Brain

(Boston) - In a new study, researchers at Boston Medical Center and Boston University have uncovered a new association between more restrictive alcohol policies and lower rates of cancer mortality.

Alcohol consumption has long been related to a number of health conditions, but has recently been identified as an emerging risk factor for developing at least seven different types of cancer. Previous studies have estimated approximately 20,000 cancer deaths are attributable to alcohol in the United States annually. However, no previous studies have looked into whether stronger (i.e. more restrictive) alcohol policies are associated with rates of alcohol-attributable cancers in the U.S.

The researchers examined the relationship between more restrictive alcohol policies and the number of alcohol-related cancer deaths per state from 2006 to 2010. They assigned each state an Alcohol Policy Scale score based on presence and implementation of twenty-nine different alcohol regulations, including restrictions on the number of locations allowed to sell alcohol, state tax laws, and others. Policy Scale Scores were then related to rates of alcohol-attributable cancers by state using data from the Centers for Disease Control and Prevention's Alcohol-Related Disease Impact application for cancers of the esophagus, mouth and throat, liver, prostate (among men) and breast (among women).

The study found that for all cancers combined, more restrictive policies were associated with a reduced risk of cancer mortality. A 10 percent increase in the strength of alcohol policies (calculated based on their Policy Scale Scores) was associated with an 8.5 percent relative decrease in cancer deaths. The findings, which were similar among men and women, underscore the potential impact that public health policies can have on preventing cancers at the population level.

"When thinking about cancer risk and cancer prevention, the focus tends to be on individual-level risk factors rather than environmental determinants of cancer, like public policies that affect the consumption of alcohol or tobacco," said Timothy Naimi, MD, MPH, a physician and researcher at both Boston Medical Center and Boston University School of Public Health who served as the paper's corresponding author. "Implementing effective policies to reduce alcohol consumption is a promising means of cancer prevention that merits further investigation."

While opioids are often prescribed to treat people with trauma-related pain, a new UCLA-led study suggests doctors should use caution before prescribing the drug to those they believe may experience severe stress in the future, in order to reduce the risk the patient will develop PTSD.

In the study, researchers administered doses of the opioid morphine to a group of 22 mice for one week, then gave the mice relatively strong foot shocks. After the morphine wore off, the mice were given mild electric foot shocks. These mice showed a substantially longer "freezing response" than a second, control group of 24 mice that had not been given morphine. When mice recall a frightening memory, they freeze. Their heart rates and blood pressure go up, and the more frightening the memory, the more they freeze.

"While we are generally aware that drug use, such as that in the current opioid crisis, has many deleterious effects, our results suggest yet another effect -- increased susceptibility to developing anxiety disorders," said senior author Michael Fanselow, UCLA distinguished Staglin family professor of psychology and director of UCLA's Staglin Family Music Festival Center for Brain and Behavioral Health. "As opioids are often prescribed to treat symptoms such as pain that may accompany trauma, caution may be needed because this may lead to a greater risk of developing PTSD, if exposed to further traumatic events, such as an accident, later on."

"The foot shocks produced lasting fear and anxiety-like behaviors, such as freezing," Fanselow said.

"Our data are the first to show a possible effect of opioids on future fear learning, suggesting that a person with a history of opioid use may become more susceptible to the negative effects of stress," Fanselow said. "The ability of opioids to increase PTSD-like symptoms far outlasted the direct effects of the drug or withdrawal from the drug, suggesting the effect may continue even after opioid treatment has stopped."

Fanselow's view is if there is reason to believe a patient is likely to experience severe emotional stress after opioid treatment, then doctors should use caution about prescribing an opioid. If opioid use is medically called for, then the patient should be kept away from potentially stressful situations. So, for example, a soldier treated with opioids for pain should not be sent back into combat for a period of time, he said. The development of post-traumatic stress disorder requires some stressful experience after opioid use, he said.

The researchers also gave some of the mice morphine after the initial trauma had occurred but before exposing them to the second, mild stressor. They found that mice treated with morphine after the initial trauma did not show enhanced fear learning following exposure to the mild stressor. This finding suggests that chronic use of opioids before -- but not after -- a traumatic event occurs affects fear learning during subsequent stressful events.

The researchers concluded the mice given morphine were more susceptible to post-traumatic stress disorder than the control group of mice not given any opioids, and inferred that people with a history of using opioids are more susceptible to PTSD than the general population.

The study is published in Neuropsychopharmacology, an international scientific journal focusing on clinical and basic science research that advances understanding of the brain and behavior.

The research was funded by the National Institute on Drug Abuse and National Institute of Mental Health.

An opiate is a drug naturally derived from the opium poppy plant, such as heroin, morphine and codeine. Opioid is a broader term that includes opiates and any substance, natural or synthetic, that binds to the brain's opioid receptors -- which play a key role in controlling pain, rewards and addictive behaviors. Synthetic opioids include the prescription painkillers Vicodin and OxyContin, as well as fentanyl and methadone.

Substance abuse and PTSD often go hand-in-hand, Fanselow said, and people with PTSD often take drugs to self-medicate. Nearly 40% of people with PTSD also have a drug disorder.

Fanselow and colleagues reported last month that a traumatic brain injury causes changes in a brain region called the amygdala; and the brain processes fear differently after such an injury.

Just as our left hand is not superposable to our right hand, the mirror image of certain molecules cannot be overlapped onto it, even when turned or twisted. These two mirror images are referred to by chemists as enantiomers and the molecule is said to be chiral. Chirality, which is a word derived from the ancient Greek word for hand, is important since it is present in our daily lives. For example, the stereoisomers of a molecule - i.e. compounds in which the binding pattern is the same but which differ in the spatial arrangement of the atoms - can produce different effects when interacting with a biological system.

The stereoisomers of a drug, for example, can have different or even opposite effects on the body making it crucial to produce certain stereoisomers of a pharmaceutical compound. A central task for chemists is to develop methods that are switchable and can selectively produce one or another stereoisomer, from simple and identical starting materials using tunable reaction conditions. A team of researchers led by Prof. Frank Glorius from the University of Münster (Germany) has developed a new synthetic method for the targeted synthesis of all four stereoisomers of so-called α,β-disubstituted γ-butyrolactones.

γ-Butyrolactones are widespread motifs in natural products that display a wide range of biological activities. One important example is pilocarpine, a drug used to treat glaucoma. The newly developed synthetic method is based on the combination of two chiral catalysts--an organocatalyst and a metal catalyst--which each independently activate one of the two reaction partners.

"I very much like the picture of these two catalysts working hand in hand together," Frank Glorius states. The catalysts are not consumed or changed during the course of the reaction, and work in sync to efficiently produce the final product, which contains two stereocenters. As each stereocenter can have two potential orientations - up or down - four possible products could be generated in this case.

The chemists use the different combinations of the two chiral catalysts to control the formation of only one of the four possible products, but are able to access any of the products. This is a quite rare feature that only few chemical processes exhibit. "Our method streamlines the synthesis of chiral α,β-disubstituted γ-butyrolactones into a single step, starting from simple precursors and using two chiral catalysts. It is a system that basically lets you chose which stereoisomer you want to make," says Dr. Santanu Singha, one of the lead authors.

"It is amazing, the enantioselectivity is perfect, better than 99 percent, in nearly all of the cases," continues Dr. Eloisa Serrano, another lead author. Since the γ-butyrolactone products are in the core of multiple natural products with interesting biological activities, the authors expect their method to be of high relevance in drug discovery. The results of the researchers' work have been published in the latest issue of the journal "Nature Catalysis".

New findings by a University of Houston psychology professor indicate that among firefighters, distress tolerance amplifies associations between posttraumatic stress disorder (PTSD) symptoms and alcohol use severity. In the world of psychology, distress tolerance is your actual or perceived ability to withstand emotional distress. It is surviving - and knowing you can survive - an emotional incident.

"Firefighters who struggle with PTSD symptoms and who think they cannot handle negative emotions are more likely to use alcohol, and are more likely to use it to cope with negative emotions," reports associate professor and director of the UH Trauma and Stress Studies Center Anka Vujanovic, in the journal Psychiatry Research. Among the findings, PTSD symptom severity was also associated with alcohol use severity. Coping-oriented alcohol use among firefighters has been associated with more severe alcohol use and greater levels of work-related stress.

Firefighters face continual exposure to traumatic events and PTSD, both significant risk and maintenance factors for alcohol use disorder. Trauma exposure among firefighters has been estimated to be 91.5%. Previous research has shown that higher rates of alcohol use and related disorders have been documented among firefighters compared to the general population.

In this study, Vujanovic gathered data from 652 mostly-male trauma-exposed firefighters, whose median age is 38. All admitted to some alcohol use. The findings were confirmed after adjusting for romantic relationship status, number of years in the fire service, occupational stress and trauma load. This is the first study to concurrently examine these variables among firefighters.

"Our study has great potential to inform intervention efforts for this vulnerable, understudied population," said Maya Zegel, psychology doctoral student and the paper's first author, who said that targeting distress tolerance in therapy can make a big difference.

"Among individuals with PTSD, preliminary research has demonstrated that increases in distress tolerance are related to improvements in PTSD symptomatology during the course of treatment" said Vujanovic. "And people who believe they can tolerate difficult emotions report a lower tendency to use alcohol to cope."

The study comes at a time when the mental health of firefighters has come into much needed focus, said Vujanovic. In 2017 in the United States, 103 firefighters committed suicide, whereas 93 firefighters died in the line of duty, but that might only represent about 40% of the suicide deaths according to a Ruderman Family Foundation study, which indicates firefighter suicides are underreported.

Materials scientists at the University of California, Riverside and The University of Texas at Austin have demonstrated that it is possible to achieve photon up-conversion, the emission of light with energy higher than the one that excites the material, when using carefully designed structures containing silicon nanocrystals and specialized organic molecules.

The accomplishment, published in Nature Chemistry, brings scientists one step closer to developing minimally invasive photodynamic treatments for cancer. The advance could also hasten new technologies for solar-energy conversion, quantum information, and near-infrared driven photocatalysis.

High energy light, such as ultraviolet laser light, can form free radicals able to attack cancer tissue. Ultraviolet light, however, doesn't travel far enough into tissues to generate therapeutic radicals close to the tumor site. On the other hand, near-infrared light penetrates deeply but doesn't have enough energy to generate the radicals.

While photon up-conversion can overcome this limitation, up-converted materials have either low efficiency or are based on toxic materials. Silicon is well-known for being nontoxic, but until now, researchers have not been able to demonstrate that silicon nanocrystals can up-convert photons, leaving this promising cancer treatment tantalizingly out of reach.

A group led by UC Riverside materials science doctoral student Pan Xia attacked this problem by carefully studying the surface chemistry of silicon nanocrystals. The group learned how to attach ligands, which help bind molecules together, to the nanoparticle that are specifically designed to transfer the energy from the nanocrystals to surrounding molecules.

The team then shined laser light into the solution. They found silicon nanocrystals with appropriate surface ligands can rapidly transfer the energy to the triplet state of surrounding molecules. A process called triplet-triplet fusion then converts the low-energy excitation to a high energy one, resulting in the emission of a photon at shorter wavelength, or higher energy, than the one originally absorbed by the nanoparticle.

"We functionalized silicon nanocrystals with anthracene. Then we excited the silicon nanocrystals and found that the energy was efficiently transferred from the nanocrystal, through the anthracene molecules, to the diphenylanthracene in solution," said Xia. "It means we got higher-energy light."

"To turn the low-energy photons into high-energy photons, you need to use triplets, you need to use quantum confined nanoparticles, and you need to hold the nanoparticles and the organic molecules very close together. This is how you get the triplets to combine energy to get the high energy photons," said co-author Ming Lee Tang, an associate professor of chemistry at UC Riverside and Xia's dissertation adviser. Tang's lab pioneered how to attach conjugated organic molecules to the silicon nanoparticles.

"This work is very fundamental," said co-author Lorenzo Mangolini, an associate professor of mechanical engineering, whose group made the silicon nanocrystals. "The novelty is really how to get the two parts of this structure -- the organic molecules and the quantum confined silicon nanocrystals -- to work together. We are the first group to really put the two together."

Co-author Sean Roberts, an assistant professor of chemistry at The University of Texas at Austin, used ultrafast lasers to investigate how energy is transferred in this hybrid structure, and determined the process is both amazingly fast and efficient.

"The challenge has been getting pairs of excited electrons out of these organic materials and into silicon. It can't be done just by depositing one on top of the other," said Roberts. "It takes building a new type of chemical interface between the silicon and this material to allow them to electronically communicate."

The discovery could also lead to improved photocatalysis, which uses light to drive chemical reactions.

"Photocatalysts generally only work with ultraviolet light or violet light, so this is a way to generate that from the rest of the solar spectrum," Tang said.

The environmentally sustainable silicon-centered approach is also relevant for quantum information science and singlet fission-driven solar cells.

Menlo Park, Calif. -- Researchers at the Department of Energy's SLAC National Accelerator Laboratory have invented a way to observe the movements of electrons with powerful X-ray laser bursts just 280 attoseconds, or billionths of a billionth of a second, long.

The technology, called X-ray laser-enhanced attosecond pulse generation (XLEAP), is a big advance that scientists have been working toward for years, and it paves the way for breakthrough studies of how electrons speeding around molecules initiate crucial processes in biology, chemistry, materials science and more.

The team presented their method today in an article in Nature Photonics.

"Until now, we could precisely observe the motions of atomic nuclei, but the much faster electron motions that actually drive chemical reactions were blurred out," said SLAC scientist James Cryan, one of the paper's lead authors and an investigator with the Stanford PULSE Institute, a joint institute of SLAC and Stanford University. "With this advance, we'll be able to use an X-ray laser to see how electrons move around and how that sets the stage for the chemistry that follows. It pushes the frontiers of ultrafast science."

Studies on these timescales could reveal, for example, how the absorption of light during photosynthesis almost instantaneously pushes electrons around and initiates a cascade of much slower events that ultimately generate oxygen.

"With XLEAP we can create X-ray pulses with just the right energy that are more than a million times brighter than attosecond pulses of similar energy before," said SLAC scientist Agostino Marinelli, XLEAP project lead and one of the paper's lead authors. "It'll let us do so many things people have always wanted to do with an X-ray laser - and now also on attosecond timescales."

A leap for ultrafast X-ray science

One attosecond is an incredibly short period of time - two attoseconds is to a second as one second is to the age of the universe. In recent years, scientists have made a lot of progress in creating attosecond X-ray pulses. However, these pulses were either too weak or they didn't have the right energy to home in on speedy electron motions.

Over the past three years, Marinelli and his colleagues have been figuring out how an X-ray laser method suggested 14 years ago could be used to generate pulses with the right properties - an effort that resulted in XLEAP.

In experiments carried out just before crews began work on a major upgrade of SLAC's Linac Coherent Lightsource (LCLS) X-ray laser, the XLEAP team demonstrated that they can produce precisely timed pairs of attosecond X-ray pulses that can set electrons in motion and then record those movements. These snapshots can be strung together into stop-action movies.

Linda Young, an expert in X-ray science at DOE's Argonne National Laboratory and the University of Chicago who was not involved in the study, said, "XLEAP is a truly great advance. Its attosecond X-ray pulses of unprecedented intensity and flexibility are a breakthrough tool to observe and control electron motion at individual atomic sites in complex systems."

X-ray lasers like LCLS routinely generate light flashes that last a few millionths of a billionth of a second, or femtoseconds. The process starts with creating a beam of electrons, which are bundled into short bunches and sent through a linear particle accelerator, where they gain energy. Travelling at almost the speed of light, they pass through a magnet known as an undulator, where some of their energy is converted into X-ray bursts.

The shorter and brighter the electron bunches, the shorter the X-ray bursts they create, so one approach for making attosecond X-ray pulses is to compress the electrons into smaller and smaller bunches with high peak brightness. XLEAP is a clever way to do just that.

Making attosecond X-ray laser pulses

At LCLS, the team inserted two sets of magnets in front of the undulator that allowed them to mold each electron bunch into the required shape: an intense, narrow spike containing electrons with a broad range of energies.

"When we send these spikes, which have pulse lengths of about a femtosecond, through the undulator, they produce X-ray pulses that are much shorter than that," said Joseph Duris, a SLAC staff scientist and paper co-first-author. The pulses are also extremely powerful, he said, with some of them reaching half a terawatt peak power.

To measure these incredibly short X-ray pulses, the scientists designed a special device in which the X-rays shoot through a gas and strip off some of its electrons, creating an electron cloud. Circularly polarized light from an infrared laser interacts with the cloud and gives the electrons a kick. Because of the light's particular polarization, some of the electrons end up moving faster than others.

"The technique works similar to another idea implemented at LCLS, which maps time onto angles like the arms of a clock," said Siqi Li, a paper co-first-author and recent Stanford PhD. "It allows us to measure the distribution of the electron speeds and directions, and from that we can calculate the X-ray pulse length."

Next, the XLEAP team will further optimize their method, which could lead to even more intense and possibly shorter pulses. They are also preparing for LCLS-II, the upgrade of LCLS that will fire up to a million X-ray pulses per second - 8,000 times faster than before. This will allow researchers to do experiments they have long dreamed of, such as studies of individual molecules and their behavior on nature's fastest timescales.

An international team of researchers has identified key networks within the brain they say interact to increase the risk that an individual will think about - or attempt - suicide.

In an article published today in Molecular Psychiatry, the researchers say their review of existing literature highlights how little research has been done into one of the world's major killers, particularly among the most vulnerable groups.

Around 800,000 worldwide people die by suicide every year, the equivalent of one every 40 seconds. Suicide is the second leading cause of death globally among 15-29 year olds. As many as one in three adolescents think about ending their lives and one in three of these will attempt suicide.

The international HOPES team (Help Overcome and Prevent the Emergence of Suicide), led by Associate Professor Lianne Schmaal from Orygen alongside Dr Anne-Laura van Harmelen from the University of Cambridge and Professor Hilary Blumberg from the Yale School of Medicine, carried out a review of two decades' worth of scientific literature relating to brain imaging studies of suicidal thoughts and behaviour. In total, they looked at 131 studies, which covered more than 12,000 people, looking at alterations in brain structure and function that might increase an individual's suicide risk.

Associate Professor Schmaal said the biggest predictor of death by suicide is a previous suicide attempt. "It's therefore essential that we intervene as early as possible to reduce an individual's risk," she said. "For many individuals, this will be during adolescence. If we can work out a way to identify those young people at greatest risk, then we will have a chance to step in and help them at this important stage in their lives."

Combining the results from all of the brain imaging studies available, the researchers looked for evidence of structural, functional, and molecular alterations in the brain that could increase risk of suicide. They identified two brain networks - and the connections between them - that appear to play an important role.

The first of these networks involves areas towards the front of the brain known as the medial and lateral ventral prefrontal cortex and their connections to other brain regions involved in emotion. Alterations in this network may lead to excessive negative thoughts and difficulties regulating emotions, stimulating thoughts of suicide.

The second network involves regions known as the dorsal prefrontal cortex and inferior frontal gyrus system. Alterations in this network may influence suicide attempts, in part, due to its role in decision making, generating alternative solutions to problems, and controlling behaviour.

The researchers suggest that if both networks are altered in terms of their structure, function or biochemistry, this might lead to situations where an individual thinks negatively about the future and is unable to control their thoughts, which might lead to situations where an individual is at higher risk for suicide.

Associate Professor Schmaal said the two brain networks could be important targets for the generation of more effective suicide prevention strategies.

The existence of language universality has been a key issue in psychology and linguistics, since the understanding of universals is crucial for the development of information perception models.

In the course of their in-depth study of linguistic universality, Lobachevsky University researchers studied readers' eye movements when reading texts in different languages. The research was aimed at studying the universal and language-specific effects of eye movements while reading texts. For this purpose, a comparison was made of Russian-speaking students' eye movements when reading Russian texts with eye movements of English-speaking students when reading English texts.

Sentences were selected as units of analysis, and indicators reflecting the global properties of the eye movements when reading were analyzed and compared. It should be noted that the texts used in the study were translated versions of the original English texts.

The study involved the use of eye tracking technology. Eye tracking is a process of determining the coordinates of the point of gaze, i.e. the point of intersection of the eyeball optical axis and the plane of the observed object or the screen where some visual stimulus is presented.

As noted by one of the authors of the study, Valeria Demareva, Associate Professor of the Psychophysiology Department at the Faculty of Social Sciences of Lobachevsky University, the researchers tested their hypothesis in which "density", i.e. the information load of the words of a language is a universal parameter that determines eye movement while reading texts in this language. Since words in the Russian language are longer than in English, the information density of words in the English language should be greater. Consequently, the number of fixations (when one's gaze point is maintained in one place for a certain amount of time) and the amplitude of saccades (length of eye movements) will be greater while the duration of fixations will be smaller when reading equivalent texts in Russian compared to those in English.

It was found that when reading equivalent texts Russian-speaking students showed a longer total time for reading sentences, with fewer fixations, smaller amplitude of right-sided saccades and shorter fixations than English-speaking students showed when reading English texts.

"Thus, the results of the study confirm the hypothesis of a shorter duration of fixations, but are contrary to the hypothesis of saccades with a higher amplitude and more fixations in a less information-dense Russian language in comparison with English. It can be assumed that eye movements in this study were influenced by other specific features of the Russian language (in addition to the information density). Consequently, the density of the language is not a universal factor affecting the eye movement when reading," says Valeria Demareva.

The results obtained on language universals and specifics of the Russian language can be used to optimize the process of teaching Russian as a foreign language. It is possible to develop an original methodology for selecting individualized exercises to improve language skills, based on eye tracking data.

Psychophysiological studies of the density effect in the Russian and English languages are important for developing cross-linguistic models for reading and are highly relevant.

(Boston)--An improvement to the premier data visualization tool t-distributed Stochastic Neighborhood Embedding (t-SNE), called optimized-t-SNE (opt-SNE), shines new light on researchers' ability to view exactly what is in their datasets.

opt-SNE is an advancement of the widely used t-SNE created nearly 10 years ago. While t-SNE can accurately analyze approximately half a million cells in any given sample, in recent years, single cell datasets have become much larger. With opt-SNE, researchers can now visualize data from samples containing tens of millions of cells with unprecedented resolution.

The development of opt-SNE was led by Anna Belkina, MD, PhD, assistant professor of pathology and laboratory medicine at Boston University School of Medicine (BUSM).

In addition to its capacity to properly process big datasets, opt-SNE was also able to successfully visualize very small, distinct populations of cells in the blood samples tested (with each cell in these groups as rare as one in a hundred thousand of the total number of cells in the sample). Prior to opt-SNE, this accurate, large-scale visualization with simultaneous magnification of miniscule populations was not possible. "t-SNE was originally a "one-size-fits-all" algorithm, but opt-SNE computations are tailored to each individual dataset and this allows both a birds-eye and up-close view of what is in your sample. With opt-SNE, both the haystack and the needles within it can be seen," explained Belkina, the corresponding author of the study. "It is a particularly valuable tool for the investigation of cytometry and single cell transcriptomics data".

The visualization of different populations within a sample of 20 million human blood cells using t-SNE (left) and opt-SNE (middle, right)

opt-SNE allows researchers to pinpoint previously undetectable features that distinguish diseased samples from controls. This new lens into disease states may reveal novel targets for therapies as well as new biological phenomena. This approach is already in use by multiple research groups due to Belkina's ongoing collaborations with developers of major single cell data analysis platforms who enabled opt-SNE implementation into the Omiq.ai cloud analysis platform (Christopher Ciccolella, MS) and FlowJo software (Josef Spidlen, PhD and Richard Halpert, PhD) and co-authored the manuscript. An open-source opt-SNE package has also been released.

Additional co-authors of the study, which appears online in Nature Communications, include Rina Anno, PhD and Jennifer Snyder-Cappione, PhD.

To understand the molecular bases of cancer, it is imperative to determine the genetic alterations responsible for the development and spread of this condition and to identify the mechanisms through which healthy cells become malignant.

In the last twenty years, various studies have identified some of the genetic alterations that disrupt protein degradation and play a key role in tumorigenesis. Cancer cells that harbour these kinds of defects accumulate certain oncogenic proteins, which cause cells to behave abnormally. However, the extent to which such deregulated protein degradation contributes to the development of cancer was unknown.

A team at the Institute for Research in Biomedicine (IRB Barcelona) led by the scientists Abel David González-Pérez and Núria López-Bigas, the latter ICREA researcher and head of the Biomedical Genomics Lab and associate professor at the Pompeu Fabra University, has revealed how some alterations in the protein degradation system play a key role in tumour development. The study has been published in the journal Nature Cancer.

Using hundreds of proteins, the team identified the specific degradation sequences, that is to say, the precise fragments that are recognised and that trigger tagging by ubiquitin for later degradation. In this first phase, the researchers developed a machine-learning model that identifies these recognition sequences on the basis of their biochemical properties.

To validate the recognition sequences identified in these proteins, the scientists examined the mutations observed in more than 7,000 tumour samples from patients and in 900 cancer cell lines. The authors of the study demonstrate that most of the mutations in protein recognition regions trigger their stabilization. These data allowed them to validate the prediction model and to determine that a considerable number of these new predictions may indeed be functional.

"During the study, we have identified hundreds of potential protein recognition sequences for ubiquitin tagging, which constitute reliable candidates for experimental validation," explains the co-leader of the study González-Pérez:

With the aim to determine which of the recognition sequences identified are used by the tumour to evade the degradation of onogenic proteins, the team later analysed the genetic mutations present in the 7,000 tumour samples and 900 cancer cell lines.

The study concludes that a considerable number of mutations caused by tumours (approximately 1 in 10) occur in oncoproteins (including some that have not previously been reported), which exploit this mechanism to evade degradation.

On the basis of their findings, the researchers propose a potential new clinical approach to tackle cancer, namely the inhibition of oncoproteins that show defective degradation.

"The idea consists of using approved drugs to inhibit an oncoprotein that is overexpressed in the cell because of impaired ubiquitin-mediated degradation machinery. This model would allow a wider spectrum of patients to benefit from therapies that are currently approved for clinical use or that are in clinical trials," says Francisco Martínez-Jiménez, IRB Barcelona researchers and first author of the work.

The study has been made possible thanks to the patients who have generously allowed their samples to be used for research purposes. The authors also acknowledge the help of the medical faculty that took the samples, and all the researchers involved in the TCGA and CCLE projects for making the data on mutations, mRNA expression and protein expression publicly available. "This study exemplifies how data sharing can push science forward," says González-Pérez.

As the holidays approach, people might be thinking of neat do-it-yourself woodworking projects to give as gifts. But there's often a disconnect between designing an object and coming up with the best way to make it.

Now researchers at the University of Washington have created Carpentry Compiler, a digital tool that allows users to design woodworking projects. Once a project is designed, the tool creates optimized fabrication instructions based on the materials and equipment a user has available. The team presented this research Nov. 19 at SIGGRAPH Asia in Brisbane, Australia.

"To make a good design, you need to think about how it will be made," said senior author Adriana Schulz, an assistant professor in the Paul G. Allen School of Computer Science & Engineering. "Then we have this very difficult problem of optimizing the fabrication instructions while we are also optimizing the design. But if you think of both design and fabrication as programs, you can use methods from programming languages to solve problems in carpentry, which is really cool."

For Carpentry Compiler, the researchers created a system called Hardware Extensible Languages for Manufacturing, or HELM. HELM is composed of two different programming languages: a high-level language for designing an object, and then a low-level language for the fabrication instructions.

"Say I want to make a piece of wood that's cut at a 45-degree angle," Schulz said. "In the design user interface, I create a box and then I draw a line where I want the cut to be and tell the computer 'Remove this part.' That's the high-level language. Then the low-level language says 'Take a two-by-four, take your chop saw, set up your chop saw for a 45-degree angle, align the lumber to your chop saw and chop.'"

As the user designs an object using the high-level language, which looks similar to standard CAD software, a compiler verifies that the design is possible based on what tools and materials the user has specified they have. Once the user is finished designing, the compiler comes up with a set of optimal fabrication instructions based on different costs.

"If you want to make a bookcase, it will give you multiple plans to make it," Schulz said. "One might use less material. Another one might be more precise because it uses a more precise tool. And a third one is faster, but it uses more material. All these plans make the same bookcase, but they are not identical in terms of cost. These are examples of tradeoffs that a designer could explore."

The compiler has to sift through a huge space of possible combinations of instructions to find the best ones. But if it treats fabrication instructions like a program, then it can use programming tricks to simplify its search and select promising candidates.

"One program might have a good way to make the edge of the table; another one finds a good way to make the legs," said co-author Zachary Tatlock, an associate professor in the Allen School. "And we can find those and recombine them to make the best overall plan."

Currently Carpentry Compiler is optimizing fabrication plans based on fabrication time and precision. In the future, the team would like it to take into account grain orientation and uncertainty in using specific types of tools. From there, the team hopes to expand this idea to more complex projects -- such as a project that requires woodworking and 3D printing.

"The future of manufacturing is about being able to create diverse, customizable high-performing parts," Schulz said. "Previous revolutions have been about productivity mostly. But now it's about what we can make. And who can make it."

Placenta changes could mean male offspring of older mums more likely to develop heart problems in later life, rat study finds.

Changes occur in the placenta in older pregnant mothers leading to a greater likelihood of poor health in their male offspring, a study in rats has shown. Both male and female fetuses do not grow as large in older mothers, but there are sex-specific differences in changes to placental development and function. These are likely to play a central role in the increased likelihood of later-life heart problems and high blood pressure in males.

In humans, women over 35 are considered to be of advanced maternal age. The study, published in Scientific Reports, looked at pregnant rats of a comparable age. In aged mothers, the placenta of female fetuses showed beneficial changes in structure and function that would maximise the support of fetal growth. In some instances, the placenta even supported the female fetus better than the placenta of a younger mother. In the case of male fetuses however, the placenta showed changes that would limit fetal growth in the aged pregnant rats.

"This new understanding of placental development and function could contribute to better management of human pregnancies, and development of targeted interventions to improve the longer-term health of children born to older mothers," said Dr Tina Napso, a postdoctoral fellow at the University of Cambridge and first author of the study.

Pregnancy in older mothers is associated with a heightened risk of complications for both the mother and her baby. These include preeclampsia - raised blood pressure in the mother during pregnancy, gestational diabetes, stillbirth and fetal growth restriction. Until now there has been limited understanding of how the placenta is altered by advanced maternal age.

"With the average age of first pregnancy in women becoming higher and higher, and especially so in developed countries, it is very important to understand how the age of the mother and the sex of the baby interact to determine pregnancy and later-life health of the child," said Dr Amanda Sferruzzi-Perri, lead author of the study and a Royal Society Fellow in the Centre for Trophoblast Research at the University of Cambridge's Department of Physiology, Development and Neuroscience.

The placenta transports nutrients and oxygen from mother to fetus, secretes signalling factors into the mother so she supports fetal development, and is the main protective barrier for the fetus against toxins, bacteria, and hormones - such as stress hormones - in the mother's blood. It is highly dynamic in nature, and its function can change to help protect the growing fetus when conditions become less favourable for its development, for example through a lack of nutrients or oxygen or when the mother is stressed.

The researchers analysed the placentas of young (3-4 months old) and aged rats (9.5-10 months old) that were pregnant with male and female offspring. The aged rats correspond to approximately 35 year-old humans. Rats are a useful model as their biology and physiology have a number of important characteristics in common with those of humans.

The study found that advanced maternal age reduced the efficiency of the placenta of both male and female fetuses. It affected the structure and function of the placenta more markedly for male fetuses, reducing its ability to support growth of the fetus.

"A pregnancy at an older age is a costly proposition for the mother, whose body has to decide how nutrients are shared with the fetus. That's why, overall, fetuses do not grow sufficiently during pregnancy when the mother is older compared to when she is young," said Dr Napso. "We now know that growth, as well as gene expression in the placenta is affected in older mothers in a manner that partially depends on sex: changes in the placentas of male fetuses are generally detrimental."

The research involved a collaboration between scientists at the University of Cambridge, the University of Alberta in Canada, the Robinson Research Institute and the University of Adelaide, Australia.

An earlier study performed by the collaborators showed that offspring from mothers who enter pregnancy at an older age have poor heart function and high blood pressure as young adults, and particularly so if they are male. This new research was conducted to understand why, and whether this sex difference may be due to how the male and female fetuses are supported within the womb in an aged mother.

Although further studies in humans are required, the results suggest the importance of considering the sex of the fetus when giving advice to older pregnant women. The researchers also hope to build on these results and find ways of improving the function of the placenta to optimise growth of the fetus.

It's long been known that the proteins that package DNA, like students at a high school dance, require a chaperone. But what exactly that guardian looks and acts like has been a mystery--until now.

A team of researchers at the University of Colorado Boulder has cracked the puzzle of the Facilitates Chromatin Transcription (FACT) protein structure. This protein is partly responsible for making sure everything goes smoothly and no improper interactions take place when DNA temporarily sheds and replaces its guardian proteins, or histones.

These findings, which are the result of a project five years in the making at CU Boulder and out today in the journal Nature, will have ripple effects for not only our understanding of the genome and gene transcription, but for our understanding of cancer and the development of anti-cancer drugs.

"This is just the start for this protein. It's not the end," said Yang Liu, a research associate in the Department of Biochemistry at CU Boulder and one of the study's lead authors.

Ever since its discovery in 1998, the FACT protein has been of great interest for those who study DNA, largely because of the possibilities it presents. But, despite decades of effort, many of the central questions of how the protein works remain unanswered.

The FACT protein is an essential type of histone chaperone. These guardian proteins escort other proteins during the deconstruction and reconstruction of nucleosomes, or the structural unit responsible for organizing and packaging DNA. This happens during gene transcription (the step where DNA is copied into RNA), DNA replication (where the entire genome is replicated faithfully) and DNA damage repair (which is essential to prevent disease such as cancer).

However, with no clear structure for the protein available, scientists have been less than clear as to how exactly it does both: How does one protein both destroy and maintain?

This new research sheds light on both.

"For a long time, people have been trying to find the mechanism behind how [this protein] helps transcription," said Keda Zhou, a research associate in biochemistry at CU Boulder and the other lead author for the paper. "People have been working on different aspects of this protein, so we're really happy that we're the first to see it in action. It's really exciting."

The research team, aided by two other labs also led by women also managed to finally solve the puzzle by isolating the FACT protein and, through a combination of hard-work, ingenuity and tenacity, map it out and catch it in the act of both destroying and maintaining the nucleosome.

What they found is that FACT resembles the saddle and fork of a unicycle, made up of multiple domains that straddle the nucleosome 'wheel' of the unicycle. Up until that point, researchers were seeing only one domain at a time, causing confusion and contradictory results.

And yet, it appears that none of those differing findings are wrong.

Liu and Zhou's work "really put everything together. And it seems like everybody's right, which is just really cool," said Karolin Luger, the endowed chair of biochemistry at CU Boulder, a Howard Hughes Medical Institute Investigator and the study's senior author.

This discovery is only the beginning for this protein, both for Luger's lab and the broader medical community.

"There are lots of unknowns," said Zhou. "But this is a starting point."

Together with colleagues from Shanghai, Brussels, Canada and the USA, researchers from the University of Bonn have uncovered the binding mechanism of an important pain receptor. The results facilitate the development of new active substances. The opioids used today to treat severe pain can be addictive and sometimes have life-threatening side effects. The results are published in the renowned journal Science Advances.

Opioids are among the most effective painkillers available today. They include for instance morphine or oxycodone, which has been prescribed very carelessly in the USA. With serious consequences: Hundreds of thousands of patients have become addicted; many of them later ended up on drugs such as heroin or fentanyl.

Oxycodone binds to so-called opioid receptors in the body. There are three different types: MOP, DOP and KOP. The painkillers available to date mainly activate the MOP (also called μ-opioid receptor). However, stimulating MOP can not only be addictive, it can also have life-threatening side effects. The most serious is respiratory paralysis, which is why the most common cause of death after heroin use is respiratory arrest.

"Drugs that selectively bind to the DOP receptor probably do not have these dramatic side effects," hopes Prof. Dr. Christa Müller from the Pharmaceutical Institute at the University of Bonn. The emphasis is on "selective": The opioid receptors are so similar that many drugs activate all three forms. In order to find substances that only dock to the DOP receptor, it is therefore necessary to know exactly what happens during the binding process.

Spatial structure made visible down to the atomic level

The current study can now answer this question. "We have activated the DOP receptor with two different molecules, purified the complex and then elucidated its structure using X-rays," explains Tobias Claff, who carried out the majority of the experiments. For this purpose, the complex of receptor and active substance is transformed into a crystalline state. The crystal lattice deflects the X-ray light in a characteristic manner. The intensity distribution of the diffracted radiation can therefore be used to deduce the spatial structure of the complex, right down to the arrangement of each individual atom.

"This enabled us to show which parts of the receptor are responsible for binding the drugs," says Claff. "This knowledge should now enable the development of targeted new substances that only activate DOP." There is great interest in such drugs, not least because, unlike its MOP counterpart, the DOP receptor is not primarily effective against acute pain, but against chronic pain. This is currently very difficult to treat.

X-ray crystallography is not a new technique. However, the structure of G protein-coupled-receptors (including opioid receptors) could not be resolved until recently. These membrane proteins are located in the thin, fat-like membrane that surrounds the cell contents like a kind of bag. Their fat solubility means that they have to be stabilized at great effort during crystallization. Otherwise they denature and change their spatial structure as a result. "There are only a few laboratories in the world that are capable of dealing with these problems," emphasizes Christa Müller.

At the University of Bonn, aspiring pharmacists can go abroad during their master's or state examination program. The Institute has a broad network of cooperation partners - a fact that is regularly rated very positively in the CHE University Ranking. Tobias Claff used this opportunity: "I spent a year of my master's program at the iHuman institute of the ShanghaiTech University," he explains. "In the last few years, the crystallography of membrane proteins has been crucially advanced there." Claff learned the complex method in Shanghai - a know-how that now also benefits his home university, to which he has meanwhile returned.

Prof. Müller emphasizes that it is not often that a master's student tackles such a complex problem. "This success is an extraordinary achievement," she says. "It also demonstrates the excellent position of the Pharmacy School with its international exchange program."