Cocaine Addiction: Ingrained Behaviors

People who are addicted to cocaine are particularly prone to developing habits that render their behaviour resistant to change, regardless of the potentially devastating consequences, suggests new research from the University of Cambridge. The findings may have important implications for the treatment of cocaine addiction as they help explain why such individuals take drugs even when they are aware of the negative consequences, and why they find their behaviour so difficult to change.

"Addiction does not happen overnight but develops from behaviour that has been repeated over and over again until individuals lose control," said Dr Karen Ersche from the Department of Psychiatry, who led the research.

In a study reported today in the journal Science, Dr Ersche and colleagues tested 125 participants, of whom 72 were addicted to cocaine and 53 had no history of drug addiction, on their inclination to develop habits. They found that people with cocaine addiction were much more likely than healthy participants to make responses in an automatic fashion, but only if they had previously been rewarded for responding in the same way. The addicted individuals simply continued repeating the same responses they had previously learned, regardless of whether their actions made sense or not.

In a different context, however, where participants had to perform an action to avoid electrical shocks, people with cocaine addiction did not develop habits. In fact, they were much less inclined than the control participants to make an effort to avoid the electric shock in the first place.

"Our experiments highlight the particular difficulties faced when it comes to changing behaviour in people with cocaine addiction: they are highly responsive if their behaviour is rewarded -- for example a 'high' from drug use -- but then quickly switch to autopilot, becoming unable to change that behaviour in light of different consequences," said Dr Ersche. "By contrast, when cocaine users are facing adversity, they are less inclined than healthy people to do something about it.

"These findings have significant implications for the treatment of people with cocaine addiction. Clearly punitive approaches are ineffective, as the prospect of something bad happening to them won't make cocaine users more likely to change their behaviour. Interventions that build on their particular strength in developing habits, by training the implementation of more desirable habits to replace drug-taking habits, are likely to be more effective. Our findings also suggest that cocaine users would need to be actively protected from -- rather than simply warned about -- adverse consequences, because they will likely fail to avoid them if left to their own devices."

There is currently no medical treatment for cocaine addiction -- most individuals are treated with talking or cognitive therapy. According to Dr Ersche, the results show that a different approach to treating cocaine addiction might be of enhanced benefit to cocaine users. The researchers are now aiming to better understand the brain systems underlying cocaine users' proneness to habits and their lack of avoidance, and to use this knowledge to develop more effective treatments for cocaine addiction.

In the first experiment conducted by Ersche and her colleagues, participants were asked to learn the relationship between pictures, and a correct response was rewarded with points. After a long training period, participants were informed that some pictures were no longer worth any points. Participants with cocaine addiction were less likely to take on board the information about the change in reward, and were also more likely to continue responding in an automatic way, regardless of whether they were rewarded or not.

In a second experiment, the same participants were shown two different pictures on a screen, which they learned to associate with receiving an electric shock. Participants were then taught a strategy on how they could avoid the shocks by pressing a foot pedal. Those participants with cocaine addiction were less good at avoiding the electric shocks in the first place, possibly due to learning and/or motivational impairment, and subsequently did not develop avoidance habits.

The work was funded by the Medical Research Council and was conducted at the NIHR Cambridge Biomedical Research Centre and the Behavioural and Clinical Neuroscience Institute.

When 'Less Is More' in the Evolution of Life

"Loss is nothing else but change and change is nature's delight" says the quote by the philosopher and emperor Marcus Aurelius, which opens the scientific article that analyses the gene loss phenomenon and its impact on the evolution of living beings.

The study was published in the magazine Nature Review Genetics and signed by professors Ricard Albalat and Cristian Cañestro, from the Department of Genetics, Microbiology and Statistics and the Biodiversity Research Institute (IRBio) of the University of Barcelona. This article has just been selected as one of the recommended works with special significance in genetics and genomics by the Faculty of 1000 Prime, an international ranking that identifies and re-evaluates the best articles on biology and medicine with the support from a scientific community of more than 10,000 academics worldwide.

Thinking of gene loss as an evolution force is a counterintuitive idea, for it is easier to think that only when we gain something -genes in this case- can we evolve. However the new work by these authors, who are members of the Research Group on Evolution and Development (EVO-DEVO) of the UB, paints the vision of gene loss as a great potential process of genetic change and evolutionary adaption.

Losing genes is also an evolution engine

A gene is lost when the genome is physically removed (by illegitimate recombination, transposition, etc.) or when it is still in the genome but with no use due to a mutation (particular changes, insertions, deficiencies, etc.). "The genome sequencing of very different organisms has shown that gene loss has been a usual phenomenon during evolution in all life cycles. In some cases, it has been proven that this loss might mean an adaptive response towards stressful situations when facing sudden environmental changes" says Professor Cristian Cañestro.

"In other cases, there are genetic losses -says Cañestro- which even though they are neutral per se, have contributed to the genetic and reproductive isolation among lineages, and thus, to speciation, or have rather participated in the sexual differentiation in contributing to the creation of a new Y chromosome. The fact that genetic loss patterns are not stochastic but rather biased in the lost genes (depending on the kind of function of the gen or its situation in the genome in different organism groups) stresses the importance of the genetic loss in the evolution of the species.

Losing to win: an evolutionary paradox

Traditionally, it was believed that insects tended to lose genes. However, the genome sequencing of a beetle (Tribolium castaneum), which proves to have few gen losses, has made it worth reconsidering. In the chordates phylum, which includes vertebrates, there are also some differences among the species, with particular cases such as the planktonic organism Oikopleura dioica -very prone to gen loss.

According to Professor Ricard Albalat, "it has been shown that the possibility of losing genes is linked to the lifestyle of the species. Parasites, for instance, show a greater tendency of gene loss because since they re-use their host's resources, lots of their genes become dispensable and end up disappearing. Species with lots of redundant genes such as the vertebrates and lots of plant species and yeasts which have doubled their genome, have also suffered from gene loss over the course of evolution.

"Interestingly -says Albalat- the massive gene losses are not always linked to radical morphological changes in the affected organism's body plan. The chordate Oikopleura dioica, for example, despite losing lots of genes -some are essential to the embryo development and design of the phylum body plan- maintains a typical body plan with organs and structures (heart, brain, thyroids, etc.) which can be considered to be homologues to the vertebrates'. However, this contradiction, which we have defined as "inverse paradox" of EvoDevo, is still very difficult to explain."

Lost genes in the human evolutionary history

Gene loss can become a positive condition. This has been proved with laboratory experiments (in yeast or bacteria) and population studies on humans. Some of the best studied cases on humans are coding gene losses with cell receptors (CCR5 and DUFFY), which make individuals more resistant to HIV infection and to plasmodium caused by malaria. In nature, there are gene losses from which some organisms benefited: losses which made colour changes in flowers which attract new pollinators, losses which made warmness-resistant insects to be able to colonize new habitats, etc.

Some studies also suggest that gene loss has been decisive in the origins of the human species. Chimpanzees and humans share more than the 98% of their genome -something which has always been of great interest- and in this context it is tempting to speculate that perhaps it would be necessary to look for the differences not in the shared genes but in the lost ones- the ones which have been lost in a different way through the human and primate evolution. "For example, it is believed that gene loss reduced the jaw muscular structure, which allowed the human brain to grow its size, or that gene losses were important in the improvement of our defence system against illnesses," says Cristian Cañestro.

How many gens can a living being lose?

A gene can be lost only if it is dispensable and, therefore, its loss doesn't involve a disadvantage for the individuals. What makes a gene to be dispensable? A gene becomes dispensable when the organism can do its function in an alternative way (functional redundancy) or when the gene is no longer needed because the organism lost its structure or the physiologic requirement in which the gene participated (regressive evolution). For this reason, some changes in the species' lifestyle can turn some genes dispensable, as seen in the gene loss related to pigmentation and vision of the species who adopted cave-dweller ways of life.

Discovering how many genes an organism can lose and how, is something essential to understand how many human genes are dispensable and why certain mutations are irrelevant while others are dramatic for our health. Actually, the recent genome sequencing in individuals from several communities around the world has shown that any healthy person has an average amount of 20 genes not working and it does not seem to provoke any unfavourable consequence.

When genes are dispensable: less is more

According to Ricard Albalat, "probably, the presences of redundant genes or environmental conditions in which we live make us to have less unnecessary genes. Researching on the differences of gene losses among different human communities has allowed, for instance, discovering that lipoprotein A gene loss grants resistance to coronary illnesses among the Finnish population who have fat-rich diets. This experimental approach which relates genes to diseases, called "genotype first," opens the door to the discovery of genes which, when disappearing, give an advantage towards some environmental tensions (diets, climate, toxics, pathogens, etc.) and therefore it could help identifying new genes with therapeutic interests."

Oikopleura dioica: a new model organism in UB's research

Promoting basic research with model organisms (bacteria, mice, yeast, plants, zebrafish, Drosophila or C. elegans) has been a key fact to promote the progress in the field of biomedicine and health. For the scientists, one 21th Century challenge is to develop animal models alternative to the classic ones which can enable applying massive sequencing technologies or also genetic systematic modifications to open new perspectives in the field of basic research. Only by creating basic knowledge is it possible to improve with society's wellbeing.

Nowadays the Evo-Devo-Genomics team of the UB is one of the few research groups around the world which studies the Oikopleura dioica from an evolutionary developmental biology perspective (Evo-Devo). This is also the only team in Spain which has launched a scientific infrastructure -there are two more in Bergen (Norway) and Osaka (Japan)- considered as an international projecting referent with the ability of developing and studying this new model organism.

The Oikopleura dioica is a small animal, with a short life cycle, very prolific and easy to keep in the laboratory. These conditions make it an excellent model animal. Its genome, sequenced, is extraordinarily compact -three times smaller than the one of the Drosophila fly- and has lost a lot of genes. Currently, the UB experts use O. dioica as evolution mutant which has lots important genes for the embryo development. The research group works in two research lines. On the one hand, they use O. dioica to research on the toxic compound effect in marine animal development and reproduction, as well as its impact on the ocean trophic chains. On the other hand, they use O. dioica to study how genetic losses have affected the cardio development mechanisms.

"We hope these studies enable us to identify the essential 'minimum gene set' to produce a heart, and would help us understand better the genetic basics of certain cardiomyopathies and discover new genes to improve the diagnosis" say Ricard Albalat and Cristian Cañestro.

Early Adoption of Poison-Tipped Arrows in Africa

Researchers studying bone artefacts discovered in the Kuumbi Cave, Zanzibar, have found evidence to suggest that bone tools were used for hunting, and even as poison arrow tips. The findings, published in the journal Azania: Archaeological Research in Africa, suggest that bone technology was a central element to the Kuumbi Cave's inhabitants over 13,000 years ago.

Bone technology -- such as its use as an arrow tip -- was essential to a Stone Age man's lifestyle and has been shown to have been in use 60,000 years ago. The majority of the evidence to support this has been found in sites in southern Africa, but now the artefacts found in the Kuumbi Cave show that this technology was being adopted in eastern Africa as well.

The researchers investigated seven bone artefacts recovered from the Kuumbi Cave, five bone projectile points, a bone awl, and a notched bone tube. By analysing the artefacts with a camera and microscopes, they were able to compare the manufacture techniques and wear to previous discoveries and to attempts to replicate this technology in the laboratory.

Their findings showed that the bone projectile points are likely to have been used for poison arrows, partly due to the slender and short nature of the arrow heads, and partly supported by a previous discovery of charcoal from the Mkunazi plant, which is known to have poisonous fruit.

The use of poison-tipped arrows by a Stone Age man is thought to have stemmed from a lack of technology and stone-tipped arrows often lack the power to directly kill larger animals, such as zebra or buffalo. Previous work has estimated that poison-tipped arrows may have been used as far back as 24,000 BP (years before present), and the researchers conclude that this technology, better known from southern Africa, may also have been used 13,000 BP in eastern Africa.

Why You Should Eat Fruit While Pregnant

Most people have heard the old adage "an apple a day keeps the doctor away." It's an old truth that encompasses more than just apples--eating fruit in general is well known to reduce risk for a wide variety of health conditions such as heart disease and stroke. But now a new study is showing the benefits of fruit can begin as early as in the womb.

The study, published in the journal EbioMedicine, found that mothers who consumed more fruit during pregnancy gave birth to children who performed better on developmental testing at one year of age. Piush Mandhane, senior author of the paper and associate professor of pediatrics at the University of Alberta's Faculty of Medicine & Dentistry, made the discovery using data from the Canadian Healthy Infant Longitudinal Development (CHILD) Study--a nationwide birth cohort study involving over 3,500 Canadian infants and their families. Mandhane leads the Edmonton site of the study.

"We wanted to know if we could identify what factors affect cognitive development," Mandhane explains. "We found that one of the biggest predictors of cognitive development was how much fruit moms consumed during pregnancy. The more fruit moms had, the higher their child's cognitive development."

The study examined data from 688 Edmonton children, and controlled for factors that would normally affect a child's learning and development such as family income, paternal and maternal education, and the gestational age of the child.

Using a traditional IQ scale as a model, the average IQ is 100 and the standard deviation is 15; two thirds of the population will fall between 85 and 115. Mandhane's study showed that if pregnant mothers ate six or seven servings of fruit or fruit juice a day, on average their infants placed six or seven points higher on the scale at one year of age.

"It's quite a substantial difference--that's half of a standard deviation," Mandhane explains. "We know that the longer a child is in the womb, the further they develop--and having one more serving of fruit per day in a mother's diet provides her baby with the same benefit as being born a whole week later."

To further build on the research, Mandhane teamed with Francois Bolduc, an associate professor in the Faculty of Medicine & Dentistry's Division of Pediatric Neurology, who researches the genetic basis of cognition in humans and fruit flies. Both researchers believe that combining pre-clinical models and epidemiological analysis is a novel approach that may provide useful new insights into future medical research.

"Flies are very different from humans but, surprisingly, they have 85 per cent of the genes involved in human brain function, making them a great model to study the genetics of memory," says Bolduc. "To be able to improve memory in individuals without genetic mutation is exceptional, so we were extremely interested in understanding the correlation seen between increased prenatal fruit intake and higher cognition."

According to Bolduc, fruit flies have a long track record in the field of learning and memory. Several genes known to be necessary in fly memory have now been found to be involved in intellectual disability and autism by Bolduc and others. In a subsequent series of experiments, he showed that flies born after being fed increased prenatal fruit juice had significantly better memory ability, similar to the results shown by Mandhane with one-year-old infants. He believes it suggests that brain function affected by fruit and the mechanisms involved have been maintained through evolution, and conserved across species.

While the findings are encouraging, Mandhane cautions against going overboard on fruit consumption as potential complications such as gestational diabetes and high birthweight--conditions associated with increased intake of natural sugars--have not been fully researched. Instead, he suggests that expectant mothers meet the daily intake recommended in Canada's Food Guide and consult with their doctors.

Mandhane also says he will continue work in the field, with plans to examine if the benefits of prenatal fruit consumption persist in children over time. He will also be looking to determine if fruit can influence childhood development related to executive functioning--in areas such as planning, organizing and working memory.

How Does Brain Learn from Immediate Experience?

Scientists have confirmed one of the brain areas responsible for rapid updating of information during learning -- the sort of information we use to negotiate many changing situations in everyday life.

In a study funded by the Medical Research Council and published in journaleLife, a team from Oxford University and Imperial College looked at an area called the mediodorsal thalamus (MD), known to be involved in decision making and learning.

Senior author and Oxford researcher Dr Anna Mitchell explained: 'We already knew that the mediodorsal thalamus is involved in learning and decision making but did not fully understand the role it played. A key question in neurosciences is how the brain computes functions like planning a day's activities or making a decision to do one thing rather than another. We process information using widespread networks across the brain, so it is useful to focus on the contribution of particular areas to the overall task. In this case, we chose to look at how the mediodorsal thalamus supports optimal processing of new learning and decision making.'

The study used Rhesus macaque monkeys, who were taught cognitive tasks on touchscreen computers that released food rewards for learning new information and making good choices. These tests were then repeated after surgery that induced selective lesions to the MD.

Monkeys who could not use their MD were less able to respond to changes that required them to adapt their behaviour to continue making the right choices to maximise rewards. They also struggled with their decisions when they were presented with a choice of several differently rewarded options.

Dr Mitchell said: 'Previously, some had thought that in these cases the monkeys would just keep repeating the same choice as before. We found that they could make different choices but they had a reduced ability to integrate information from recent choices that they had made combined with the result of their most recent choice to optimally guide their decisions.

'This study has shown that the mediodorsal thalamus has a key role in rapidly integrating new information to learn something new or make a decision. This skill is vital in day-to-day activities like driving or even just walking down a busy street.'

Future studies will look at how the MD interacts with other areas of the brain, helping us to understand the processes that underlie our own abilities to learn, re-learn and adapt our choices as we get new information.

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Untangling Ambiguity in Neural Circuits

Every day humans and animals face ambiguous circumstances. If we become sick after eating, we blame the food; however, if we then fall ill without having eaten that food, the causal link becomes ambiguous. New findings from the RIKEN Brain Science Institute in Japan and New York University reveal where and how such ambiguous associations are processed in the brains of rats.

Learning how to predict dangerous relationships in the environment -- such as between odors and food, lightning and thunder, or sounds and predators -- is essential for survival. While we know much about how experiences become linked with unpleasant outcomes when the associations are clear, how these links are updated in the brain when the relationships are ambiguous was unknown. In a new study published in Nature Neuroscienceon May 23, 2016 scientists report that ambiguity in these types of associations can be observed in rats that had previously learned a tone-shock association and were then given shocks without the tone. In the brain, they found traces of both the memory and its associated uncertainty stored in neural circuits of a central brain area called the amygdala.

When given shocks after hearing a tone, rats who have learned the association normally freeze, anticipating the shock. However, when the same animals learned that shocks could also arrive without a tone, they showed less anticipatory freezing because the causal link between tone and shock was not clear. In the brain, this uncertainty was reflected in reduced strength of neural connections between the auditory system (where tones are processed) and the amygdala, a brain region critical for storing unpleasant memories. Strong connections that formed after learning the tone-shock association were reversible if the relationship later became ambiguous.

By blocking the formation of tone-shock association memories with optogenetics -- a technique to control brain cell activity with bursts of light -- the researchers showed that specific neurons in the amygdala were responsible for enabling the uncertainty. When those neurons were silenced as animals experienced shocks without a preceding tone, surprisingly, rather than acting unsure and freezing less often, the animals always acted as if they expected to be shocked when they heard the tone. This indicated that the amygdala not only stores unpleasant memories, but also plays an active role in an animal's evaluation of the associated level of ambiguity.

The authors also mathematically analyzed how rats responded when different patterns of lights, tones, and shocks unfolded in their environment under ambiguous conditions. A longstanding theory suggested that different sensory cues in the environment compete for association with outcomes such as food or threats resulting in one association winning out. Contradicting this theory, the authors found that the way rats evaluate ambiguity can be best described with a dynamic model that considers several different configurations of how tones, lights or other features of the environment might interact during learning.

Tamas Madarasz, the lead author of the study now based at the University of Geneva, explained: "To make successful predictions the brain needs to consider different models of what these configurations could be, and perform computations in parallel using each of the possible models of the environment and the associated uncertainty. This leads to a distributed neural representation for each association. This approach has helped inspire better learning algorithms for computers, and it looks like animals are using this strategy too." The authors suggest that humans may also evaluate their environment and its events using a statistical approach that computes the probabilities of associations to estimate ambiguity.

"We believe we've discovered a new framework for the amygdala and how its neurons process ambiguous associations," said senior author Joshua Johansen of BSI. "Our results are important for understanding how memories and associations are formed and modified." The findings may also have implications for understanding diseases involving ambiguous associations such as anxiety, and in the design of more flexible computer architectures.

Medical Errors 3rd Leading Cause of Death in US ascensionschools.blogspot.com

Adult songbirds modify their vocalizations when singing to juveniles in the same way that humans alter their speech when talking to babies. The resulting brain activity in young birds could shed light on speech learning and certain developmental disorders in humans, according to a study by McGill University researchers.

Lead author Jon Sakata, a professor of neurobiology at McGill, says that songbirds learn vocalizations like humans learn speech. "Songbirds first listen to and memorize the sound of adult songs and then undergo a period of vocal practice-in essence, babbling-to master the production of song."

Researchers have been studying song learning in birds for some time. But the degree to which social interaction with adult birds contributes to that learning has been unclear. That's because, unlike this current work, past studies didn't control for the time exposed to song and the presence of other birds.

Vocal learning

In this study, published in the journal Proceedings of the National Academy of Sciences, a group of juvenile zebra finches was allowed to interact with an adult. Another group simply heard adult songs played through a speaker. After a brief period of "tutoring" the juveniles were house individually for months as they practiced their tunes.

Sakata and his team found that avian pupils who socialized with an adult learned the adult's song much better. That was true even if the social tutoring lasted just one day. In analyzing why this would be so, Sakata and his team made a surprising discovery.

Adult zebra finches change their vocalizations when singing to juveniles. Sakata says just as people speak more slowly and repeat words more often when speaking to infants, so do these birds. "We found that adult zebra finches similarly slow down their song by increasing the interval between song phrases and repeat individual song elements more often when singing to juveniles."

What's more, the researchers found that juvenile birds pay more attention to this "baby talk" compared to other songs. And the more the juveniles paid attention, the better they learned.

Activating neurons

The researchers took their work a step further by examining the activity of certain neurons in parts of the brain associated with attention. They found that more neurons that produce the chemicals dopamine and norepinephrine were turned on after socially interacting with a singing adult than after simply hearing song through a speaker.

Dr. Sakata says this finding could have implications beyond the avian world. "Our data suggest that dysfunctions in these neurons could contribute to social and communicative disorders in humans. For example, children who suffer from autism spectrum disorders have difficulty processing social information and learning language, and these neurons might be potential targets for treating such disorders."

Dr. Sakata is now testing whether raising dopamine and norepinephrine levels in the brain can help birds learn song when they only hear adult songs. As he puts it, "We are testing whether we can "trick" a bird's brain into thinking that the bird is being socially tutored."

Medical Errors 3rd Leading Cause of Death in US

Analyzing medical death rate data over an eight-year period, Johns Hopkins patient safety experts have calculated that more than 250,000 deaths per year are due to medical error in the U.S. Their figure, published May 3 in The BMJ, surpasses the U.S. Centers for Disease Control and Prevention's (CDC's) third leading cause of death -- respiratory disease, which kills close to 150,000 people per year.

The Johns Hopkins team says the CDC's way of collecting national health statistics fails to classify medical errors separately on the death certificate. The researchers are advocating for updated criteria for classifying deaths on death certificates.

"Incidence rates for deaths directly attributable to medical care gone awry haven't been recognized in any standardized method for collecting national statistics," says Martin Makary, M.D., M.P.H., professor of surgery at the Johns Hopkins University School of Medicine and an authority on health reform. "The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used."

In 1949, Makary says, the U.S. adopted an international form that used International Classification of Diseases (ICD) billing codes to tally causes of death.

"At that time, it was under-recognized that diagnostic errors, medical mistakes and the absence of safety nets could result in someone's death, and because of that, medical errors were unintentionally excluded from national health statistics," says Makary.

The researchers say that since that time, national mortality statistics have been tabulated using billing codes, which don't have a built-in way to recognize incidence rates of mortality due to medical care gone wrong.

In their study, the researchers examined four separate studies that analyzed medical death rate data from 2000 to 2008, including one by the U.S. Department of Health and Human Services' Office of the Inspector General and the Agency for Healthcare Research and Quality. Then, using hospital admission rates from 2013, they extrapolated that based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from a medical error, which the researchers say now translates to 9.5 percent of all deaths each year in the U.S.

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer and 149,205 died of chronic respiratory disease -- the top three causes of death in the U.S. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.

"Top-ranked causes of death as reported by the CDC inform our country's research funding and public health priorities," says Makary. "Right now, cancer and heart disease get a ton of attention, but since medical errors don't appear on the list, the problem doesn't get the funding and attention it deserves."

The researchers caution that most of medical errors aren't due to inherently bad doctors, and that reporting these errors shouldn't be addressed by punishment or legal action. Rather, they say, most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

"Unwarranted variation is endemic in health care. Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in health care. More research on preventing medical errors from occurring is needed to address the problem," says Makary.

Michael Daniel of Johns Hopkins is a co-author on the study.

Even a Little Air Pollution Harms Baby in Utero

Even small amounts of air pollution appear to raise the risk of a condition in pregnant women linked to premature births and lifelong neurological and respiratory disorders in their children, new Johns Hopkins Bloomberg School of Public Health research suggests.

Fine particles from car exhaust, power plants and other industrial sources are breathed into the lungs, but the scientists have now found evidence of the effects of that pollution in the pregnant women's placentas, the organ that connects her to her fetus and provides blood, oxygen and nutrition. They found that the greater the maternal exposure to air pollution, the more likely the pregnant women suffered from a condition called intrauterine inflammation, which can increase the risk of a number of health problems for her child from the fetal stage well into childhood.

The researchers, reporting online April 27 in Environmental Health Perspectives, say the findings add to the growing evidence that the air a pregnant woman breathes could have long-term health consequences for her child and that current U.S. Environmental Protection Agency air pollution standards may not be stringent enough to protect her developing fetus.

"Twenty years ago, we showed that high levels of air pollution led to poor pregnancy outcomes, including premature births. Now we are showing that even small amounts of air pollution appear to have biological effects at the cellular level in pregnant women," says the study's senior author, Xiaobin Wang, MD, ScD, MPH, the Zanvyl Krieger Professor and Director of the Center on the Early Life Origins of Disease at Bloomberg School.

Says the study's lead author Rebecca Massa Nachman, PhD, a postdoctoral fellow in Department of Environmental Health Sciences at the Bloomberg School: "This study raises the concern that even current standards for air pollution may not be strict enough to protect the fetus, which may be particularly sensitive to environmental factors. We found biological effects in women exposed to air pollution levels below the EPA standard."

For the study, researchers analyzed data from 5,059 mother-child pairs in the Boston Birth Cohort, a predominantly low-income minority population. They assessed the presence of intrauterine inflammation based on whether the mother had a fever during labor and by looking under a microscope at the placenta, which was collected and preserved after birth. They assessed maternal exposure to fine particulate matter (PM2.5) air pollution using data from EPA air quality stations located near the mothers' homes. Boston, where the women lived, is known as a relatively clean city when it comes to air pollution. The majority of the women in the study were exposed to air pollution below the level that EPA deems acceptable, fewer than 12 micrograms per cubic meter. A subset of 1,588 women (or 31 percent) were exposed to air pollution at or above the EPA standard.

The researchers found that pregnant women who were exposed to the highest levels of air pollution were nearly twice as likely as those exposed to the lowest levels to have intrauterine inflammation and it appeared that the first trimester might be a time of highest risk. These results held up even when researchers accounted for factors including smoking, age, obesity and education levels.

Intrauterine inflammation is one of the leading causes of premature birth, which occurs in one of every nine births in the United States and one in six African-American births, the researchers say. Babies born prematurely can have lifelong developmental problems. Researchers have linked preterm birth to both autism and asthma.

While maternal exposure to air pollution during pregnancy is associated with adverse birth outcomes, the biological mechanism has not been well understood. There are few outward signs of intrauterine inflammation in most women. But the researchers say that the placenta -- which is typically discarded after birth -- offered vital clues to the condition and could be the source of other important health information.

"The placenta may be a window into what is going on in terms of early life exposure and what it means for future health problems," Wang says. "This organ is discarded, but testing it is non-invasive and could be a valuable source of all kinds of environmental information."

Bird Genomes Contain 'Fossils' of Human Parasites

In rare instances, DNA is known to have jumped from one species to another. If a parasite's DNA jumps to its host's genome, it could leave evidence of that parasitic interaction that could be found millions of years later -- a DNA 'fossil' of sorts. An international research team led from Uppsala University has discovered a new type of so-called transposable element that occurred in the genomes of certain birds and nematodes.

The results are published in Nature Communications.

Dr. Alexander Suh at Uppsala University is an expert on the small stretches of DNA that tend to jump from one place to another, called transposable elements. Working with a team from eleven institutions in five countries, the researchers discovered a new type of transposable element that occurred in certain bird genomes but not others.

By searching DNA databases, the team discovered that the only other animals that shared the new transposable element were nematode worms that are parasites of humans and other mammals.

'This finding was so unexpected that we were literally speechless at first,' says Alexander Suh.

By comparing the DNA sequences of each instance of the transposable element, Suh and his team were able to figure out that the transfer of DNA between nematodes and birds occurred in two waves across the entire tropics, including remote places like Madagascar. They involved charismatic groups of birds such as parrots, hummingbirds, manakins.

Certain human diseases, such as avian flu and HIV/AIDS, are known to have jumped onto our species from animal hosts. Epidemiologists have only recently realized the importance of these so-called 'zoonoses'. However, there are many more human diseases whose host-origins are unknown. These include lymphatic filariasis and loiasis, two serious human tropical diseases that are caused by nematode worms and spread by mosquitoes. The present study reveals that these modern human parasite species were parasites of birds from at least 25-17 million years ago. They probably did not infect mammals at the time that the transposable element was actively jumping between species, because there is no trace of it in mammal genomes. The genomes show that the bird parasites were widespread because they infected different bird groups that occurred in each of the world's major tropical regions and would have been isolated from each other at the time.

Genome sequences continue to reveal evolutionary history in surprising ways. Not only can comparisons of genomes assess relatedness, but interactions between specific host and parasite species can also be permanently recorded in the genome via jumping of transposable element DNA from one to the other. In this first example of that phenomenon in birds and nematodes, we learned that a class of parasites that is a present-day scourge once switched hosts from birds to mammals -- a process that is all too familiar to modern epidemiologists.

New HIV Vaccine Target Discovered

A team led by scientists at the National Institutes of Health (NIH) has reported a research trifecta. They discovered a new vulnerable site on HIV for a vaccine to target, a broadly neutralizing antibody that binds to that target site, and how the antibody stops the virus from infecting a cell. The study was led by scientists at the Vaccine Research Center (VRC) of the National Institute of Allergy and Infectious Diseases, part of NIH.

The new target is a part of HIV called the fusion peptide, a string of eight amino acids that helps the virus fuse with a cell to infect it. The fusion peptide has a much simpler structure than other sites on the virus that HIV vaccine scientists have studied.

The scientists first examined the blood of an HIV-infected person to explore its ability to stop the virus from infecting cells. The blood was good at neutralizing HIV but did not target any of the vulnerable spots on the virus where broadly neutralizing HIV antibodies (bnAbs) were known to bind.

The researchers isolated a powerful bnAb in the blood that they named VRC34.01, and found that it binds to the fusion peptide and a sugar molecule. The scientists then crystallized the antibody while it was bound to the virus. This allowed them to characterize in atomic-level detail how VRC34.01 attaches to HIV and revealed that the antibody stops the virus from infecting a cell by binding to a key cell-surface molecule.

The scientists also report that it is not unusual for the immune system to try to stop HIV from infecting a cell by attacking the fusion peptide. When they screened the blood of 24 HIV-infected volunteers, they found that blood samples from 10 people targeted a similar binding site as VRC34.01.

The researchers are now working to create a vaccine designed to elicit antibodies similar to the VRC34.01 antibody.

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New IVF Technique Appears Safe: Study

A new IVF-based technique is likely to lead to normal pregnancies and reduce the risk that babies born will have mitochondrial disease, according to researchers at the Wellcome Trust Centre for Mitochondrial Disease at Newcastle University.

Published in the journal Nature, scientists report the first in-depth analysis of human embryos created using a new technique designed to reduce the risk of mothers passing on mitochondrial disease to their children, which is debilitating and often life-limiting.

The new technique, called "early pronuclear transfer," involves transplanting the nuclear DNA from a fertilised egg into a donated egg, which contains healthy mitochondria, on the day of fertilisation.

Today researchers, in a study involving over 500 eggs from 64 donor women, publish results that indicate that the new procedure does not adversely affect human development and will greatly reduce the level of faulty mitochondria in the embryo. Their results suggest that the technique will lead to normal pregnancies whilst also reducing the risk of babies having mitochondrial disease.

The results of this study will be considered by the Human Fertilisation and Embryology Authority's (HFEA) Expert Scientific Panel. The HFEA will ultimately decide whether to issue the first licence to a clinic. A licensed clinic would allow couples affected by mitochondrial disease to have the choice of whether to use pronuclear transfer to try and have healthy children.

Professor Mary Herbert, senior author of the study, said: "Having overcome significant technical and biological challenges, we are optimistic that the technique we have developed will offer affected women the possibility of reducing the risk of transmitting mitochondrial DNA disease to their children."

Extensive studies conducted in collaboration with researchers from University of Oxford and the Francis Crick Institute indicated that embryos created using the new technique are indistinguishable from those created by conventional IVF. Analysis of thousands of genes in single cells detected no difference between the two types of embryos. There was also no increase in chromosomal abnormalities, which can cause miscarriage and birth defects. These findings provide reassurance that the new procedure does not have a harmful effect on early embryonic development.

The research findings also indicate that the new technique will result in a minimal amount (less than 2%) carryover of disease-causing mitochondrial DNA to the embryos. The importance of keeping carryover to a minimum is highlighted by studies on embryonic stem cell lines. The team found that one of five stem cell lines derived from embryos created using the new technique, showed an increase in the percentage of mitochondrial DNA carryover. While stem cells are very different from embryos, the observation raises the possibility that faulty mitochondrial DNA may persist in some cases. However, the research team is optimistic that the new technique will be effective in reducing the risk of disease in children of affected women.

A further important finding of the study is that the technique will work best if patient (rather than donor) eggs are frozen. It will therefore be possible for affected women to have their eggs frozen for future use. This is likely to increase the success of the treatment by helping to avoid the decline in egg quality as women get older.

Professor Doug Turnbull, Director of the Centre for Mitochondrial Research, and co-author of the paper said: "This study using normal human eggs is a major advance in our work towards preventing transmission of mitochondrial DNA disease. The key message is that we have found no evidence the technique is unsafe. Embryos created by this technique have all the characteristics to lead to a pregnancy."

He added: "Our studies on stem cells does express a cautionary note that it might not be 100% efficient in preventing transmission, but for many women who carry these mutations the risk is far less than conceiving naturally."

In the event of a positive outcome from the Expert Panel, the team at Newcastle Fertility Centre, which is part of the Newcastle Hospitals NHS Foundation Trust, will submit an application for an HFEA license to offer pronuclear transfer to women at high risk of transmitting mitochondrial DNA disease to their children. The team is also working to secure the necessary funding to be able to offer clinical treatments on the NHS.

Professor Herbert said: "Our ongoing research is focussed on refining the techniques to further reduce the risk of transmitting disease."

She added: "I would also like to thank the women who donated eggs for this research. It would not have been possible to do this work without their help."

Dr Beth Thompson, Senior Policy Advisor at the Wellcome Trust said: "This study adds to the extensive body of evidence built up over the past ten years suggesting that mitochondrial replacement therapy is not unsafe. The results bring the UK closer to being able to offer mitochondrial replacement technique to couples affected by mitochondrial disease. The UK's strong regulatory system will now kick in to decide whether there is enough evidence that this technique is safe enough to be a good choice for families.

"Ultimately, couples affected by mitochondrial disease will be the best placed to decide whether the new technique is right for them, with advice from their doctors."

Custom-Engineered Living Tissue to Fix a Heart

Jianyi "Jay" Zhang, M.D., Ph.D., brought his biomedical engineering expertise to the University of Alabama at Birmingham to fix hearts.

His dream -- and the dream of other heart experts at major research universities around the world -- is creating new tissue that can replace or protect damaged muscle after a heart attack.

Zhang already took a major step toward that goal when he and colleagues protected pigs from post-heart attack heart failure. As described in his 2014Cell Stem Cell paper, the researchers placed a mat of fibrin over the area where muscle had died and injected three types of cardiovascular cells underneath the mat. This is somewhat akin to starting new lawn by scattering grass seeds beneath a protective layer of hay. The fibrin helped some of the injected cells survive and grow, and they in turn protected the heart from further damage.

While Zhang's colleague at the University of Paris Descartes, Philippe Menasché, M.D., Ph.D., is currently testing this approach on five patients, Zhang is launching a new effort in biomedical engineering to improve heart repair, supported by a new $3 million grant from the National Heart, Lung and Blood Institute of the NIH.

Instead of injecting individual cells and hoping they take seed, Zhang plans to robotically build and grow a mat of heart tissue made from individual cells, using a custom 3-D printer. Surgeons will then place this custom mat of living cells over the dead, infarcted tissue of the heart, somewhat akin to starting a new lawn by laying sod.

"We will make our own printer, using machinery experts, robotic experts and computer science experts," said Zhang, who last fall became the new leader of UAB Biomedical Engineering, a joint department of the UAB School of Medicine and School of Engineering. "A robotic arm will pick up cells of various types from petri dishes and place them onto fine needles that are a few microns apart. The growing cells fuse after three to seven days, and the shape is based on the needles."

"Then we can lift off the tissue," Zhang said. "It is scaffold-less tissue engineering. I already have two Ph.D. students on the project."

The piece of engineered tissue will be "printed-to-order" to match the size and shape of the dead tissue in the heart, as measured by MRI. The prevascularized heart tissue could be quite large, up to 2 by 4 centimeters in area and 5 millimeters thick (about 0.8 by 1.6 by 0.2 inches). All the work must be done under sterile conditions in a culture medium that provides the oxygen and nutrients to keep the cells alive.

This UAB myocardial tissue patch, done in collaboration with Menasché, Duke University and the University of Wisconsin, will need to be tested in a pig model before it can move to human trials. "We want to take it to clinical practice in seven years," Zhang said. "That's why I came to UAB."

UAB's clinical and research expertise in heart electrophysiology will be vital, Zhang says, because the patch could cause heart arrhythmias, or uneven beating, if it interferes with the careful timing of the electrophysiological wave that directs each smooth contraction of the pumping heart. Engineers and clinicians would need to learn how to build the 3-D tissue to avoid any complications.

As Zhang expands UAB capacity in tissue engineering, he is also bringing experts to the UAB campus for the annual, NIH-sponsored Cardiovascular Tissue Engineering Workshop that he leads.

In 2015, before Zhang came to UAB, the Zhang-led group of physicians and scientists met at Stanford University, and a perspective piece on the five central challenges to realizing heart repair, "Distilling complexity to advance cardiac tissue engineering," was published June 8 in the journal Science Translational Medicine. Besides Zhang, authors include researchers from the University of Minnesota, Duke University, Harvard Medical School, Stanford University, the University of Paris Descartes, the University of Washington, the University of Toronto, Georg-August University Göttingen and Columbia University.

The workshop met at UAB last March for the 2016 meeting, and will again meet at UAB in 2017.

Details of the research

After a heart attack, the heart muscle cells around the edge of the infarcted scar of the left ventricle, the most powerful pump chamber of the heart, get overstretched. Weeks, months or years later this can cause an enlargement of the heart called post-infarction left ventricle remodeling. This leads to heart failure.

Groundwork for producing the engineered tissue meant to prevent remodeling relies on research progress with stem cells, cells that have the ability to differentiate into different types of cells. The 2014 Cell Stem Cell paper, for example, used a combination of three types of cardiovascular cells derived from human induced pluripotent stem cells -- cardiomyocytes, endothelial cells and smooth muscle cells. The fibrin patch was also engineered to release insulin-like growth factor.

The cardiomyocytes were able to integrate into the heart and generate organized muscle structure, while the endothelial and smooth muscle cells contributed to heart blood vessels. Pigs getting this trilineage cell transplant had significant improvements in left ventricular function, myocardial metabolism and density of arterioles that branch out from a heart artery. The transplant also reduced infarct size, ventricular wall stress and apoptosis, or programmed cell death. Furthermore, the treatment did not produce arrhythmias.

For the clinical test with human patients in Paris, Menasché is using trilineage cells derived from human embryonic stem cells.

Innovative Delivery Method Helps Shrinks Tumor

In a pair of firsts, researchers at Case Western Reserve University and Massachusetts Institute of Technology have shown that the drug candidate phenanthriplatin can be more effective than an approved drug in vivo, and that a plant-virus-based carrier successfully delivers a drug in vivo.

Triple-negative breast cancer tumors of mice treated with the phenanthriplatin -carrying nanoparticles were four times smaller than those treated either with cisplatin, a common and related chemotherapy drug, or free phenanthriplatin injected intravenously into circulation.

The scientists believe the work, reported in the journal ACS Nano, is a promising step toward clinical trials.

"We may have found the perfect carrier for this particular drug candidate," said Nicole Steinmetz, an assistant professor of biomedical engineering at Case Western Reserve, who has spent 10 years studying the use of plant viruses for medical purposes.

She teamed with Stephen J. Lippard, Arthur Amos Noyes Professor of chemistry at MIT, and an expert in biological interactions involving platinum-based chemotherapies.

Platinum-based drugs are used to treat more than half of cancer patients receiving chemotherapy. Two of the most commonly used drugs are cisplatin and carboplatin. They form bifunctional cross-links with DNA in cancer cells, which block the DNA from transcribing genes and result in cell death, Lippard explained.

Despite widespread use, cisplatin has been shown to cure only testicular cancer, and many cancers have or develop immunity to the drug.

Lippard's lab altered cisplatin by replacing a chloride ion with phenanthridine and found that the new molecule also binds to DNA. Instead of forming cross-links, however, phenanthriplatin binds to a single site but still blocks transcription.

In fact, his lab found that phenanthriplatin is up to 40 times more potent than traditional platins when tested directly against cancer cells of lung, breast, bone and other tissues. The molecule also appears to avoid defense mechanisms that convey resistance.

But when injected into mouse models of cancer, the drug candidate performed no better than standard platins.

Lippard realized phenanthriplatin wasn't reaching its target. He had a drug delivery problem.

He found a potential solution while visiting Case Western Reserve's campus and heard Steinmetz explain her work investigating tobacco mosaic virus (TMV) for drug delivery more than a year ago.

"I envisioned that TMV would be the perfect vehicle," Lippard said. "So we had a beer and formed a collaboration."

The long, thin tobacco mosaic virus nanoparticles are naturals for delivering the drug candidate into tumors, said Steinmetz, who was appointed by the Case Western Reserve School of Medicine.

The virus particles, which won't infect humans, are hollow. A central tube about 4 nanometers in diameter runs the length of the shell and the lining carries a negative charge.

Phenanthriplatin is about 1 nanometer across and, when treated with silver nitrate, has a strong positive charge. It readily enters and binds to the central lining.

The elongated shape of the nanoparticle causes it to tumble along the margins of blood vessels, remain unnoticed by immune cells and pass through the leaky vasculature of tumors and accumulate inside. Little healthy tissue is exposed to the toxic drug.

Inside tumors, the nanoparticles gather inside the lysosomal compartments of cancer cells, where they are, in essence, digested. The pH is much lower than in the circulating blood, Steinmetz explained. The shell deteriorates and releases phenanthriplatin.

The shell is broken down into proteins and cleared through metabolic or natural cellular processes within a day while the drug candidate starts blocking transcription, leading to greater amounts of cell death through apoptosis than cross-linking platins.

The researchers say delivery of the phenanthriplatin into the tumor led to its improved performance over cisplatin or free phenanthriplatin.

Lippard and Steinmetz continue to collaborate, investigating use of this system to deliver other drugs or drug candidates, use in other types of cancers, the addition of agents on the exterior of the shell to increase accumulation inside tumors and more.