easy to understand."

During his Ph.D. research at Sorbonne University, Jambon-Puillet was studying the behavior of water droplets covered with small beads. Searching for a simpler way to understand the complicated problem before him, he looked to the literature to find a model for how elastic capsules work. But he came up empty. Perplexed and intrigued, he was forced to set the capsules question aside for a few years and move on to other problems.

When he joined Pierre-Thomas Brun's Liquids and Elasticity Laboratory at Princeton, he saw the perfect opportunity to turn back to that question from his graduate school work. When a water balloon strikes a surface, what happens to the elastic shell?

"The study really makes sense in the broader context of fluid mechanics," said Brun, an assistant professor of chemical and biological engineering and the paper's senior author. "People for decades have been wracking their brains studying drop impact, and somehow Etienne found that there was this little puzzle that was completely untouched."

To control the experiment's parameters, the team custom-made elastic capsules about the size of a gumball. They then filled those to exact capacity -- without stretching them -- and smashed the balloons against a wall at around 100 miles per hour using a small air cannon. With the camera rolling at 20,000 frames per second, the researchers were able to take fine measurements of the thin shell as it made impact. They repeated the experiment with two different kinds of liquids, glycerol and honey, to see how the dynamics changed with greater viscosity. Again, the analogy to liquid drops held.

The team then turned to commercial water balloons to see what happens when an elastic shell is stretched with fluid, the way we typically think of filling balloons with water. Not so full you can't throw it, but full enough to burst on impact, soaking an unsuspecting friend. (Whether that friend remains friendly is another story). It turns out there is a critical value at which a balloon traveling at a given speed must be stretched for it to burst. Anyone who's ever thrown a dud, watching it bounce off a would-be victim and roll sadly away, knows the importance of this critical value. You either needed to fill it more or throw it harder.

Much like the rest of us, when it comes to water balloons and their ilk, engineers have been flying blind, according to Brun. Those critical values had never been formalized.

A range of technologies rely on similar fluid-filled capsules, and as bioengineering efforts become ever more sophisticated, that number of technologies is certain to grow. The stomach, the bladder, the lungs, blood cells -- many organs and essential biological functions rely on such thin, expandable fluid-filled chambers.

Brun and his team have given researchers a mathematical framework to understand how these objects deform with impact. And for the engineers working on these problems, the best part is that the framework is already familiar. It was just hiding in plain sight.

"The model is fairly simple," Brun said. "But that's what's beautiful about it."

PHILADELPHIA - As adults age, they accumulate a number of medications for chronic conditions. Older patients take anywhere between 5-15 medications per year, which increases the risk that some of the drugs will counteract each other. Older patients also make up the majority of cancer patients, and the majority of cancer deaths. What happens when cancer therapy is added onto an already full plate of medications?

In the largest retrospective population-based study to date, Jefferson researchers showed that hospitalization increase by as much as 114% in patients battling breast, prostate, and lung cancers, when those patients took 15 or more medications prior to chemotherapy treatment. "The comprehensive real-world data we looked at gives us a sense of what's happening today, and offers clues on how we could reduce hospitalizations in older cancer patients," says senior author Grace Lu-Yao, PhD, associate director of Population Science at the Sidney Kimmel Cancer Center (SKCC)--Jefferson Health.

The study was published in the Journal of Geriatric Oncology on March 19th.

"The older patients get, typically the more complex their care becomes - this is especially true when cancer treatment is combined with pre-existing conditions," says co-author Andrew Chapman, DO, co-director of the Senior Adult Oncology Center and chief of Cancer Services at the SKCC.

The researchers identified a pool of 13,959 patients with prostate, lung, and breast cancer from a national database of Medicare cancer patients. They grouped patients by the number of medicines they were on for the 6-months prior to starting intravenous chemotherapy for their cancer. "By looking at hospitalization rates in the 6-months leading up to the start of chemotherapy, we were able to get a baseline, or 'before' data point for these patients, that we could compare against the rates of hospitalization after chemo," said Dr. Lu-Yao.

Drug-drug interactions - where one drug can reduce the effectiveness of another and cause dangerous accumulations of another drug or other effects - are nearly a certainty when people take over eight medicines at once. The researchers saw that the cancer patients studied were starting at a high number of medications already. Lung cancer patients were taking a median of 11 medications, prostate cancer patients were at 10, and those with breast cancer were on a median of 6 therapies.

"Polypharmacy, defined as patients taking 5 or more medications, is a serious problem in patients," says Ginah Nightingale, PharmD, an associate professor in the College of Pharmacy at Thomas Jefferson University, who is an emerging leader in the field of geriatric polypharmacy. "Older patients see multiple specialists, and those specialists rarely coordinate with each other to ensure that the medications are absolutely essential, or weighed against a patient's priorities. So patients end up accumulating more than they absolutely need to take."

The researchers found that lung cancer patients taking between 5-9 medications had a 42% higher rate of hospitalization, those taking 10-14 medications had a 75% increase, and those taking over 15 medications prior to chemotherapy had a 114% higher rate compared to patients taking fewer than five medicines. The researchers saw similar increases in both breast and prostate cancer patients as well.

"The question is whether we can work with patients and their multiple healthcare providers to de-prescribe medicines that might no longer be essential and may interfere with their cancer care," says Dr. Nightingale. "We are in the process of designing a randomized study to test whether we can improve cancer-patient outcomes by reducing the number of medications in the older population of patients."

Creating and controlling on Earth the fusion energy that powers the sun and stars is a key goal of scientists around the world. Production of this safe, clean and limitless energy could generate electricity for all humanity, and the possibility is growing closer to reality. Now a landmark report released this week by the American Physical Society Division of Plasma Physics Community Planning Process proposes immediate steps for the United States to take to accelerate U.S. development of this long-sought power. The report also details opportunities for advancing our understanding of plasma physics and for applying that understanding to benefit society.

The report, the Community Plan for Fusion Energy and Discovery Plasma Sciences, "reflects the enthusiasm among the U.S. fusion and plasma physics community to take bold steps to make fusion energy a reality, to expand our understanding of plasma physics, and to use that understanding to benefit society," said physicist Nathan Ferraro of the U.S. Department of Energy's (DOE) Princeton Plasma Physics Laboratory (PPPL), a co-chair of the plan assembled over a year by the community.

Professional societies

The 199-page document, put together with input from hundreds of U.S. scientists and engineers from many professional societies, makes numerous recommendations, including the following proposed steps:

In the words of the report, research going forward "should be driven by the mission to enable construction of a fusion pilot plant (FPP) that produces net electricity and thereby establishes the scientific and technological basis for commercial fusion energy."

Development of this mission should include immediate design of a new U.S. tokamak, or doughnut-shaped fusion facility, capable of handling conditions consistent with those that an FPP will encounter. Also immediately begun should be design and construction of a specialized device to demonstrate the effect that neutrons released by fusion reactions will have on the facility that houses the reactions.

Advancing theory and modeling capabilities needed to understand and sustain burning plasmas, in which the plasma is chiefly heated by fusion reactions. The U.S. should also sustain full membership in ITER, the international experiment under construction in France to demonstrate the production of burning plasma.

Scaling up research in plasma science fields ranging from astrophysics to nanotechnology. Proposed steps include construction of a general plasma science facility to study astrophysically-relevant magnetized plasma phenomena, ensuring stable funding for a balanced research portfolio, and developing networks of scientists and facilities to enable a broad range of frontier scientific research.

Designed to help fulfill a charge

The report is designed to help the Fusion Energy Sciences Advisory Committee (FESAC) fulfill a DOE charge for the development of a long-range strategy for the Fusion Energy Sciences program of the DOE Office of Science. The document calls for partnerships with other offices and governmental agencies, as well as with private industry and international partners, to enact the full recommendations of the strategic plan. "We are encouraged to see that this process brought the community together to recognize the full scope of this challenge," said Ferraro, "and that coordinated, multi-disciplinary research and development is needed to achieve our goals."

G protein-coupled receptors (GPCRs) play essential roles in cell signal transduction and serve as important therapeutic targets for a large number of diseases. Upon binding to extracellular agonists, GPCRs stimulate various signaling pathways by recruiting different G proteins (Gs, Gi, Gq, etc.) to mediate a wide variety of physiological functions. The selective coupling between a GPCR and specific G proteins is critical for the biological action of the receptor.

However, the molecular details that define how an individual GPCR recognizes different G protein subtypes remain elusive, thus limiting the understanding of mechanisms of GPCR signal transduction.

In a study published in Science on Mar. 20, a group led by WU Beili and ZHAO Qiang at the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), a group led by SUN Fei at the Institute of Biophysics of CAS, and a group led by Denise Wootten from Monash University, determined two cryo-electron microscopy (cryo-EM) structures of the human glucagon receptor (GCGR) in complex with its cognate agonist glucagon and distinct classes of G proteins, Gs or Gi.

These structures, for the first time, provide a detailed molecular map of interaction patterns between a GPCR and different G protein subtypes, and unexpectedly disclose many molecular features that govern G protein specificity, thereby greatly deepening the understanding of GPCR signaling mechanisms.

GCGR, a member of the class B GPCR family, is critical to glucose homeostasis by triggering the release of glucose from the liver, making it a potential drug target for type 2 diabetes and obesity.

Although GCGR canonically exerts its physiological action through Gs signaling, it can also couple to other G proteins such as Gi and Gq, leading to diverse cellular responses. In 2017 and 2018, the scientists at SIMM determined the crystal structures of the full-length GCGR bound to a negative allosteric modulator or a partial peptide agonist, providing insights into signal recognition and modulation of class B GPCRs.

This time, the scientists made further progress by solving the complex structures of GCGR bound to two transducer proteins with opposing biological activities. This study offers valuable insights into pleiotropic GPCR-G protein coupling and G protein specificity. Notably, it revealed that the sixth transmembrane helix (helix VI) of GCGR adopts a similar outward shift in the two G protein-bound GCGR structures, forming a common binding cavity to accommodate Gs and Gi. This is contrary to the hypothesis based on the previously determined GPCR-G protein complex structures, which proposed that the positional difference of helix VI is a major discriminator in the coupling specificity of Gs and Gi.

The common G protein binding pocket observed in the GCGR-G protein complex structures is consistent with the signaling pleiotropy of GCGR and allows for maximal efficiency in activating various pathways. Although GCGR couples to both G proteins through the common pocket, it does so with different interaction patterns, which account for G protein specificity. The measured interaction interface between GCGR and Gs is much larger than for Gi, resulting in higher binding affinity of Gs to the receptor. This offers a structural basis for the preferential coupling of GCGR to Gs.

Based on the structures of GCGR-Gs and GCGR-Gi complexes, the scientists performed extensive functional studies using techniques such as mutagenesis, G protein activation and cell signaling to investigate the roles of key residues in the receptor-G protein binding interface in Gs and Gi activation.

The results show that conformational differences of intracellular loops and residue side chains in the receptor are sufficient to guide G protein selectivity. The interactions contributed by the second intracellular loop (ICL2) and helix VII/VIII junction of the receptor play a crucial role in Gs coupling, while the other two intracellular loops, ICL1 and ICL3, and the receptor hydrophobic intracellular binding cavity are more important for Gi recognition.

These findings extend knowledge about GPCR activation, pleiotropic coupling, and G protein specificity. They also present new opportunities for drug discovery by designing biased ligands to selectively block one specific signaling pathway, thus resulting in reduced side effects.

Working memory, the ability to hold a thought in mind even through distraction, is the foundation of abstract reasoning and a defining characteristic of the human brain. It is also impaired in disorders such as schizophrenia and Alzheimer's disease.

Now Yale researchers have found a key molecule that helps neurons maintain information in working memory, which could lead to potential treatments for neurocognitive disorders, they report March 19 in the journal Neuron.

"Working memory arises from neuronal circuits in the prefrontal cortex," said senior author Min Wang, senior research scientist in neuroscience. "We have been learning that these circuits have special molecular maintenance requirements."

Neurons in the prefrontal cortex excite each other to keep information "in mind." These circuits act as a sort of mental sketch pad, allowing us to remember that caramelized onions are cooking in the frying pan while we search the next room for a pair of scissors.

The new study shows that these prefrontal cortical circuits depend upon the neurotransmitter acetylcholine stimulating muscarinic M1 receptors aligned on the surface of neurons of the prefrontal cortex. Blocking muscarinic M1 receptors reduced the firing of neurons involved in working memory, while activating the M1 receptors helped restore neuronal firing. Because acetylcholine actions at M1 receptors are reduced in schizophrenia and Alzheimer's disease, the M1 receptor may serve as a potential therapeutic target, the authors suggest.

Wang notes that a drug currently under development for the treatment of schizophrenia stimulates this M1 receptor and has shown promise in early clinical trials.

Researchers at the University of Cincinnati are helping to identify those most at risk in Ohio of overdosing on opiates.

A new study published in the Nature journal Scientific Reports examined Ohio Health Department records from 2010 to 2017 and found that white men between the ages of 30 and 39 were most at risk of fatal overdoses. The epidemic is disproportionately affecting white men over white women in all age categories, the study found.

Opioid fatalities also affected black men ages 30 to 39 at disproportionate rates compared to the total population, the study found.

Likewise, UC's analysis identified 12 clusters or hot zones across Ohio where the rate of fatal overdoses is highest. The clusters were predominantly but not exclusively in the biggest cities. These geographic areas were home to 21% of the state's at-risk population but witnessed 40% of the opiate-related mortalities in Ohio over the eight years examined.

Diego Cuadros, an assistant professor of geography in UC's College of Arts and Sciences, said UC's findings could help steer health policy in Ohio to help groups most at risk avoid the pitfalls of addiction.

"Treatment is important, but prevention is better. We want to reduce the use and abuse of opioids," he said.

Cuadros runs UC's Health Geography and Disease Modeling Laboratory, which applies geographical information, perspectives and methods to the study of health, disease and health care.

Cuadros and his students collaborated with UC's James L. Winkle College of Pharmacy, Oregon State University and Drexel University.

Cuadros said researchers are investigating why some populations seem more susceptible to opiate addiction.

"We're just beginning the conversation to figure out what is driving this," he said.
Opiates are insidious because they attack the body's ability to produce natural endorphins that make people feel better.

"Opiates desensitize natural endorphins so you don't get the same feeling of contentment as you would otherwise from daily activities like exercise or food or fun activities. Each time you'll need more and more opiates," Cuadros said.

UC College of Pharmacy Dean Neil MacKinnon, a study co-author, serves as co-chairman of the UC/UC Health Opioid Task Force, which was established in 2017 to bring together researchers, educators, doctors and public advocates to address the epidemic.

"This study has provided valuable new insights into the opioid crisis in Ohio," MacKinnon said. "It also demonstrates the value of interdisciplinary work as Dr. Cuadros and his colleagues from the Department of Geography made important contributions to our research team in pharmacy. I hope this is an ongoing partnership moving forward for the UC/UC Health Opioid Task Force."

UC doctoral student Andres Hernandez, the study's lead author, said substance abuse disorders are complex, influenced by family history, economic welfare and mental health.

"For example, an individual with relatives who suffered substance abuse disorders is 10 times more likely to suffer from substance abuse," Hernandez said.
The study identified 12 mostly urban parts of Ohio that were disproportionately affected by the epidemic. Many of these clusters were in southwest Ohio.

"This area has a history of high rates of drug consumption and illegal drug flow," Hernandez said. "I think understanding the characteristics of the population with higher risk will result in better strategies to mitigate the epidemic."

UC's analysis suggests several phases of the epidemic, Cuadros said.

Researchers believe the opiate epidemic began with a surge in legal prescription painkillers. Nearly 20 million Americans suffer from chronic pain that is so severe that it affects their daily activities, according to the Centers for Disease Control and Prevention.

But regulators and law enforcement began scrutinizing prescription opiates and passing laws limiting refills or reducing dosages. Some doctors were prosecuted.
In the absence of easy access to prescription opiates, some people turned to illicit opiates, particularly heroin, which was comparatively cheap and readily available.

"And now this latest phase has seen the rise of fentanyl in the opioid epidemic," Cuadros said.

Fentanyl is a synthetic opioid that is 50 to 100 times more powerful than morphine. It's often added to heroin or other illicit drugs. Because of its potency, the risk of a fatal overdose is higher.

"It's more potent than other prescription opioids. And it seems to be cheaper to produce and distribute. So we're getting a new element in the epidemic," Cuadros said.

Cuadros said he would like to expand the analysis nationwide using data provided by the CDC. Negotiating access to these records can be tricky because federal health privacy laws cover even the deceased.

"If not nationwide, we'd like to conduct the same analysis for Kentucky and West Virginia, the epicenter of the opioid epidemic. It's a regional problem. So it's important knowing what's going on," Cuadros said.

BOSTON - In patients with advanced ovarian cancer, a combination of drugs known as immune checkpoint inhibitors and PARP inhibitors can produce powerful remissions, clinical trials have shown, but up until now investigators haven't been able to predict which patients won't benefit from the treatment and should explore other options. A new study by Dana-Farber Cancer Institute researchers, is showing that it's now possible to identify such patients in advance.

The study, published online today by Nature Communications, will help investigators testing this combination direct such patients to trials that may have a better chance of helping them.

The study authors found that two factors - a specific pattern of gene mutations in the tumor cells and evidence of a vigorous immune response to the cancer - are markers of whether patients will respond to the combination therapy. Patients whose tumor tissue had either of these features were more likely to have their disease held in check for an extended period of time, whereas those whose tissue lacked either feature showed no benefit from the drug combination.

"By taking these factors into account, researchers leading trials of this combination in patients with advanced, chemotherapy-resistant ovarian cancer may select individuals who may respond to this combination of drugs," says Panagiotis Konstantinopoulos, MD, PhD, director of translational research, Gynecologic Oncology, at Dana-Farber, the co-senior author of the study with Alan D. D'Andrea, MD, director of Dana-Farber's Susan F. Smith Center for Women's Cancers.

While checkpoint inhibitors - which strip tumors of certain protections against an attack by the immune system - work exceptionally well in many types of cancer, ovarian cancer has been an exception. The PD-1 checkpoint inhibitor pembrolizumab, for example, produces responses in less than 5% of patients with PD-L1-negative cancers. The same is true of PARP inhibitors, which undermine cancer cells by reducing their ability to repair DNA damage. As a single agent, the PARP inhibitor niraparib has a beneficial effect in just 3% of patients with ovarian cancer that is resistant to platinum-based chemotherapy and isn't BRCA-mutated.

When checkpoint and PARP inhibitors are used together, however, those benefits multiply. The TOPACIO/Keynote-162 clinical trial led by Konstantinopoulos found that the pembrolizumab-niraparib combination produced complete or partial responses - total or limited shrinkage of ovarian tumors - in 18% of patients with platinum-resistant ovarian cancer. Furthermore, 65% of the study participants had their disease kept under control. For some of those who responded, the benefits lasted for well over a year. The results were especially impressive because all the participants had received multiple previous treatments for ovarian cancer, making them especially hard to treat.

Encouraging as these findings were, study leaders had no way to determine, in advance, which participants wouldn't be helped by the therapy. To see if they could be identified, Konstantinopoulos and his colleagues conducted two analyses of participants' tumor samples: a letter-by-letter search of the tumor cells' genome for abnormalities, and a census of "exhausted" immune system T cells within the tumor tissue. (T cells are said to be exhausted when they are primed to attack tumor cells but fail to do so. Tumors containing large numbers of such T cells can be especially vulnerable to checkpoint-inhibiting drugs.) The researchers then correlated their findings with information on whether, and how extensively, patients responded to the combination therapy.

They found that patients whose tumor cells carried either "mutational signature 3" (a pattern of gene mutations associated with an inability to repair certain kinds of DNA damage) or a "positive immune score" (a measure of signaling activity between tumor cells and the immune system) may derive a benefit from the pembrolizumab-niraparib combination. Patients whose cells lacked either of these features received no such benefit.

"Patients with advanced or metastatic ovarian cancer who are resistant to standard platinum-based chemotherapy agents often have few further options for treatment," Konstantinopoulos remarks. "Our findings will help ensure that patients for whom a PARP inhibitor-checkpoint inhibitor combination won't be beneficial can focus on other clinical trials of treatments that may be more effective for them."

Teens who feel personally empowered are less likely to bully, harass or commit acts of sexual violence, according to a study by Rutgers University, the University of Nebraska, and the University of New Hampshire.

The study, published in the Journal of Youth and Adolescence, also found that teens who think their friends support violence prevention and healthy relationships are less likely to mistreat their peers.

"Coping mechanisms that help adolescents thrive and do well, even in the face of stress and adversity, are important to preventing interpersonal violence. This is an important finding, as studies of bullying typically examine risk factors rather than protective factors," said lead author Victoria Banyard, professor and associate director of the Center on Violence Against Women and Children at the Rutgers School of Social Work.

The findings suggest that bullying, harassment and sexual violence can be reduced when adolescents learn to cope with stress, build community connections, engage with individuals from diverse backgrounds and feel empowered and able to build a positive future.

Adults can help young people develop these strengths, said Banyard. "Positive conversations with teens about healthy relationships support the positive social norms we know are important."

Adolescence is a high-risk age for perpetration of different forms of peer-based violence including in-person and online bullying, harassment, racial bullying, and unwanted sexual contact, the researchers explained.

The researchers surveyed a set of 2,232 middle and high school students online during the school year by seeking their level of agreement or disagreement with statements including "If I am feeling sad, I can cheer myself up," "My opinion is important because it could someday make a difference in my community," "I work hard now to make a good future for myself," "I am comfortable being with people who are of a different race than I am," and others. They were asked about bullying and harassment, alcohol use, positive social norms related to violence prevention, and a combination of interpersonal strengths.

The teens were surveyed again six months later.

The findings are part of a larger study on involving youth as leaders in order to help prevent sexual violence among middle and high school students.

Banyard partnered with the University of Nebraska Lincoln Center on Children, Youth, Families, and Schools and the University of New Hampshire.

CML is a blood cancer that can be controlled by continuously taking an expensive type of medicine called a tyrosine kinase inhibitor (TKI). In almost all patients, stopping TKI treatment results in recurrence of CML. While most CML patients respond well to life-long TKI usage, about 10 per cent of patients become resistant to TKIs, and progress to late-stage or blast crisis (BC) CML. Patients with BC almost always die from their disease. While many genetic mutations are known to be associated with BC progression, the mechanisms by which they and other factors cause BC remain largely unknown. This knowledge gap prevents clinicians from identifying which CML patients are at risk of BC progression, and treating BC when it occurs.

"To fill these critical gaps, we employed the latest molecular approaches to establish that the so-called 'polycomb repressive complex', or PRC, alters the regulation of a set of genes which drive BC progression," said Dr Tun Kiat Ko, Research Fellow at Duke-NUS' Cancer and Stem Cell Biology (CSCB) programme. He also added, "We found that the consequences of altered PRC activity were common to the majority of BC cases, regardless of the different leukaemia-causing mutations we also found in them."

Using this increased understanding, the team devised novel drug combinations, which reverse the downstream effects of the PRC in BC. At the same time, they also developed methods to identify CML patients who were at increased risk of developing TKI-resistance and progressing to BC.

"Our discovery is like finding the 'one ring that rules them all'. Since there are many cancer-causing genetic mutations that occur when chronic phase CML transforms to blast crisis, it has been very challenging to determine which ones are critical to BC, and therefore important to target. By discovering this 'one ring' and how to 'destroy' it with a novel drug combination, we open the door to treating this deadly cancer with the same combination of drugs regardless of the myriad mutations that exist in any particular patient. In addition, our study demonstrates the ability of scientists and clinicians to make exciting discoveries that can be translated to the improved health of patients all over the world, as well as Singaporeans," said Associate Professor Ong Sin Tiong from the Duke-NUS CSCB programme and corresponding author of this study.

"The multi-omics approach was critical to the success of the study. Each layer of information provided us corroborative evidence and insight into the dysfunction of the polycomb repressive complex leading to the progression to blast crisis stage of CML," asserted Asif Javed, co-corresponding author of the study.

"This study is another example of how interdisciplinary research leads to new insight," says Axel Hillmer, Group Leader at the GIS who led the genomics part of the project.

Patrick Tan, Executive Director of GIS, adds, "Due to technology advancements over the last years, it is now possible to apply more complex genomic analyses to translate such findings into routine diagnostics."

"As a haematologist treating patients with advanced blast crisis CML, it is disheartening when we run out of treatment options for them. And that is why we are very encouraged by the study findings and certainly hopeful that our patients may one day benefit from the efforts of our collaboration," Associate Professor Charles Chuah, Senior Consultant, Department of Haematology, SGH.

The team is currently working on approaches to identify CML patients who are at risk of BC transformation, and also to determine why the key PRC-related events occur in the first place.